SNPMiner Trials by Shray Alag


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Report for Mutation M184V

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There are 60 clinical trials

Clinical Trials


1 A Phase II, Randomized Study of the Antiviral Activity and Resistance Interactions of Lamivudine (3TC) in Combination With Zidovudine (AZT), Stavudine (d4T), or Didanosine (ddI) Versus Monotherapy With ddI or d4T in HIV-Infected Individuals With 200 - 600 CD4+ Cells/mm3 and No Previous Nucleoside Experience

To evaluate the efficacy, safety, and pharmacokinetics of lamivudine (3TC) combined with zidovudine (AZT), stavudine (d4T), or didanosine (ddI) in comparison with d4T or ddI monotherapy in HIV-infected patients with no prior nucleoside therapy. 3TC may be uniquely effective in combination with AZT due to the interaction of AZT and 3TC resistance mutations. One explanation is that the M184V mutation, which confers resistance to 3TC, suppresses AZT resistance. This benefit of 3TC may not extend to combination therapy with other nucleoside analogs.

NCT00000838 HIV Infections Drug: Lamivudine Drug: Stavudine Drug: Zidovudine Drug: Didanosine
MeSH: HIV Infections

One explanation is that the M184V mutation, which confers resistance to 3TC, suppresses AZT resistance. --- M184V ---


2 A Phase 2 Trial of 4 Weeks of ACH-126,443 in Comparison With Continued Lamivudine in Stable Triple Antiretroviral Combination Therapy in HIV-Infected Subjects With Modestly Detectable Viral Load

To determine safety and efficacy of ACH-126,443 on the treatment of adults with HIV infection who have modestly detectable viral load while on stable triple combination antiretroviral therapy including 3TC.

NCT00040157 HIV Infections Drug: ACH126-443 (Beta-L-Fd4C)
MeSH: Infection HIV Infections Acquired Immunodeficiency Syndrome

Inclusion Criteria: - Adults ≥18 years of age - Receiving a stable triple combination antiretroviral regimen including 3TC, one other NRTI and either an NNRTI or a protease inhibitor for at least 4 months (16 weeks) - Demonstration of initial viral suppression and subsequent rebound to be defined as an initial virological drop of at least 0.5 Logs on a 3TC-containing regimen - Plasma HIV RNA level > 1000 and < 30,000 copies/mL on two occasions - Genotypically documented M184V variant of HIV RT - Clinically stable HIV status with no AIDS-defining events - CD4 > 200 cells/mm3 - Basic hematologic and chemistry parameters within acceptable limits (defined in protocol) - All women of child bearing potential must have a negative serum or urine pregnancy test (minimum sensitivity of 25 IU/L of b-HCG) within 72 hours prior to the start of study medication - No active opportunistic infection requiring treatment - Subject must be able to provide written informed consent - Baseline laboratory values measured within 28 days of initiating study drug as follows: - HGB≥9.0g/dl or HCT≥27% (in the absence of blood transfusions or erythropoietin treatment in the preceding two weeks - Absolute neutrophil count≥1000 cells/mm(^3) (in the absence of on-going G-CSF therapy - Platelet count ≥75,000/mm(^3) - AST <7.0 times the upper limit of normal - ALT ,7.0 times the upper limit of normal - Serum creatinine <1.1 times the upper limit of normal Exclusion Criteria - Evidence of active HBV infection as demonstrated by HBsAg positivity - Hepatitis C co-infection - Concurrent systemic antiviral treatment - Previous therapy with agents with significant systemic myelosuppressive or cytotoxic potential within 3 months of study start or the expected need for such therapy at study start. --- M184V ---

- Use of any other drug or substance with anti-HBV activity Inclusion Criteria: - Adults ≥18 years of age - Receiving a stable triple combination antiretroviral regimen including 3TC, one other NRTI and either an NNRTI or a protease inhibitor for at least 4 months (16 weeks) - Demonstration of initial viral suppression and subsequent rebound to be defined as an initial virological drop of at least 0.5 Logs on a 3TC-containing regimen - Plasma HIV RNA level > 1000 and < 30,000 copies/mL on two occasions - Genotypically documented M184V variant of HIV RT - Clinically stable HIV status with no AIDS-defining events - CD4 > 200 cells/mm3 - Basic hematologic and chemistry parameters within acceptable limits (defined in protocol) - All women of child bearing potential must have a negative serum or urine pregnancy test (minimum sensitivity of 25 IU/L of b-HCG) within 72 hours prior to the start of study medication - No active opportunistic infection requiring treatment - Subject must be able to provide written informed consent - Baseline laboratory values measured within 28 days of initiating study drug as follows: - HGB≥9.0g/dl or HCT≥27% (in the absence of blood transfusions or erythropoietin treatment in the preceding two weeks - Absolute neutrophil count≥1000 cells/mm(^3) (in the absence of on-going G-CSF therapy - Platelet count ≥75,000/mm(^3) - AST <7.0 times the upper limit of normal - ALT ,7.0 times the upper limit of normal - Serum creatinine <1.1 times the upper limit of normal Exclusion Criteria - Evidence of active HBV infection as demonstrated by HBsAg positivity - Hepatitis C co-infection - Concurrent systemic antiviral treatment - Previous therapy with agents with significant systemic myelosuppressive or cytotoxic potential within 3 months of study start or the expected need for such therapy at study start. --- M184V ---


3 A Multicenter, Randomized, Double-Blind, Comparative Trial Of A Novel CCR5 Antagonist, UK-427,857, In Combination With Zidovudine/Lamivudine Versus Efavirenz In Combination With Zidovudine/Lamivudine For The Treatment Of Antiretroviral-Naive HIV-1 Infected Subjects

Maraviroc (UK-427,857), a selective and reversible CCR5 coreceptor antagonist, has been shown to be active in vitro against a wide range of clinical isolates (including those resistant to existing classes). In HIV-1 infected patients, maraviroc (UK-427,857) given as monotherapy for 10 days reduced HIV-1 viral load by up to 1.6 log, consistent with currently available agents. Safety and toleration have been studied in over 400 subjects for up to 28 days at 300 mg twice daily. No significant effects were seen on the QTc interval. The goal of this study is to compare the safety and efficacy of maraviroc (UK-427,857) versus efavirenz, when each are combined with two other antiretroviral agents, in patients who are previously naive to antiretroviral therapy. This study will involve approximately 200 centers from around the world to achieve a total randomized subject population of 1071 subjects. Patients will be randomly assigned to one of three groups: maraviroc (UK-427,857) 300 mg once daily added to zidovudine/lamivudine (300 mg/150 mg twice daily), Maraviroc (UK-427,857) 300 mg twice daily added to zidovudine/lamivudine (300 mg/150 mg twice daily) or efavirenz (600 mg once daily) added to zidovudine/lamivudine (300 mg/150 mg twice daily). The study will enroll over approximately an 18 month period (5 months Phase 2b run-in, 13 months Phase 3) with 96 weeks of treatment. This may be extended for an additional 3 years depending on the results at 96 weeks. Physical examinations will be performed at study entry, weeks 4, 8, 12, 16, 20, 24, 32, 40, 48, 60, 72, 84 and 96. Blood samples will also be taken at study entry, weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, 60, 72, 84 and 96. Additionally, blood samples will be drawn twice, at least 30 minutes apart, at weeks 2 and 48 for maraviroc (UK-427,857) pharmacokinetic analysis. As part of this clinical study a blood sample will be taken for non-anonymized pharmacogenetic analysis. Patients will undergo a 12-lead electrocardiogram at study entry, weeks 24, 48 and 96. A computerized tomography (CT) scan will also be performed, at selected centers, at study entry and week 96. Patients will be asked to complete a symptom distress questionnaire at study entry, weeks 12, 24, 48 and 96.

NCT00098293 HIV-1 Drug: Maraviroc + Zidovudine/Lamivudine Drug: Efavirenz + Zidovudine/Lamivudine Drug: Maraviroc (UK-427,857) + Zidovudine/Lamivudine

Following mutations associated with NRTIs were summarized at time of failure: Any zidovudine/lamivudine (Zid/Lam), Any thymidine analogue-associated mutation (TAM), methionine (M) to valine/isoleucine (V/I) substitution at residue (r) 184 (M184V/I), lysine (K) to arginine (R) substitution at residue 65 (K65R) and any other NRTI mutations.. Number of Participants With Efavirenz Associated Mutations at Time of Treatment Failure Through Week 48 and 96. --- M184V ---

Primary Outcomes

Measure: Percentage of Participants With Viral Load of Less Than 400 Copies/Milliliter [Copies/mL] and Less Than 50 Copies/mL of Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) at Week 48 for Full Analysis Set (FAS) Population

Time: Week 48

Description: Percentage of participants with viral load of less than 400 copies/mL and less than 50 copies/mL of HIV-1 RNA were not analyzed for participants originally randomized to maraviroc once daily arm since after termination, focus was shifted from efficacy and safety to only safety as reflected in the abbreviated set of efficacy measures noted in the amended planned analysis.

Measure: Percentage of Participants With Viral Load of Less Than 400 Copies/mL and Less Than 50 Copies/mL of HIV-1 RNA at Week 48 for Per Protocol (PP) Population

Time: Week 48

Secondary Outcomes

Measure: Percentage of Participants With HIV-1 RNA Levels of Less Than 400 Copies/mL and Less Than 50 Copies/mL at Week 48 Analyzed Using Logistic Regression

Time: Week 48

Measure: Percentage of Participants With HIV-1 RNA Levels of Less Than 400 Copies/mL and Less Than 50 Copies/mL at Week 96 Analyzed Using Logistic Regression

Time: Week 96

Description: Change from baseline in log 10-transformed plasma viral load (HIV-1 RNA) levels (log10 copies/mL). Baseline value calculated as average of pre-dose measurements collected at screening, randomization, and immediately pre-dose.

Measure: Change From Baseline in Log 10-transformed Plasma Viral Load (HIV-1 RNA) Levels at Week 48 and 96

Time: Baseline, Week 48, Week 96

Description: TAD from baseline was calculated as area under the curve (AUC) of HIV-1 RNA load (log10 copies/mL) divided by time period minus baseline HIV-1 RNA load (log10 copies/mL). Baseline value calculated as average of pre-dose measurements collected at screening, randomization, and immediately pre-dose. Data not analyzed for participants originally randomized to maraviroc once daily arm since after termination, focus was shifted from efficacy and safety to only safety as reflected in the abbreviated set of efficacy measures noted in the amended planned analysis.

Measure: Time-Averaged Difference (TAD) in log10-transformed HIV-1 RNA Levels

Time: Baseline up to Week 48 and Week 96

Description: Baseline value calculated as the average of pre-dose measurements collected at screening and immediately pre-dose.

Measure: Change From Baseline in Lymphocyte Cluster of Differentiation 4 (CD4) Count at Week 48 and 96

Time: Baseline, Week 48, Week 96

Description: Baseline value calculated as the average of pre-dose measurements collected at screening and immediately pre-dose. Change from baseline in lymphocyte CD8 count at Week 48 and 96 was not analyzed for participants originally randomized to maraviroc once daily arm since after termination, focus was shifted from efficacy and safety to only safety as reflected in the abbreviated set of efficacy measures noted in the amended planned analysis.

Measure: Change From Baseline in Lymphocyte Cluster of Differentiation 8 (CD8) Count at Week 48 and 96

Time: Baseline, Week 48, Week 96

Description: Time to virologic failure based on observed HIV-1 RNA levels and failure events (death;permanent discontinuation of drug;lost to follow-up [LTFU];new anti-retroviral drug added [except background drug change to drug of same class];or on open label for early non-response or rebound). Failure:at Time 0 if level not <400 copies/mL(2 consecutive visits) before events or last available visit;at time of earliest event if level <400 copies/mL(2 consecutive visits);failure if level >=400 copies/mL(2 consecutive visits) or 1 visit >=400 copies/mL followed by permanent discontinuation of drug or LTFU.

Measure: Time to Virologic Failure

Time: Week 48, Week 96

Description: Number of participants per tropism status (C-X-C chemokine receptor 5 {CCR5} [R5], C-X-C chemokine receptor type 4 {CXCR4} [X4], Dual/mixed [DM], or Non-reportable/Non-phenotypable [NR/NP]) at baseline and time of treatment failure analyzed through week 48 visit. Treatment failure: discontinuation due to insufficient clinical response. Tropism result was censored for participants with viral load <500 copies/mL at time of treatment failure categorized as below lower limit of quantification (BLQ). The assessment for time of treatment failure was defined as last on treatment assessment.

Measure: Number of Participants Per Tropism Status at Baseline and at the Time of Treatment Failure Through Week 48

Time: Baseline, time of failure through Week 48

Description: Number of participants per tropism status (R5, X4, DM, or NR/NP) at baseline and time of treatment failure analyzed through week 96 visit. Treatment failure defined as insufficient clinical response. Tropism result was censored for participants with viral load <500 copies/mL at time of treatment failure categorized as BLQ. The assessment for time of treatment failure was defined as last on treatment assessment.

Measure: Number of Participants Per Tropism Status at Baseline and at the Time of Treatment Failure Through Week 96

Time: Baseline, time of failure through Week 96

Description: Phenotypic resistance to nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) assessed at screening by Monogram Bioscience PhenoSense genotype (MBPSGT) assay, repeated if viral load >500 copies/mL at treatment failure through week 48, 96. Phenotypic resistance to maraviroc was assumed in maraviroc treatment failures with X4-using virus and in R5 maraviroc treatment failures using Monogram Bioscience PhenoSense Entry Assay. Phenotypic resistance to zidovudine, lamivudine, efavirenz and maraviroc at time of failure was summarized.

Measure: Number of Participants With Phenotypic Resistance at Time of Treatment Failure Through Week 48 and 96

Time: Screening, time of failure through Week 48, Week 96

Description: Genotypic resistance to NRTIs was assessed by identification of relevant mutations at screening using MBPSGT assay and repeated for all participants with HIV-1 viral load more than 500 copies/mL at treatment failure through week 48 and week 96. Following mutations associated with NRTIs were summarized at time of failure: Any zidovudine/lamivudine (Zid/Lam), Any thymidine analogue-associated mutation (TAM), methionine (M) to valine/isoleucine (V/I) substitution at residue (r) 184 (M184V/I), lysine (K) to arginine (R) substitution at residue 65 (K65R) and any other NRTI mutations.

Measure: Number of Participants With NRTI Associated Mutations at Time of Treatment Failure Through Week 48 and 96

Time: Screening, time of failure through Week 48, Week 96

Description: Genotypic resistance: mutations at screening by MBPSGT assay, repeated if viral load >500 copies/mL at treatment failure through week 48, 96. Efavirenz mutation:lysine to aspargine at r103(K103N);tyrosine to cysteine/isoleucine at r181(Y181C/I);tyrosine to cysteine/leucine/histidine at r188(Y188C/L/H);glycine to alanine/serine at r190(G190A/S);valine to alanine to r106(V106A);leucine to isoleucine at r100(L100I);alanine to glycine at r98(A98G);lysine to glutamic acid at r101(K101E);valine to isoleucine at r108(V108I);proline to histidine at r225(P225H);methionine to leucine at r230(M230L).

Measure: Number of Participants With Efavirenz Associated Mutations at Time of Treatment Failure Through Week 48 and 96

Time: Screening, time of failure through Week 48, Week 96

Description: Association between baseline resistance and virological response was assessed as percentage of participants with HIV-1RNA levels less than 50 copies/mL by OSS at screening. OSS categorized as 0, 1, 2, >3 (maximum value of 6) and calculated as the sum of the net assessment of in-vitro phenotypic and genotypic susceptibility using a binary scoring system (0= resistant, 1= sensitive or susceptible) for each antiretroviral agent in OBT. Higher scores indicate greater susceptibility.

Measure: Percentage of Participants With HIV-1 RNA Levels Less Than 50 Copies/mL at Week 48 and Week 96 by Overall Susceptibility Score (OSS) at Screening

Time: Baseline, Week 48, Week 96

Other Outcomes

Measure: Percentage of Participants With Viral Load of Less Than 400 Copies/mL and Less Than 50 Copies/mL of HIV-1 RNA at Week 96

Time: Week 96

4 A Phase 4, Single-Arm Study to Evaluate the Safety, Antiviral Activity and Pharmacokinetics of Tenofovir Disoproxil Fumarate in Combination With Emtricitabine in HIV-1 Infected Patients Experiencing Various Degrees of Renal Impairment

The purpose of this study is to provide long-term clinical safety and efficacy data for tenofovir disoproxil fumarate and emtricitabine in HIV-infected patients experiencing various degrees of renal impairment.

NCT00106379 HIV Infections Drug: Truvada (tenofovir DF + emtricitabine) Drug: Emtriva (emtricitabine) Drug: Viread (tenofovir DF)
MeSH: HIV Infections

- Women of childbearing potential who are unwilling to use an effective contraceptive method during the study - Contraindications to tenofovir DF, emtricitabine or efavirenz - Undergoing treatment for tuberculosis - Using atazanavir - Prior history of mutation M184V, K65R or T69 insertion - Z-score on pre-baseline DEXA scan less than -2.5 - The following laboratory values within 30 days prior to study entry: *absolute neutrophil count (ANC) less than 750/mm3, *hemoglobin less than 9.0 g/dL, *platelet count less than 50,000/mm3, *AST (SGOT) or ALT (SGPT) less than 5 x ULN and *CD4 cell count less than 100/mm3. --- M184V ---

Primary Outcomes

Measure: HIV-1 infection

Secondary Outcomes

Measure: HIV-1 infection in renally impaired HIV infected patients

5 A Phase II, Open Label, Single Arm Study of the 48-Week Virologic and Immunologic Response to Lopinavir/Ritonavir (Kaletra) as a Single Agent in a Cohort of HIV Positive Adult Patients

Expected Enrollment: 40 patients Study Start Date: June 2005 Study Objectives: - To conduct a pilot study to assess the safety, tolerability, and antiviral activity of Kaletra 400/100 mg taken twice a day (bid) in antiretroviral (ARV)-naïve HIV-infected patients at Week 48 Primary Objectives: - To determine the proportion of patients with HIV RNA <400 copies/mL at weeks 24 and 48 - To determine the proportion of patients with HIV RNA < 50 at weeks 24 and 48 - To elucidate the specific adverse event (AE) profile of Kaletra single agent therapy Secondary Objectives: - To assess the proportion of patients below the limit of quantification (LOQ) at each visit. Patients will be observed at baseline, weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48. - To determine the time to HIV RNA reaching <400 and <50 copies/mL - To determine the time to virologic failure - To assess change from baseline at each visit for HIV RNA and CD4 count at weeks 4, 8, 12, 24 and 48. - To assess changes in genotype from baseline to time of confirmed virologic failure (2 consecutive HIV RNA measurements >400 copies/mL after suppressing to <400 copies/mL) or at time of treatment intensification. - To characterize changes in lipid and triglyceride concentrations over time and the effect of treatment with appropriate drugs (fibrate or statin, if necessary) on these elevations. - To evaluate the safety and tolerability of subjects through 48 weeks of drug exposure. - To describe virologic response following intensification in Kaletra single agent virologic failures

NCT00116636 HIV Infections Drug: Kaletra
MeSH: HIV Infections HIV Seropositivity

- Patient has an M184V mutation in reverse transcriptase, or mutations at 10, 20, 32, 46, 47, 48, 50, 54, 71, 73, 82, 84, or 90; - K65R mutation or 2 or more TAMs at baseline - History of active substance abuse, excluding cannabis, or psychiatric illness that, in the opinion of the investigator, would preclude compliance with protocol, dosing schedule and assessments. --- M184V ---

Primary Outcomes

Measure: Proportion of patients with plasma HIV-1 RNA <400 copies/mL at Week 24 and 48

Measure: Proportion of patients with plasma HIV-1 RNA < 50 copies/mL at Week 48

Secondary Outcomes

Measure: Proportion of patients with plasma HIV-1 RNA <400 copies/mL or <50 copies/mL at each study visit

Measure: Proportion of patients with plasma HIV-1 RNA <50 copies/mL at Weeks 24 and 48 Weeks

Measure: Number of weeks until HIV RNA <400 copies/mL and <50 copies/mL, respectively

Measure: Change from baseline to each study visit in plasma HIV-1 RNA and CD4+ cell count

Measure: Time-averaged change from baseline to Weeks 12, 24 and 48 (AUCMB) in plasma HIV-1 RNA and CD4+cell count

Measure: Change in HIV genotype and phenotype in patients who either intensify study therapy or experience virologic rebound

Measure: HIV genomic sequence in treatment failures

Measure: Adverse events and treatment-limiting toxicities at all time points

Measure: Baseline and on-therapy assessment of clinical laboratory parameters

Measure: Change from baseline over time in clinical laboratory parameters including fasted triglycerides, total cholesterol, direct HDL cholesterol and LDL cholesterol

6 Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Exploring the Safety, Tolerability, and Antiviral Effect of Substituting 600 mg Racivir for 3TC in HIV-Infected Subjects Who Have the M184V Mutation and Are Currently Failing on a HAART Regimen Containing Lamivudine

Racivir ® (RCV) is an experimental drug which means it is not approved for use by the United States Food and Drug Administration (FDA), but it can be used in research studies like this one. RCV (Racivir®) is part of a class of drugs known as "Nucleoside Reverse Transcriptase Inhibitors" (NRTIs), which are intended to block a further increase in the amount of HIV virus in the body. Laboratory research suggests that RCV (Racivir®) may be effective in patients who have developed resistance to other NRTIs, particularly 3TC (lamivudine, Epivir®). However, a study of RCV (Racivir®) has not been done with patients who have previously been treated with other HAART (Highly Active Antiretroviral Therapy -- taking multiple HIV drugs at once) medications including 3TC (lamivudine, Epivir®). The purpose of this study is to evaluate the safety and effectiveness of RCV (Racivir®) when used together with other HIV drugs in people who have previously been treated with 3TC (lamivudine, Epivir®) and are failing with their current HAART treatments. This study will include a total of 60 HIV infected, HAART-experienced subjects currently receiving 3TC (lamivudine, Epivir®) as part of their HAART therapy. The study will take place at approximately 11 study sites in the US and Latin America.

NCT00121979 HIV Infections Drug: Racivir, a non-nucleoside reverse transcriptase inhibitor
MeSH: HIV Infections

Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Exploring the Safety, Tolerability, and Antiviral Effect of Substituting 600 mg Racivir for 3TC in HIV-Infected Subjects Who Have the M184V Mutation and Are Currently Failing on a HAART Regimen Containing Lamivudine. --- M184V ---

- Subjects who have the M184V HIV mutation, as determined by the FDA-approved Bayer assay, TRUGENE® HIV-1 Genotyping Kit and the OpenGene® DNA Sequencing System. --- M184V ---

Primary Outcomes

Measure: Change from baseline in virological response of HIV (log10 HIV-RNA levels) at the end of week 2

Measure: Change from baseline in CD4+ count at the end of week 2

Measure: Adverse events

Secondary Outcomes

Measure: Proportion of subjects in each treatment arm with viral load reduction ≥ 0.5 log10 from baseline

Measure: Proportion of subjects in each treatment arm with viral load below 50 copies/mL

7 Prospective Trial to Evaluate How Therapeutic Drug Monitoring of Protease Inhibitors Increases Virologic Success and Tolerance of HAART (ANRS 111 COPHAR2)

This Cophar2 study is a trial which evaluates repeated early therapeutic drug monitoring, from weeks 2 to 24, after the initiation of HAART including either indinavir/r, lopinavir/r or the new 625 mg formulation of nelfinavir twice-a-day (bid). If trough concentrations were out of the range given for each protease inhibitor (PI), the PI dose was adjusted.

NCT00122590 HIV Infections Drug: nelfinavir Drug: lopinavir/r Drug: indinavir Drug: ritonavir
MeSH: HIV Infections

Inclusion Criteria: - Patients infected with HIV-1 - Needing an antiretroviral treatment according to standard of care - HIV viral load greater than 1000 copies/ml - Beginning a treatment containing a PI (indinavir with or without ritonavir, nelfinavir, lopinavir + ritonavir) and 2 reverse transcriptase inhibitors - PI-naive - Antiretroviral treatment-naive or already treated with reverse transcriptase inhibitors but if the viral genotypic test does not show more than 2 major mutations (including T215Y/F, Q151M, M184V/I, V75M/S, L74V) and if 3 nucleoside analogues are still active except for didanosine. --- T215Y --- --- Q151M --- --- M184V ---

Exclusion Criteria: - Pregnant women and nursing mothers - Acute HIV infection - Diabetes - Renal insufficiency with creatinine clearance below 30 ml/min - Cardiac insufficiency - Hepatic insufficiency with TP below 60% - Treatment with known interactions with PI - Chemotherapy against Kaposi's sarcoma, lymphoma, neoplasia - Treatment containing interferon (INF) or interleukin-2 (IL2) or HIV- immune vaccine - Treatment with hypolipemic drugs - Laxative treatment - Previous renal colic - Diarrhoea with more than 5 stools/day since one week Inclusion Criteria: - Patients infected with HIV-1 - Needing an antiretroviral treatment according to standard of care - HIV viral load greater than 1000 copies/ml - Beginning a treatment containing a PI (indinavir with or without ritonavir, nelfinavir, lopinavir + ritonavir) and 2 reverse transcriptase inhibitors - PI-naive - Antiretroviral treatment-naive or already treated with reverse transcriptase inhibitors but if the viral genotypic test does not show more than 2 major mutations (including T215Y/F, Q151M, M184V/I, V75M/S, L74V) and if 3 nucleoside analogues are still active except for didanosine. --- T215Y --- --- Q151M --- --- M184V ---

Primary Outcomes

Measure: treatment failure defined as viral load greater than 200 copies/ml between week 16 (W16) and week 48 (W48) (confirmed by 2 samples spiked at least 15 days apart but no more than 45 days after virological failure, assayed by 50 copies/ml method)

Measure: toxicity related to PI, defined as adverse event grade 3 or 4 with ANRS quotation, renal colic, diarrhoea grade 2, or cholesterolemia over 10 times the normal value

Secondary Outcomes

Measure: virological failure: viral load over 200 copies/ml between W16 and W48 (confirmed by 2 samples spiked at least 15 days apart but no more than 45 days after virological failure, assayed by 50 copies/ml method)

Measure: toxicity related to PI: adverse events grade 3 or 4 with ANRS quotation, renal colic, diarrhoea grade 2, or cholesterolemia over 10 times the normal value

Measure: patients with trough plasma concentrations outside the therapeutic range at W24 and W48

Measure: concentration changes with dosage variation

Measure: time to obtain a viral load below 200 copies/ml

Measure: relationship between adverse events grade 3 or 4 related to PI and plasma concentration at week 2 (W2)

Measure: relationship between pharmacokinetic parameters and/or plasma concentrations and the drop of viral load between day 0 (D0) and W2 and between D0 and week 4 (W4)

Measure: relationship between pharmacokinetic parameters and viral mutations occurring during the treatment of patients with virological failure (over 1000 copies/ml after week 24 [W24])

Measure: PI pharmacokinetic parameter estimation and evaluation of variability

Measure: pharmacokinetic variability of nucleoside analogues at W2

Measure: intracellular concentration of nucleoside triphosphate derivatives at W2 (trough and maximum) and relationship between virological response and adverse events

Measure: relationship between inhibitory quotient of indinavir and virological response

8 A Phase II, Randomised, Double-blind, Dose-ranging Study of AVX754 Versus Lamivudine in Treatment-experienced HIV-1 Infected Patients With the M184V Mutation in Reverse Transcriptase

The study will measure how safe and effective AVX754 (a new drug for the treatment of HIV) is in treating HIV-1 infected people who have failed treatment with lamivudine.

NCT00126880 HIV Infections Drug: AVX754 Drug: 3TC
MeSH: HIV Infections

A Phase II, Randomised, Double-blind, Dose-ranging Study of AVX754 Versus Lamivudine in Treatment-experienced HIV-1 Infected Patients With the M184V Mutation in Reverse Transcriptase. --- M184V ---

Inclusion Criteria: - HIV-1 infected - M184V mutation in reverse transcriptase - Currently taking lamivudine - Viral load >2000 copies/ml Exclusion Criteria: - Hepatitis B surface antigen positive - Pregnant or breastfeeding females - Hepatitis C RNA positive and requiring treatment Inclusion Criteria: - HIV-1 infected - M184V mutation in reverse transcriptase - Currently taking lamivudine - Viral load >2000 copies/ml Exclusion Criteria: - Hepatitis B surface antigen positive - Pregnant or breastfeeding females - Hepatitis C RNA positive and requiring treatment HIV Infections HIV Infections Lamivudine or emtricitabine are commonly used in combination with other drugs for first-line treatment of HIV infection. --- M184V ---

Inclusion Criteria: - HIV-1 infected - M184V mutation in reverse transcriptase - Currently taking lamivudine - Viral load >2000 copies/ml Exclusion Criteria: - Hepatitis B surface antigen positive - Pregnant or breastfeeding females - Hepatitis C RNA positive and requiring treatment Inclusion Criteria: - HIV-1 infected - M184V mutation in reverse transcriptase - Currently taking lamivudine - Viral load >2000 copies/ml Exclusion Criteria: - Hepatitis B surface antigen positive - Pregnant or breastfeeding females - Hepatitis C RNA positive and requiring treatment HIV Infections HIV Infections Lamivudine or emtricitabine are commonly used in combination with other drugs for first-line treatment of HIV infection. --- M184V --- --- M184V ---

Resistance is associated with characteristic mutations, which for lamivudine is the M184V mutation. --- M184V ---

Primary Outcomes

Measure: Change from baseline in HIV RNA levels at day 21

Time: day 21

Measure: Time-weighted average change from baseline in HIV RNA levels through 21 days

Time: 21 days

Secondary Outcomes

Measure: Change from baseline in HIV RNA levels at days 7, 14, 21

Time: days 7, 14, 21

Measure: Proportion of subjects with HIV RNA levels <400 or <50 at days 7, 14, 21, and weeks 24 and 48

Time: days 7, 14, 21, and weeks 24 and 48

Measure: Change from baseline and change in ratio of CD4+ and CD8+ cells at day 21 and weeks 24 and 48

Time: day 21 and weeks 24 and 48

9 The Role of 3TC/FTC in Partially Suppressive Antiretroviral Regimens: The Switch Study

In this study the researchers will be enrolling patients who are failing their current antiretroviral regimen who also have resistance to 3TC or FTC. Patients will have their current antiretroviral regimen changed based on resistance testing and also be randomly assigned to either include, or not include 3TC/FTC in this new regimen. The purpose of the research is to investigate whether the change in therapy results in a decrease in the amount of virus particles and an increase in the CD4 cell count. In addition the researchers are investigating the relationship between the existence of resistance and the rate of decrease in viral load, and also to determine if continuing 3TC/FTC (despite being resistant to the medications) has any effect on the rate of decrease of viral load, or effect on CD4 counts.

NCT00152061 HIV Infections Drug: 3TC and FTC
MeSH: HIV Infections

To evaluate the impact of continued versus discontinued 3TC/FTC on the prevalence, frequency and dynamics of the M184V/I amino acid substitution over 24 weeks.. null. --- M184V ---

Inclusion Criteria: - HIV-1 seropositive patients >= 18 years of age - Willingness and ability to understand and sign a written informed consent and comply with the protocol procedure - Prior treatment with nucleoside reverse transcriptase inhibitors (NRTI's), non-nucleoside reverse transcriptase inhibitors (NNRTI's) and protease inhibitor (PI)-containing regimens - On a stable PI and 3TC or FTC -containing regimen for >= 2 months - Plasma HIV-1 RNA >5000 copies/ml - CD4 >100 - Documented M184V or I on genotype within 3 months of study entry - At least 3 PI-associated resistance mutations on genotype within 3 months of study entry, (including known resistance mutations at codons 10, 30, 46, 50, 54, 71, 82, 84, and 90) Exclusion Criteria: - In the opinion of the investigator a patient that is either unwilling or unable to be adherent to antiretroviral drugs - Requirement for concomitant treatment with medicines that interfere with the therapy prescribed in the study - Patients who have never taken 3TC or FTC, or with no prior documentation of the M184V mutation - Active hepatitis B infection - Vaccination within 2 weeks of entering the study - An acute opportunistic illness within 4 weeks of entering the study; chronic infections will not be excluded - Use of immunomodulatory medications such as IL-2 - Planned use of enfuvirtide, (T20) in salvage regimen, (in T20 naïve subjects) Inclusion Criteria: - HIV-1 seropositive patients >= 18 years of age - Willingness and ability to understand and sign a written informed consent and comply with the protocol procedure - Prior treatment with nucleoside reverse transcriptase inhibitors (NRTI's), non-nucleoside reverse transcriptase inhibitors (NNRTI's) and protease inhibitor (PI)-containing regimens - On a stable PI and 3TC or FTC -containing regimen for >= 2 months - Plasma HIV-1 RNA >5000 copies/ml - CD4 >100 - Documented M184V or I on genotype within 3 months of study entry - At least 3 PI-associated resistance mutations on genotype within 3 months of study entry, (including known resistance mutations at codons 10, 30, 46, 50, 54, 71, 82, 84, and 90) Exclusion Criteria: - In the opinion of the investigator a patient that is either unwilling or unable to be adherent to antiretroviral drugs - Requirement for concomitant treatment with medicines that interfere with the therapy prescribed in the study - Patients who have never taken 3TC or FTC, or with no prior documentation of the M184V mutation - Active hepatitis B infection - Vaccination within 2 weeks of entering the study - An acute opportunistic illness within 4 weeks of entering the study; chronic infections will not be excluded - Use of immunomodulatory medications such as IL-2 - Planned use of enfuvirtide, (T20) in salvage regimen, (in T20 naïve subjects) HIV Infections HIV Infections In this randomized, open-label, controlled trial, HIV-infected patients who are failing 3TC/FTC-containing highly active antiretroviral therapy, (HAART), will be offered individual treatment selection based on best clinical judgment and genotypic HIV-RNA resistance analysis. --- M184V ---

Inclusion Criteria: - HIV-1 seropositive patients >= 18 years of age - Willingness and ability to understand and sign a written informed consent and comply with the protocol procedure - Prior treatment with nucleoside reverse transcriptase inhibitors (NRTI's), non-nucleoside reverse transcriptase inhibitors (NNRTI's) and protease inhibitor (PI)-containing regimens - On a stable PI and 3TC or FTC -containing regimen for >= 2 months - Plasma HIV-1 RNA >5000 copies/ml - CD4 >100 - Documented M184V or I on genotype within 3 months of study entry - At least 3 PI-associated resistance mutations on genotype within 3 months of study entry, (including known resistance mutations at codons 10, 30, 46, 50, 54, 71, 82, 84, and 90) Exclusion Criteria: - In the opinion of the investigator a patient that is either unwilling or unable to be adherent to antiretroviral drugs - Requirement for concomitant treatment with medicines that interfere with the therapy prescribed in the study - Patients who have never taken 3TC or FTC, or with no prior documentation of the M184V mutation - Active hepatitis B infection - Vaccination within 2 weeks of entering the study - An acute opportunistic illness within 4 weeks of entering the study; chronic infections will not be excluded - Use of immunomodulatory medications such as IL-2 - Planned use of enfuvirtide, (T20) in salvage regimen, (in T20 naïve subjects) Inclusion Criteria: - HIV-1 seropositive patients >= 18 years of age - Willingness and ability to understand and sign a written informed consent and comply with the protocol procedure - Prior treatment with nucleoside reverse transcriptase inhibitors (NRTI's), non-nucleoside reverse transcriptase inhibitors (NNRTI's) and protease inhibitor (PI)-containing regimens - On a stable PI and 3TC or FTC -containing regimen for >= 2 months - Plasma HIV-1 RNA >5000 copies/ml - CD4 >100 - Documented M184V or I on genotype within 3 months of study entry - At least 3 PI-associated resistance mutations on genotype within 3 months of study entry, (including known resistance mutations at codons 10, 30, 46, 50, 54, 71, 82, 84, and 90) Exclusion Criteria: - In the opinion of the investigator a patient that is either unwilling or unable to be adherent to antiretroviral drugs - Requirement for concomitant treatment with medicines that interfere with the therapy prescribed in the study - Patients who have never taken 3TC or FTC, or with no prior documentation of the M184V mutation - Active hepatitis B infection - Vaccination within 2 weeks of entering the study - An acute opportunistic illness within 4 weeks of entering the study; chronic infections will not be excluded - Use of immunomodulatory medications such as IL-2 - Planned use of enfuvirtide, (T20) in salvage regimen, (in T20 naïve subjects) HIV Infections HIV Infections In this randomized, open-label, controlled trial, HIV-infected patients who are failing 3TC/FTC-containing highly active antiretroviral therapy, (HAART), will be offered individual treatment selection based on best clinical judgment and genotypic HIV-RNA resistance analysis. --- M184V --- --- M184V ---

Inclusion Criteria: - HIV-1 seropositive patients >= 18 years of age - Willingness and ability to understand and sign a written informed consent and comply with the protocol procedure - Prior treatment with nucleoside reverse transcriptase inhibitors (NRTI's), non-nucleoside reverse transcriptase inhibitors (NNRTI's) and protease inhibitor (PI)-containing regimens - On a stable PI and 3TC or FTC -containing regimen for >= 2 months - Plasma HIV-1 RNA >5000 copies/ml - CD4 >100 - Documented M184V or I on genotype within 3 months of study entry - At least 3 PI-associated resistance mutations on genotype within 3 months of study entry, (including known resistance mutations at codons 10, 30, 46, 50, 54, 71, 82, 84, and 90) Exclusion Criteria: - In the opinion of the investigator a patient that is either unwilling or unable to be adherent to antiretroviral drugs - Requirement for concomitant treatment with medicines that interfere with the therapy prescribed in the study - Patients who have never taken 3TC or FTC, or with no prior documentation of the M184V mutation - Active hepatitis B infection - Vaccination within 2 weeks of entering the study - An acute opportunistic illness within 4 weeks of entering the study; chronic infections will not be excluded - Use of immunomodulatory medications such as IL-2 - Planned use of enfuvirtide, (T20) in salvage regimen, (in T20 naïve subjects) Inclusion Criteria: - HIV-1 seropositive patients >= 18 years of age - Willingness and ability to understand and sign a written informed consent and comply with the protocol procedure - Prior treatment with nucleoside reverse transcriptase inhibitors (NRTI's), non-nucleoside reverse transcriptase inhibitors (NNRTI's) and protease inhibitor (PI)-containing regimens - On a stable PI and 3TC or FTC -containing regimen for >= 2 months - Plasma HIV-1 RNA >5000 copies/ml - CD4 >100 - Documented M184V or I on genotype within 3 months of study entry - At least 3 PI-associated resistance mutations on genotype within 3 months of study entry, (including known resistance mutations at codons 10, 30, 46, 50, 54, 71, 82, 84, and 90) Exclusion Criteria: - In the opinion of the investigator a patient that is either unwilling or unable to be adherent to antiretroviral drugs - Requirement for concomitant treatment with medicines that interfere with the therapy prescribed in the study - Patients who have never taken 3TC or FTC, or with no prior documentation of the M184V mutation - Active hepatitis B infection - Vaccination within 2 weeks of entering the study - An acute opportunistic illness within 4 weeks of entering the study; chronic infections will not be excluded - Use of immunomodulatory medications such as IL-2 - Planned use of enfuvirtide, (T20) in salvage regimen, (in T20 naïve subjects) HIV Infections HIV Infections In this randomized, open-label, controlled trial, HIV-infected patients who are failing 3TC/FTC-containing highly active antiretroviral therapy, (HAART), will be offered individual treatment selection based on best clinical judgment and genotypic HIV-RNA resistance analysis. --- M184V --- --- M184V --- --- M184V ---

Inclusion Criteria: - HIV-1 seropositive patients >= 18 years of age - Willingness and ability to understand and sign a written informed consent and comply with the protocol procedure - Prior treatment with nucleoside reverse transcriptase inhibitors (NRTI's), non-nucleoside reverse transcriptase inhibitors (NNRTI's) and protease inhibitor (PI)-containing regimens - On a stable PI and 3TC or FTC -containing regimen for >= 2 months - Plasma HIV-1 RNA >5000 copies/ml - CD4 >100 - Documented M184V or I on genotype within 3 months of study entry - At least 3 PI-associated resistance mutations on genotype within 3 months of study entry, (including known resistance mutations at codons 10, 30, 46, 50, 54, 71, 82, 84, and 90) Exclusion Criteria: - In the opinion of the investigator a patient that is either unwilling or unable to be adherent to antiretroviral drugs - Requirement for concomitant treatment with medicines that interfere with the therapy prescribed in the study - Patients who have never taken 3TC or FTC, or with no prior documentation of the M184V mutation - Active hepatitis B infection - Vaccination within 2 weeks of entering the study - An acute opportunistic illness within 4 weeks of entering the study; chronic infections will not be excluded - Use of immunomodulatory medications such as IL-2 - Planned use of enfuvirtide, (T20) in salvage regimen, (in T20 naïve subjects) Inclusion Criteria: - HIV-1 seropositive patients >= 18 years of age - Willingness and ability to understand and sign a written informed consent and comply with the protocol procedure - Prior treatment with nucleoside reverse transcriptase inhibitors (NRTI's), non-nucleoside reverse transcriptase inhibitors (NNRTI's) and protease inhibitor (PI)-containing regimens - On a stable PI and 3TC or FTC -containing regimen for >= 2 months - Plasma HIV-1 RNA >5000 copies/ml - CD4 >100 - Documented M184V or I on genotype within 3 months of study entry - At least 3 PI-associated resistance mutations on genotype within 3 months of study entry, (including known resistance mutations at codons 10, 30, 46, 50, 54, 71, 82, 84, and 90) Exclusion Criteria: - In the opinion of the investigator a patient that is either unwilling or unable to be adherent to antiretroviral drugs - Requirement for concomitant treatment with medicines that interfere with the therapy prescribed in the study - Patients who have never taken 3TC or FTC, or with no prior documentation of the M184V mutation - Active hepatitis B infection - Vaccination within 2 weeks of entering the study - An acute opportunistic illness within 4 weeks of entering the study; chronic infections will not be excluded - Use of immunomodulatory medications such as IL-2 - Planned use of enfuvirtide, (T20) in salvage regimen, (in T20 naïve subjects) HIV Infections HIV Infections In this randomized, open-label, controlled trial, HIV-infected patients who are failing 3TC/FTC-containing highly active antiretroviral therapy, (HAART), will be offered individual treatment selection based on best clinical judgment and genotypic HIV-RNA resistance analysis. --- M184V --- --- M184V --- --- M184V --- --- M184V ---

Primary Outcomes

Measure: To evaluate the role of lamivudine, (3TC), and emtricitabine, (FTC), in salvage regimens in patients with prior 3TC/FTC use, documented resistance to 3TC/FTC, and ongoing viremia as assessed by:

Measure: Impact on the initial rate of change in HIV-1 viral load after removing 3TC/FTC from the failing regimen, and

Measure: Overall change from baseline in HIV-1 viral load at 24 weeks (HIV-VL AUC 24 wks).

Secondary Outcomes

Measure: To evaluate the impact of continued versus discontinued 3TC/FTC on the prevalence, frequency and dynamics of the M184V/I amino acid substitution over 24 weeks.

Measure: To determine the proportion of patients failing and/or not responding to therapy after 24 weeks as defined by failure to achieve HIV-1 viral load less than 400 copies/ml and/or less than 50 copies/ml

Measure: To assess the changes from baseline in absolute CD4 (and CD8) cell counts at 24 weeks.

10 Directly Administered vs. Self-administered Antiretroviral Therapy in Methadone Clinics

The purpose of this study is to determine whether providing directly administered antiretroviral therapy to HIV-infected who receive methadone therapy leads to better treatment outcomes than if they take HIV medications on their own.

NCT00279110 HIV Infections Heroin Dependence Behavioral: Directly administered antiretroviral therapy (DAART)
MeSH: Heroin Dependence

Current plasma HIV RNA > 500 copies/ml 7. Initiating ART for first time, reinitiating therapy after stopping, or changing therapy due to virologic failure 8. ART with at least 3 agents, including a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor, or abacavir 9. Methadone or buprenorphine maintenance therapy > 3 weeks, with no planned detoxification Exclusion Criteria: 1. Need to use ART dosed more frequently than twice daily, 2. Need to use a liquid preparation of antiretroviral medication, 3. Documented triple-class antiretroviral resistance (defined below), 4. Participation in another study or program that includes directly observed therapy. 5. Use of ART regimens that are expressly discouraged in DHHS HIV clinical care guidelines Triple-class antiretroviral resistance will be defined according to IAS-USA interpretive guidelines: NRTI class - 3 thymidine or non-thymidine-associated mutations (excluding the M184V mutation) or a multi-nucleoside resistance mutation in reverse transcriptase; PI class - 3 protease mutations, including 1 primary mutation; NNRTI class - 1 primary (K103N or Y188L) or 2 secondary NNRTI-associated mutations in reverse transcriptase. --- M184V ---

Primary Outcomes

Measure: HIV RNA < 50 c/mL

Time: 12 months

Secondary Outcomes

Measure: Log10 change in HIV RNA from baseline

Time: 12 months

Measure: HIV RNA < 50 c/mL 6 mos. after intervention

Time: 18 months

Measure: Log10 change in HIV RNA from baseline 6 months post intervention

Time: 18 months

Measure: Change in CD4 cell count from baseline

Time: 18 months

Measure: ART utilization

Time: 12 months

Measure: Development of antiretroviral resistance

Time: 12 months

Measure: Retention to substance abuse treatment

Time: 12 months

Measure: Urine drug screen positivity in follow-up

Time: 12 months

Measure: Electronically monitored adherence

Time: 2 months

11 A 14 Day Randomized, Double Blind, Study of Once Daily Elvucitabine Versus Lamivudine in Subjects With a Documented M184V Mutation

HIV-1 infected patients receiving long-term therapy with lamivudine or emtricitabine (nucleoside reverse transcriptase inhibitors [NRTIs]) are at risk for the development of a mutation at position M184 on the HIV reverse transcriptase gene. This mutation confers resistance to both drugs (> 100 fold increase in IC50). In-vitro studies with elvucitabine have shown that HIV-1 isolates with the M184V mutation show only a 10-fold increase in IC50 as compared to wild type HIV-1. Achillion Pharmaceutical's intention is to demonstrate that 10 mg of elvucitabine, administered once per day for 14 days with continued background anti-HIV-1 medications, will demonstrate a fall in HIV-1 RNA plasma levels, as compared to baseline. The data from this study will guide dosing in future long-term studies in HIV-1 infected patients with the M184V mutation.

NCT00312039 HIV Infections Drug: elvucitabine Drug: Lamivudine
MeSH: HIV Infections

A 14 Day Randomized, Double Blind, Study of Once Daily Elvucitabine Versus Lamivudine in Subjects With a Documented M184V Mutation. --- M184V ---

Study of Once Daily Elvucitabine Versus Lamivudine in Subjects With a Documented M184V Mutation HIV-1 infected patients receiving long-term therapy with lamivudine or emtricitabine (nucleoside reverse transcriptase inhibitors [NRTIs]) are at risk for the development of a mutation at position M184 on the HIV reverse transcriptase gene. --- M184V ---

In-vitro studies with elvucitabine have shown that HIV-1 isolates with the M184V mutation show only a 10-fold increase in IC50 as compared to wild type HIV-1. --- M184V ---

The data from this study will guide dosing in future long-term studies in HIV-1 infected patients with the M184V mutation. --- M184V ---

Inclusion Criteria: - Clinically stable HIV-1 infected patients - Ages > 18 and < 65 years - Documented M184V mutation - CD4 cell count > 100 cells/mL - Plasma HIV-1 RNA levels > 5000 and < 150,000 copies/mL - Currently receiving lamivudine or emtricitabine - Other hematologic and metabolic parameters must be met. --- M184V ---

HIV Infections HIV Infections Protocol Title: A 14-Day, Randomized, Double-Blind, Comparative Viral Kinetic Study of Elvucitabine Versus Lamivudine Administered Once Daily to HIV-1 Infected Subjects With a Documented M184V Variant Protocol Number: ACH443-014A Clinical Phase: 2a Primary Objectives: • To assess the viral kinetics of 10 mg of elvucitabine administered once daily (QD) for 14 days in combination with background antiretroviral therapy in HIV-1-infected subjects with a documented M184V variant - To demonstrate the antiviral activity of 10 mg of elvucitabine administered QD for 14 days in combination with background antiretroviral therapy as compared with lamivudine in combination with background antiretroviral therapy in HIV-1 infected subjects with a documented M184V variant - To assess the safety of elvucitabine therapy in HIV-1 infected subjects with a documented M184V variant Number of Subjects: 20 Number of Study Centers: Multi-center study Study Population: HIV-1 infected subjects who are presently failing an antiretroviral therapy regimen containing lamivudine or emtricitabine, genotypically demonstrate a MI84V variant, and have an HIV RNA plasma level ≥ 2,000 and ≤ 150,000 copies/mL. --- M184V ---

HIV Infections HIV Infections Protocol Title: A 14-Day, Randomized, Double-Blind, Comparative Viral Kinetic Study of Elvucitabine Versus Lamivudine Administered Once Daily to HIV-1 Infected Subjects With a Documented M184V Variant Protocol Number: ACH443-014A Clinical Phase: 2a Primary Objectives: • To assess the viral kinetics of 10 mg of elvucitabine administered once daily (QD) for 14 days in combination with background antiretroviral therapy in HIV-1-infected subjects with a documented M184V variant - To demonstrate the antiviral activity of 10 mg of elvucitabine administered QD for 14 days in combination with background antiretroviral therapy as compared with lamivudine in combination with background antiretroviral therapy in HIV-1 infected subjects with a documented M184V variant - To assess the safety of elvucitabine therapy in HIV-1 infected subjects with a documented M184V variant Number of Subjects: 20 Number of Study Centers: Multi-center study Study Population: HIV-1 infected subjects who are presently failing an antiretroviral therapy regimen containing lamivudine or emtricitabine, genotypically demonstrate a MI84V variant, and have an HIV RNA plasma level ≥ 2,000 and ≤ 150,000 copies/mL. --- M184V --- --- M184V ---

HIV Infections HIV Infections Protocol Title: A 14-Day, Randomized, Double-Blind, Comparative Viral Kinetic Study of Elvucitabine Versus Lamivudine Administered Once Daily to HIV-1 Infected Subjects With a Documented M184V Variant Protocol Number: ACH443-014A Clinical Phase: 2a Primary Objectives: • To assess the viral kinetics of 10 mg of elvucitabine administered once daily (QD) for 14 days in combination with background antiretroviral therapy in HIV-1-infected subjects with a documented M184V variant - To demonstrate the antiviral activity of 10 mg of elvucitabine administered QD for 14 days in combination with background antiretroviral therapy as compared with lamivudine in combination with background antiretroviral therapy in HIV-1 infected subjects with a documented M184V variant - To assess the safety of elvucitabine therapy in HIV-1 infected subjects with a documented M184V variant Number of Subjects: 20 Number of Study Centers: Multi-center study Study Population: HIV-1 infected subjects who are presently failing an antiretroviral therapy regimen containing lamivudine or emtricitabine, genotypically demonstrate a MI84V variant, and have an HIV RNA plasma level ≥ 2,000 and ≤ 150,000 copies/mL. --- M184V --- --- M184V --- --- M184V ---

HIV Infections HIV Infections Protocol Title: A 14-Day, Randomized, Double-Blind, Comparative Viral Kinetic Study of Elvucitabine Versus Lamivudine Administered Once Daily to HIV-1 Infected Subjects With a Documented M184V Variant Protocol Number: ACH443-014A Clinical Phase: 2a Primary Objectives: • To assess the viral kinetics of 10 mg of elvucitabine administered once daily (QD) for 14 days in combination with background antiretroviral therapy in HIV-1-infected subjects with a documented M184V variant - To demonstrate the antiviral activity of 10 mg of elvucitabine administered QD for 14 days in combination with background antiretroviral therapy as compared with lamivudine in combination with background antiretroviral therapy in HIV-1 infected subjects with a documented M184V variant - To assess the safety of elvucitabine therapy in HIV-1 infected subjects with a documented M184V variant Number of Subjects: 20 Number of Study Centers: Multi-center study Study Population: HIV-1 infected subjects who are presently failing an antiretroviral therapy regimen containing lamivudine or emtricitabine, genotypically demonstrate a MI84V variant, and have an HIV RNA plasma level ≥ 2,000 and ≤ 150,000 copies/mL. --- M184V --- --- M184V --- --- M184V --- --- M184V ---

Study Design: HIV-1 infected subjects, with a documented M184V variant, will be randomized to receive elvucitabine 10 mg QD or lamivudine 300 mg QD for 14 days. --- M184V ---

Primary Outcomes

Measure: Reduction in viral load

Time: 14 days

Secondary Outcomes

Measure: safety

Time: 14 days

12 Evolution of L74V or K65R Mutations in VIremic Subjects on TDF or ABC (EVITA)

This is a multicenter, open-label, non-randomized, dual-arm pilot study to investigate the prevalence of the reverse transcriptase (RT) resistance mutations, K65R/x or L74V/x, in HIV-1 plasma from subjects experiencing confirmed first-time incomplete virologic suppression during treatment with an initial antiretroviral (ARV) regimen consisting of at least 12 weeks of TDF or ABC + emtricitabine (FTC) or lamivudine (3TC) + non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI). Subjects will be followed until a substantial loss of virologic or immunologic control requires a treatment switch. Confirmed first-time incomplete virologic suppression is defined as an initial plasma HIV-1 RNA response < 400 copies/mL, and subsequent virologic rebound > 400 copies/mL measured at two consecutive times. Subjects will have a screening genotype to establish adherence to their non-suppressive TDF- or ABC-containing regimen by the presence of M184V (or other treatment-related primary) mutation and to demonstrate that the evolution of treatment-emergent RT mutations can be characterized. Twenty subjects (a maximum of 10 per arm) will be enrolled at 10-20 United States (U.S.) sites. If fewer than 20 subjects can be enrolled, the study may be discontinued early by the sponsor. Equal numbers of subjects on Arm A versus Arm B will be a goal.

NCT00312169 HIV Infections
MeSH: HIV Infections

Subjects will have a screening genotype to establish adherence to their non-suppressive TDF- or ABC-containing regimen by the presence of M184V (or other treatment-related primary) mutation and to demonstrate that the evolution of treatment-emergent RT mutations can be characterized. --- M184V ---

4. Screening HIV-1 genotype with M184V or at least one treatment-related primary mutation. --- M184V ---

Subjects will have screening genotype to establish adherence to their non-suppressive TDF- or ABC-containing regimen by the presence of M184V (or other treatment-related primary) mutation and to demonstrate that the evolution of treatment-emergent RT mutations can be characterized. --- M184V ---

4. Screening HIV-1 genotype with M184V or at least one treatment-related primary mutation. --- M184V ---


13 Phase IIIb Multicenter, Single Arm, Open-Label Pilot Study to Evaluate the Effectiveness and Safety of Maintenance With Atazanavir/Ritonavir as Single Enhanced Protease Inhibitor Therapy in HIV-Infected Patients Evidencing Virologic Suppression OREY (Only REYataz) Study

The main purpose is to explore whether atazanavir/ritonavir (ATV/RTV) single enhanced protease inhibitor therapy can maintain virologic suppression without a marked increase in virologic failure.

NCT00337467 Human Immunodeficiency Virus (HIV) Infections Drug: Atazanavir + Ritonavir
MeSH: Acquired Immunodeficiency Syndrome HIV Infections Immunologic Deficiency Syndromes
HPO: Immunodeficiency

Reverse Transcriptase (RT) are TAMS and M184V.. Number of Participants With Genotype Substitutions for Virologic Rebounds (HIV-RNA ≥ 400 c/mL) Through Week 96. --- M184V ---

Reverse Transcriptase (RT) are TAMS and M184V.. Inclusion Criteria: - On continued antiretroviral (ARV) treatment, with no discontinuation periods, for the previous 6 months (24 weeks). --- M184V ---

Primary Outcomes

Description: Treatment Failure through Week 48 defined as virologic rebound (HIV RNA >=400 c/mL) on or before Week 48 or study discontinuation before Week 48. Virological rebound is defined as confirmed on-treatment HIV ribonucleic acid (RNA) >= 400 c/mL at 2 consecutive visits or last on-treatment HIV RNA >=400 c/mL followed by discontinuation of study therapy.

Measure: Percentage of Participants With Treatment Failure Through Week 48

Time: Week 48

Secondary Outcomes

Description: Treatment Failure through Week 96 defined as virologic rebound (HIV RNA >=400 c/mL) on or before Week 96 or study discontinuation before Week 96. In addition, treatment failure defined based on HIV RNA >= 50 c/mL, latter analysis performed on treated subjects with baseline HIV RNA < 50 c/mL.

Measure: Percentage of Participants With Treatment Failure Through Week 96

Time: Week 96

Description: Virological rebound is defined as confirmed on-treatment HIV RNA >= 400 c/mL at 2 consecutive visits or last on-treatment HIV RNA >=400 c/mL followed by discontinuation of study therapy. In addition, virologic rebound defined based on HIV RNA >=50 c/m, latter analysis performed on subjects with baseline HIV RNA < 50 c/mL.

Measure: Percentage of Participants With Virological Rebound Through Week 48

Time: Week 48

Description: Virological rebound is defined as confirmed on-treatment HIV RNA >= 400 c/mL at 2 consecutive visits or last on-treatment HIV RNA >=400 c/mL followed by discontinuation of study therapy. In addition, virologic rebound defined based on HIV RNA >=50 c/m, latter analysis performed on subjects with baseline HIV RNA < 50 c/mL.

Measure: Percentage of Participants With Virological Rebound Through Week 96

Time: Week 96

Description: This Kaplan-Meier life table reports the cumulative proportion of participants without treatment failure up to the end of the respective time interval. Failure time is measured from the start of study therapy, and is based on the earliest event defining failure (virologic rebound at or before Week 96, or discontinuation prior to Week 96).

Measure: Cumulative Proportion of Participants Without Treatment Failure Through Week 100

Time: Through Week 100

Description: Virologic rebound is defined as confirmed on-study HIV RNA ≥ 400 c/mL or last on-study HIV RNA ≥ 400 c/mL followed by treatment discontinuation.

Measure: Proportion of Participants With Virologic Rebound Through Week 96

Time: Through Week 96

Measure: Mean Change From Baseline in Cluster of Differentiation 4 (CD4) Cell Count at Week 24

Time: Baseline, Week 24

Measure: Mean Change From Baseline in CD4 Cell Count at Week 48

Time: Baseline, Week 48

Measure: Mean Change From Baseline in CD4 Cell Count at Week 96

Time: Baseline, Week 96

Description: AE=any new untoward medical occurrence or worsening of a pre-existing medical condition that does not necessarily have a causal relationship to treatment. SAE=any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event. AE grades are: mild (1), moderate (2), severe (3), life-threatening (4), and death (5).

Measure: Percentage of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Due to AEs

Time: From Baseline through Week 96

Description: Lipid values after starting lipid-reducing agents are excluded from analyses. Baseline values are provided in Baseline Characteristics.

Measure: Mean Percent Changes From Baseline in Fasting Total Cholesterol, High Density Lipoprotein (HDL) Cholesterol, Non-HDL Cholesterol, Low Density Lipoprotein (LDL) Cholesterol, and Triglycerides at Week 48

Time: Baseline, Week 48

Description: Lipid values after starting lipid-reducing agents are excluded from analyses. Baseline values are provided in Baseline Characteristics.

Measure: Mean Percent Changes From Baseline in Fasting Total Cholesterol, High Density Lipoprotein (HDL) Cholesterol, Non-HDL Cholesterol, Low Density Lipoprotein (LDL) Cholesterol, and Triglycerides at Week 96

Time: Baseline, Week 96

Description: International Aids Society of the United States (IAS-USA)-defined major protease inhibitor (PI) substitutions are V32I, L33F, M46I/L, I47V, G48V, I50L/V, I54M/L, I76V, I82A/F/T/S, I84V, N88S, and L90M. Reverse Transcriptase (RT) are TAMS and M184V.

Measure: Number of Participants With Genotype Substitutions for Virologic Rebounds (HIV-RNA ≥ 400 c/mL) Through Week 48

Time: Week 48

Description: International Aids Society of the United States (IAS-USA)-defined major protease inhibitor (PI) substitutions are V32I, L33F, M46I/L, I47V, G48V, I50L/V, I54M/L, I76V, I82A/F/T/S, I84V, N88S, and L90M. Reverse Transcriptase (RT) are TAMS and M184V.

Measure: Number of Participants With Genotype Substitutions for Virologic Rebounds (HIV-RNA ≥ 400 c/mL) Through Week 96

Time: Week 96

14 A Randomized, Blinded, 12-week Comparison of Elvucitabine/Efavirenz/Tenofovir Versus Lamivudine/Efavirenz/Tenofovir in HIV-1 Infected, Treatment Naive Subjects. There is a 36 Week, Open Label, Extension Phase for Eligible Subjects.

Elvucitabine is a novel nucleoside analog that is being studied as a treatment for patients infected with HIV-1. This Phase II study will enroll 60 HIV-1 naive subjects to assess the efficacy and safety of elvucitabine compared to lamivudine in combination with tenofovir and efavirenz measured by changes in the patient's HIV-RNA level and CD4 cell count. The study treatment will be 12 weeks of blinded study medication followed by an additional 84 weeks of open label treatment if the patient's response to treatment meets certain endpoints. Also there will be assessment of the pharmacokinetics of elvucitabine during the study.

NCT00350272 HIV Infections Drug: elvucitabine Drug: Lamivudine Drug: Tenofovir Drug: Efavirenz
MeSH: HIV Infections

2. Are 18 through 65 years old 3. Have documented HIV-1 infection by written prior history and clinically stable with no AIDS-defining events in the 3 months prior to Screening 4. Have plasma HIV-1 RNA levels greater than or equal to 5000 copies/mL at Screening 5. Are HIV-1 strain sensitive to elvucitabine, lamivudine, emtricitabine as demonstrated by the absence of the M184V, M184I, and D237E mutations by TRUGENE HIV-1 Genotyping Kit 6. Are HIV-1 strain genotypically sensitive to efavirenz (negative for K103 and Y188L mutations) and tenofovir (negative for K65R mutation) by TRUGENE HIV-1 Genotyping Kit 7. Have a CD4 count greater than or equal to 200 cells/mL and less than 500 cells/mL 8. Have acceptable hematologic and chemistry parameters, including the following: - Hemoglobin (Hgb) greater than or equal to 11g/dL - Absolute neutrophil count greater than or equal to 2000 cells/mm3 - Platelets greater than or equal to 125 000/mm3 - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 1.5 times the upper limit of normal - Total bilirubin less than or equal to 1.5 times the upper limit of normal - Creatinine within normal range 9. Are capable of understanding and has signed the informed consent document 10. --- M184V ---

Subjects must be sensitive to elvucitabine, lamivudine, and emtricitabine as demonstrated by the absence of the M184V, M184I, and D237E mutations by TRUGENE HIV-1 Genotyping Kit. --- M184V ---

Primary Outcomes

Description: Proportion of subjects having achieved a virologic response for elvucitabine 10 mg/day in combination with efavirenz and tenofovir in HIV-1-infected subjects over 12 weeks compared with the proportion of subjects having achieved a virologic response for lamivudine 300 mg/day in combination with efavirenz and tenofovir. Virologic response was defined as having achieved undetectable (<50 copies/mL) HIV-1 RNA levels from baseline assessment.

Measure: The Proportion of Subjects With Virologic Response for 10 mg/Day Elvucitabine in HIV-1-infected Subjects by 12 Weeks Compared With the Proportion of Subjects With Lamivudine 300 mg/Day.

Time: 12 Weeks

Description: Determination of the safety profile of elvucitabine as defined by the frequency, type and severity of treatment-emergent adverse events and the frequency of Grade 3 and Grade 4 laboratory abnormalities.

Measure: The Safety Profile of Elvucitabine.

Time: 12 Weeks

15 Open-Label, Single-Centre, Randomised Pilot Study to Evaluate Immunovirological and Clinical Evolution of a Combination With Nucleoside Analogues/Nucleotides (Trizivir +Tenofovir) in Multiresistant Patients With Virological Failure

To evaluate whether the combined therapy of two nucleosides plus one nucleotide (Trizivir + TDF) manages to keep CD4 lymphocytes stable in patients with HIV infection on antiretroviral treatment that present virological failure and multiple resistance to antiretrovirals.

NCT00356616 HIV Infections Drug: Trizivir (AZT+3HT+Abacavir) twice daily Drug: Viread (300 mg Tenofovir disoproxil fumarate) once daily
MeSH: HIV Infections

- Existence of the M184V mutation or probable presence in the cellular archives. --- M184V ---

Primary Outcomes

Measure: Variations in the immune status of patients in each group throughout follow-up.

Time: 48 weeks

Secondary Outcomes

Measure: Percentage of patients that increase viral load by > 0.5 log

Time: weeks 12, 24, 36 and 48

Measure: Percentage of patients that increase viral load by > 100,000 copies/mL

Time: weeks 12, 24, 36 and 48

Measure: Percentage of patients that present some clinical event, B or C classification according to the CDC.

Time: during the 48 weeks of follow-up

Measure: Percentage of patients that present clinical or analytical adverse effects degree > 2 according to the WHO classification.

Time: weeks 12, 24, 36 and 48

Measure: Percentage of patients that drop out of treatment.

Time: weeks 12, 24, 36 and 48

Measure: Percentage of patients that drop out of the study due to intolerance or adverse effects.

Time: weeks 12, 24, 36 and 48

Measure: Percentage of change in lipid determinations.

Time: weeks 12, 24, 36 and 48 with regard to baseline

Measure: Percentage of patients that report changes, improvement or worsening in redistribution of body fat.

Time: weeks 12, 24, 36 and 48

Measure: Percentage of patients that present adherence to the antiretroviral treatment > 95%.

Time: weeks 12, 24, 36 and 48

Measure: Percentage of patients that present improvement in the quality of life (MOS-HIV) and satisfaction questionnaires.

Time: weeks 12, 24, 36 and 48

Measure: Percentage of patients that present an increase in the number of active drugs.

Time: at the end of the study

16 GMB: Phase IV, Multicenter, Randomized, Open-Label Pilot Study of Truvada (TDF+FTC) or Emtricitabine (FTC) Alone Versus HAART Interruption in HIV-Infected Patients Who Need to Interrupt HAART and Who Are Infected With HIV Isolates Containing at Least 2 TAMs (or K65R) and M184V

Many patients who already harbor drug-resistant HIV require interruption of HAART due to poor compliance, poor quality of life, toxicity or development of resistance. In these patients interruption of HAART has a negative impact on patient immune status due to the reemergence of wild-type virus which is in general more pathogenic than HIV isolates containing resistance mutations. There is a need for "bridging" antiretroviral regimens that might prolong time off conventional HAART whilst waiting for a new regimen that is either fully suppressive or less toxic or less demanding for the patient.

NCT00362687 HIV Infections Drug: Truvada (TDF+FTC) alone Drug: FTC alone Procedure: No HAART
MeSH: HIV Infections

GMB: Phase IV, Multicenter, Randomized, Open-Label Pilot Study of Truvada (TDF+FTC) or Emtricitabine (FTC) Alone Versus HAART Interruption in HIV-Infected Patients Who Need to Interrupt HAART and Who Are Infected With HIV Isolates Containing at Least 2 TAMs (or K65R) and M184V. --- K65R --- --- M184V ---

- Available genotype (current or historical) showing M184V and (≥ 2 TAMs or K65R). --- M184V ---

Primary Outcomes

Measure: To compare CD4 cell loses 24 weeks after HAART discontinuation

Time: Through 48 weeks

Secondary Outcomes

Measure: Proportion of patients with re-initiation of HAART within 24 and 48 weeks

Time: Through 48 weeks

Measure: To compare CD4 cell loses 48 weeks after HAART discontinuation

Time: Through 48 weeks

Measure: To compare HIV viral loads 4, 24 and 48 weeks after HAART discontinuation:time-weighted average change from baseline through 24 and 48 weeks (DAVG24 and DAVG48) for log10 plasma HIV-1 RNA for patients with plasma HIV-1 RNA >50 copies/mL at baseline

Time: Through 48 weeks

Measure: To compare HIV viral loads 4, 24 and 48 weeks after HAART discontinuation: time-weighted average change from 4 weeks through 24 and 48 weeks (DAVG24 and DAVG48) for log10 plasma HIV-1 RNA for patients with <50 copies/mL at baseline

Time: Through 48 weeks

Measure: To compare HIV viral loads 4, 24 and 48 weeks after HAART discontinuation: proportion of patients with HIV RNA <400 and <50 copies/mL at 4 weeks for subjects with plasma HIV-1 RNA <50 copies/mL at baseline

Time: Through 48 weeks

Measure: To compare HIV viral loads 4, 24 and 48 weeks after HAART discontinuation: compare log10 plasma HIV-1 RNA at week 4 for patients with HIV-RNA < 50 copies/mL at baseline.

Time: Through 48 weeks

Measure: To compare development of new mutations in the reverse transcriptase gene 24 and 48 weeks after HAART discontinuation.

Time: Through 48 weeks

Measure: Proportion of patients with any adverse event.

Time: Through 48 weeks

Measure: Proportion of patients for each adverse event.

Time: Through 48 weeks

Measure: Distribution of the intensity if each adverse event (the greatest intensity for each adverse event within a patient will be considered).

Time: Through 48 weeks

Measure: Distribution of the relationship between the adverse effect and the study drug (the strongest relation with the study drug for each adverse event within each patient will be considered).

Time: Through 48 weeks

Measure: Proportion of patients who discontinue the study prematurely (before week 48)due to adverse events.

Time: Through 48 weeks

Measure: Changes in patient's quality of life analyses.

Time: Through 48 weeks

17 An Open Label Long Term Safety Extension Study of Apricitabine in Treatment-experienced HIV-1 Infected Subjects

The study will examine how safe and effective apricitabine is when given long term (as ongoing treatment) to HIV patients who have already completed the AVX-201 trial

NCT00367952 HIV Infection Drug: apricitabine
MeSH: HIV Infections

Inclusion Criteria: - Completed AVX-201 protocol, Plasma HIV RNA <5000 copies/ml, CD4 cells >50 Exclusion Criteria: - Pregnant or breastfeeding females, withdrawal from AVX-201 Inclusion Criteria: - Completed AVX-201 protocol, Plasma HIV RNA <5000 copies/ml, CD4 cells >50 Exclusion Criteria: - Pregnant or breastfeeding females, withdrawal from AVX-201 HIV Infection HIV Infections An ongoing study (AVX-201) is examining the safety and efficacy of apricitabine compared to 3TC in HIV patients who are failing therapy containing 3TC and have the presence of the M184V mutation in reverse transcriptase. --- M184V ---

Primary Outcomes

Measure: Time to virological failure (DHSS definition)

Time: week 144

Measure: incidence of AEs and laboratory abnormalities

Time: Week 144

Measure: time to withdrawal due to AEs

Time: Week 144

Secondary Outcomes

Measure: Change from baseline HIV RNA

Time: weeks 72, 96, 120, and 144

Measure: Proportion of subjects with plasma HIV RNA <400 and <50 copies/ml

Time: at weeks 72, 96, 120, and 144

Measure: Change from baseline and change in ratio of CD4+ and CD8+ counts

Time: at weeks 72, 96, 120, and 144

18 14-Day Randomized Double-Blind Comparative Viral Kinetic Study of Elvucitabine Versus Lamivudine Once Daily to HIv-1 Subjects With M184V

The purpose of this 28 day study is to assess the viral kinetics and safety of elvucitabine.

NCT00405249 HIV Infections Drug: elvucitabine
MeSH: HIV Infections

14-Day Randomized Double-Blind Comparative Viral Kinetic Study of Elvucitabine Versus Lamivudine Once Daily to HIv-1 Subjects With M184V. --- M184V ---

Inclusion Criteria: - HIV infected, clinically stable, adults - HIVRNA 5000 -150,000, CD4 100 - Genotypically documented M184V variant - Receiving stable ART. --- M184V ---

Exclusion Criteria: - Hep B - HIV-1 genotype for 4 protease inhibitors - HIV-1 genotype positive for 2 NNRTI mutations - Previous therapy with system myelosuppressive potential within 3 months of study start - Use of Epogen or Neupogen - History of cirrhosis - Alcohol or drug dependence - Inability to tolerate oral medication - Women who are pregnant or breast feeding Inclusion Criteria: - HIV infected, clinically stable, adults - HIVRNA 5000 -150,000, CD4 100 - Genotypically documented M184V variant - Receiving stable ART. --- M184V ---

Exclusion Criteria: - Hep B - HIV-1 genotype for 4 protease inhibitors - HIV-1 genotype positive for 2 NNRTI mutations - Previous therapy with system myelosuppressive potential within 3 months of study start - Use of Epogen or Neupogen - History of cirrhosis - Alcohol or drug dependence - Inability to tolerate oral medication - Women who are pregnant or breast feeding HIV Infections HIV Infections This is a 14 day on treat/14 day off treatment randomized, double blind viral kinetic study of elvucitabine versus lamivudine administered once daily to HIV infected subjects with a documented M184V variant. --- M184V ---


19 A Randomized, Placebo-Controlled Study to Evaluate Safety, Tolerance, Pharmacokinetics and Antiviral Activity of Amdoxovir and Zidovudine in Untreated HIV-1 Infected Subjects Currently Untreated

The purpose of this study is to determine the short term safety, tolerance, and antiviral effect of zidovudine (AZT) and amdoxovir (AMDX, DAPD) in combination, and whether the dosage for AZT can be reduced, potentially decreasing side effects, while maintaining antiviral effects. Study hypothesis: DADP in combination with AZT is safe and effective, and AZT dosing may be reduced, resulting in lower levels of AZT-monophosphate associated with toxicity and maintaining levels of AZT-triphosphate associated with efficacy.

NCT00432016 HIV Infections Drug: zidovudine Drug: amdoxovir Procedure: pharmacokinetic sampling
MeSH: HIV Infections

Therefore, second line treatments that are currently in development should provide activity against resultant mutations, primarily M184V/I (17%) and much less commonly K65R (0 to 5%), and ideally prevent or be effective against mutations that may occur during second line therapy. --- M184V ---

DAPD has increased sensitivity to M184V/I strains and is active against thymidine analog mutations (TAMs) that may have occurred during previous antiretroviral regimens. --- M184V ---

Primary Outcomes

Measure: Proportion of subjects in each arm with Grade 3 or greater treatment emergent adverse events (AE)

Measure: Plasma Cmax, Cmin, tmax, AUC0→τ, AUC0→∞, t1/2, CL/F of DAPD and AZT in each group at Days 1 and 10

Measure: Intracellular Cmax, Cmin, tmax, AUC0→τ, AUC0→∞, and t1/2 of DXG-TP, -MP and -DP and AZT-TP, -MP, and -DP at Days 1 and 10

Secondary Outcomes

Measure: Change in viral load (plasma HIV-1 RNA) from Baseline through Day 10

Measure: Correlate intracellular DXG-TP and AZT-TP with viral response, as measured by plasma HIV-1 RNA

Measure: Quantitate DXG, AZT, and GAZT in urine with and without DAPD

Measure: Characterize viral rebound (plasma HIV-1 RNA) following drug discontinuation for 48 hr

Measure: Measure CD4+ count changes from Baseline to Day 10

20 Phase 2 Dose-escalating, P-C, D-B, Parallel Group Study in HIV Treatment-experienced Patients to Evaluate the Safety, Tolerability and Efficacy of PA103001-04 Administered as Functional Monotherapy for 14 Days *(PART B)

The purpose of this study is to evaluate antiretroviral activity of up to five different oral doses administered for two weeks of bevirimat versus placebo in HIV treatment experienced patients, who have documented genotypic resistance to at least one major mutation from the IAS-USA list (2007)of resistance mutations for NRTIs, NNRTIs, or PIs. Patients will also be monitored for side effects, and the pharmacokinetics of bevirimat will be determined.

NCT00511368 HIV Infections Drug: matching placebo Drug: Bevirimat
MeSH: HIV Infections

- Have documented evidence of genotypic resistance in their medical records (at screening) or have resistance at screening by genotype to any major mutation from the IAS-USA list of resistance drug mutations, defined as: NRTI resistance: M41L, K65R, D67N, K70R, K70E, L74V, Y115F, M184V, M184V/I, L210W, T215Y/F, K219Q/E; NNRTI resistance: L100I, K103N, V106M, V106A/M, V108I, Y181C, Y181C/I, Y188L, Y188C/L/H, G190S/A, G190A, P225H; Major PI resistance: D30N, V32I, L33F, M46I/L, I47V/A, G48V, I50L, I50V, I54M/L, L76V, V82A/F/T, V82A/F/T/S, V82L/T, I84V, N88S, L90M - Be receiving an antiretroviral therapy regimen containing at least 3 drugs (regimens containing ritonavir must not exceed a total daily dose of 400 mg) which has been unchanged for at least 8 weeks prior to initial screening. --- M41L --- --- K65R --- --- D67N --- --- K70R --- --- K70E --- --- L74V --- --- Y115F --- --- M184V ---

- Have documented evidence of genotypic resistance in their medical records (at screening) or have resistance at screening by genotype to any major mutation from the IAS-USA list of resistance drug mutations, defined as: NRTI resistance: M41L, K65R, D67N, K70R, K70E, L74V, Y115F, M184V, M184V/I, L210W, T215Y/F, K219Q/E; NNRTI resistance: L100I, K103N, V106M, V106A/M, V108I, Y181C, Y181C/I, Y188L, Y188C/L/H, G190S/A, G190A, P225H; Major PI resistance: D30N, V32I, L33F, M46I/L, I47V/A, G48V, I50L, I50V, I54M/L, L76V, V82A/F/T, V82A/F/T/S, V82L/T, I84V, N88S, L90M - Be receiving an antiretroviral therapy regimen containing at least 3 drugs (regimens containing ritonavir must not exceed a total daily dose of 400 mg) which has been unchanged for at least 8 weeks prior to initial screening. --- M41L --- --- K65R --- --- D67N --- --- K70R --- --- K70E --- --- L74V --- --- Y115F --- --- M184V --- --- M184V ---

Primary Outcomes

Measure: HIV-1 RNA change from baseline over the first 14 days of study

Time: 14 days

Secondary Outcomes

Measure: safety and tolerability; pharmacokinetics

Time: 14 days

21 A Phase II, Randomized Trial of Open-Label Truvada With Darunavir/Ritonavir Versus Multiclass Therapy With Truvada, Darunavir/Ritonavir, Maraviroc and Raltegravir in Acutely HIV-1 Infected Antiretroviral-Naïve Subjects

The researchers are involved in a phase II, randomized, two-arm study, comparing the efficacy, safety, and tolerability of open-label ritonavir (RTV)-enhanced darunavir with Truvada to a 5-drug multi-class regimen including truvada, darunavir/ritonavir/maraviroc/and raltegravir on acutely HIV-1-infected, antiretroviral (ARV) drug-naïve men and women. Subjects will participate for at least 60 weeks and up to 96 weeks if in the opinion of the investigator and patient that continued therapy is in the patient's best interest. Hypotheses: - Multi-class antiretroviral therapy (ART) is superior to RTV-enhanced ATV in combination with Emtricitabine/Tenofovir DF (FTC/TDF) with respect to suppression of viral replication. - Multi-class ART is superior to RTV-enhanced ATV in combination with FTC/TDF with respect to immune reconstitution in peripheral blood and in the gastrointestinal mucosa. - Multi-class ART is equivalent to RTV-enhanced ATV in combination with FTC/TDF with respect to tolerability.

NCT00525733 HIV Infections Drug: darunavir 800 mg Drug: FTC 200 mg/TDF 300mg Drug: Maraviroc Drug: Raltegravir Drug: Ritonavir 100 mg
MeSH: Infection HIV Infections

Major resistance-associated mutations include: NRTI: K65R or inserts Q151M, M184V/I, PI: I50L/V, I84V, N88S. --- K65R --- --- Q151M --- --- M184V ---

Primary Outcomes

Measure: The Primary Outcome of This Study is the Proportion of Patients Having Detectable HIV-1 RNA Using the Single Copy Assay After 48 Weeks of Treatment and the Study Hypothesis is That New Treatment is Better Than the Control Group.

Time: 48 weeks

22 Once-daily Antiretroviral Therapy in HIV-1 Infected Patients With CD4+ Cell Counts Below 100 Cells/Mcl. A Prospective, Randomized, Multicentre, Open Clinical Study.

There are few randomized clinical trials in advanced HIV patients. This is a multicenter, randomized, open clinical trial, comparing three parallel groups, to compare the immunological reconstitution and the virological efficacy and safety of three different combinations of antiretroviral therapy given once a day (QD): tenofovir plus emtricitabine plus either efavirenz, lopinavir-ritonavir or atazanavir-ritonavir during 96 weeks in advanced antiretroviral naïve HIV-1 infected patients with less than 100 CD4+ T-cells/mm3. Primary endpoint is the median increase in CD4+ T-cell count at 48 weeks after starting HAART.

NCT00532168 HIV Infections Drug: tenofovir + emtricitabine + efavirenz Drug: tenofovir + emtricitabine + lopinavir-ritonavir Drug: tenofovir + emtricitabine + atazanavir-ritonavir
MeSH: HIV Infections

- No mutations of drug resistance at baseline (M184V/I, K65R, resistance to efavirenz or 2 or more PRAMs (L33I/F/V, V82A/F/L/T, I84V, L90M) - Written informed consent Exclusion Criteria: - Hypersensibility to study drugs. --- M184V ---

Primary Outcomes

Measure: Median increase in CD4+ T-cell count at 48 weeks after starting the HAART combination randomly assigned

Time: 48 weeks

23 Parallel Comparison of Tenofovir and Emtricitabine/Tenofovir Pre-Exposure Prophylaxis to Prevent HIV-1 Acquisition Within HIV-1 Discordant Couples

Randomized, blinded, placebo-controlled trial to demonstrate if pre-exposure prophylaxis decreases HIV-1 acquisition among HIV-1 uninfected individuals within HIV-1 discordant couples.

NCT00557245 HIV-1 Infections HIV Infections Drug: Tenofovir Disoproxil Fumarate (TDF) Drug: Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) Drug: Placebo
MeSH: Infection Communicable Diseases HIV Infections

HIV-1 resistance as measured by the number of seroconverters who had an HIV-1 reverse transcriptase mutation (K65R, K70E, M184I, or M184V) conferring resistance to TDF or FTC. --- K65R --- --- K70E --- --- M184I --- --- M184V ---

Primary Outcomes

Description: The efficacy of once daily PrEP in preventing HIV-1 acquisition among uninfected heterosexuals in HIV-1 discordant partnerships, measured by calculating the HIV incidence per 100 person-years in each of three arms.

Measure: Incidence of HIV-1 Seroconversion Among HIV-1 Uninfected Participants

Time: Up to 36 months

Description: Safety of daily TDF or FTC/TDF among HIV-1 uninfected individuals randomized to TDF or FTC/TDF compared to those randomized to placebo measured as the number of participants with Serious Adverse Events (SAEs) during follow-up.

Measure: Number of Participants With Serious Adverse Events (SAEs)

Time: Up to 36 months

Secondary Outcomes

Description: Adherence to study medication as assessed by pill count at follow-up visits. We assessed the total number of doses taken of the total dispensed doses.

Measure: Study Drug Adherence: Total Number of Study Drug Doses Taken of the Total Dispensed Doses.

Time: Up to 36 months

Description: Adherence to study drug measured as the percentage of visits when participants reported missing 1) any dose of study drug in the prior month and 2) 2 or more consecutive doses of study drug.

Measure: Study Drug Adherence: Self-reported Missed Doses of Study Drug

Time: Up to 36 months

Description: HIV-1 resistance as measured by the number of seroconverters who had an HIV-1 reverse transcriptase mutation (K65R, K70E, M184I, or M184V) conferring resistance to TDF or FTC. These mutation types were pre-defined. Plasma samples for resistance testing were collected at the visit seroconversion was first detected and again at a visit within 1 month of seroconversion. Mutations detected at either of those visits are reported. Both seroconverters found to have a resistance mutation had been HIV infected at enrollment (TDF arm: n=1; FTC-TDF arm: n=1).

Measure: Number of Seroconverters With an HIV-1 Mutation Conferring Resistance to TDF or FTC

Time: Up to 36 months

Description: Prevalence of STIs measured as the number of participants with a positive test result for N. gonorrhoeae, C. trachomatis, or T. vaginalis during follow-up. Participants were tested for STIs at annual follow-up visits and at intervening visits at which the participant presented with symptoms of an STI. Assessment for symptomatic sexually transmitted infections was conducted quarterly. N. gonorrhoeae and C. trachomatis testing were by APTIMA Combo 2 (Gen-Probe) or COBAS Amplicor (Roche Diagnostics). T. vaginalis testing was by APTIMA TV TMA (Gen-Probe) or In Pouch TV (Biomed Diagnostics).

Measure: Number of Participants With a Sexually Transmitted Infection (STI) During Follow-up

Time: Up to 36 months

Description: Sexual risk behavior of participants, measured as the percentage of visits when participants reported having unprotected sex during follow-up.

Measure: Prevalence of Unprotected Sex During Follow-up

Time: Up to 36 months

Description: Infant outcomes measured as the number of live-born infants born to female participants taking study drug that had any congenital anomalies.

Measure: Congenital Abnormalities Among Infants Born to Female Participants Taking Study Drug.

Time: Up to 36 months

Description: The slope of the linear model of the growth of infants (length) during the entirety of follow-up. The length of the infant was measured as a z-score, in terms of standard deviations from the age and gender specific median using the World Health Organization growth curve, accounting for skewness. The slope, representing the change over time of the z-score, was calculated using all available z-scores over 12 months and regressing against study month.

Measure: Length Among Infants Born to Female Participants Taking Study Drug

Time: up to 12 months

Description: The slope of the linear model of the growth of infants (weight) during the entirety of follow-up. The weight of the infant was measured as a z-score, in terms of standard deviations from the age and gender specific median using the World Health Organization growth curve, accounting for skewness. The slope, representing the change over time of the z-score, was calculated using all available z-scores over 12 months and regressing against study month.

Measure: Weight Among Infants Born to Female Participants Taking Study Drug

Time: up to 12 months

Description: The slope of the linear model of the growth of infants (head circumference) during the entirety of follow-up. The head circumference of the infant was measured as a z-score, in terms of standard deviations from the age and gender specific median using the World Health Organization growth curve, accounting for skewness. The slope, representing the change over time of the z-score, was calculated using all available z-scores over 12 months and regressing against study month.

Measure: Head Circumference Among Infants Born to Female Participants Taking Study Drug

Time: up to 12 months

24 A Phase 2b/3, Randomized, Double Blind, Dose Confirming Study of the Safety, Efficacy and Tolerability of Apricitabine Versus Lamivudine in Treatment-experienced HIV-1 Infected Patients With the M184V/I Mutation in Reverse Transcriptase

Apricitabine is a new NRTI which is active against drug-resistant HIV. NRTIs are often included as part of patients' treatment, but many HIV-infected patients develop resistance to commonly used NRTIs such as lamivudine (3TC) and emtricitabine (FTC). This study will examine whether including apricitabine as part of patients' treatment is more effective than including lamivudine,when patients change treatment because of drug resistance.

NCT00612898 HIV Infections Drug: apricitabine Drug: lamivudine
MeSH: Infection Communicable Diseases HIV Infections Acquired Immunodeficiency Syndrome

A Phase 2b/3, Randomized, Double Blind, Dose Confirming Study of the Safety, Efficacy and Tolerability of Apricitabine Versus Lamivudine in Treatment-experienced HIV-1 Infected Patients With the M184V/I Mutation in Reverse Transcriptase. --- M184V ---

Inclusion Criteria: - HIV-1 positive with M184V/I mutation in reverse transcriptase; - 18 years of age or older; - Currently taking lamivudine (3TC) or emtricitabine (FTC) Exclusion Criteria: - Female patients who are pregnant or breastfeeding; - Current hepatitis B virus (HBV) infection; - Current treatment for hepatitis C virus infection; - Renal function not adequate Inclusion Criteria: - HIV-1 positive with M184V/I mutation in reverse transcriptase; - 18 years of age or older; - Currently taking lamivudine (3TC) or emtricitabine (FTC) Exclusion Criteria: - Female patients who are pregnant or breastfeeding; - Current hepatitis B virus (HBV) infection; - Current treatment for hepatitis C virus infection; - Renal function not adequate HIV Infections Infection Communicable Diseases HIV Infections Acquired Immunodeficiency Syndrome ATC has potent antiviral activity both in vitro (against wild-type HIV-1 and HIV-1 with mutations in reverse transcriptase that confer resistance to NRTIs), and in clinical studies in both treatment-naïve and treatment-experienced patients with M184V, including in the presence of additional NRTI mutations in reverse transcriptase. --- M184V ---

Inclusion Criteria: - HIV-1 positive with M184V/I mutation in reverse transcriptase; - 18 years of age or older; - Currently taking lamivudine (3TC) or emtricitabine (FTC) Exclusion Criteria: - Female patients who are pregnant or breastfeeding; - Current hepatitis B virus (HBV) infection; - Current treatment for hepatitis C virus infection; - Renal function not adequate Inclusion Criteria: - HIV-1 positive with M184V/I mutation in reverse transcriptase; - 18 years of age or older; - Currently taking lamivudine (3TC) or emtricitabine (FTC) Exclusion Criteria: - Female patients who are pregnant or breastfeeding; - Current hepatitis B virus (HBV) infection; - Current treatment for hepatitis C virus infection; - Renal function not adequate HIV Infections Infection Communicable Diseases HIV Infections Acquired Immunodeficiency Syndrome ATC has potent antiviral activity both in vitro (against wild-type HIV-1 and HIV-1 with mutations in reverse transcriptase that confer resistance to NRTIs), and in clinical studies in both treatment-naïve and treatment-experienced patients with M184V, including in the presence of additional NRTI mutations in reverse transcriptase. --- M184V --- --- M184V ---

Inclusion Criteria: - HIV-1 positive with M184V/I mutation in reverse transcriptase; - 18 years of age or older; - Currently taking lamivudine (3TC) or emtricitabine (FTC) Exclusion Criteria: - Female patients who are pregnant or breastfeeding; - Current hepatitis B virus (HBV) infection; - Current treatment for hepatitis C virus infection; - Renal function not adequate Inclusion Criteria: - HIV-1 positive with M184V/I mutation in reverse transcriptase; - 18 years of age or older; - Currently taking lamivudine (3TC) or emtricitabine (FTC) Exclusion Criteria: - Female patients who are pregnant or breastfeeding; - Current hepatitis B virus (HBV) infection; - Current treatment for hepatitis C virus infection; - Renal function not adequate HIV Infections Infection Communicable Diseases HIV Infections Acquired Immunodeficiency Syndrome ATC has potent antiviral activity both in vitro (against wild-type HIV-1 and HIV-1 with mutations in reverse transcriptase that confer resistance to NRTIs), and in clinical studies in both treatment-naïve and treatment-experienced patients with M184V, including in the presence of additional NRTI mutations in reverse transcriptase. --- M184V --- --- M184V --- --- M184V ---

The M184V mutation is most commonly present amongst patients failing regimens containing either of the two deoxycytidine analogs lamivudine and emtricitabine. --- M184V ---

Whilst lamivudine therapy is often maintained in patients harboring the M184V mutation in some settings, there are no deoxycytidine analogs currently available that effectively suppress replication of HIV-1 containing the M184V/I mutation, particularly in the presence of other additional NRTI mutations. --- M184V ---

Whilst lamivudine therapy is often maintained in patients harboring the M184V mutation in some settings, there are no deoxycytidine analogs currently available that effectively suppress replication of HIV-1 containing the M184V/I mutation, particularly in the presence of other additional NRTI mutations. --- M184V --- --- M184V ---

The purpose of this study is to extend the efficacy and safety established in study AVX-201 of ATC in patients who are HIV-1 infected and have failed treatment with lamivudine or emtricitabine and have confirmed M184V/I mutation. --- M184V ---

Primary Outcomes

Measure: Proportion of patients with plasma HIV-1 RNA <50 copies/mL at W24

Time: week 24

Secondary Outcomes

Measure: Time to loss of virological response (TLOVR analysis; FDA algorithm) at W12, W24 and W48 (<50 copies/mL)

Time: week 12, 24, and 48

Measure: Proportion of patients with plasma HIV-1 RNA <50 copies/mL at W48

Time: week 48

25 A Phase 3, Open Label 96-week Extension Study of the Safety of Apricitabine in Treatment-experienced HIV-1 Infected Patients Who Have Completed Protocol AVX-301 or AVX-302 or Who Have Met the Criteria for Open-label Access to ATC Because of Virological Failure/Lack of Response

This study will examine the long term safety of apricitabine in HIV-1 infected patients from studies AVX-301 or AVX-302. Eligible patients are those who have either (a)completed studies AVX-301 or AVX-302; or (b)met the criteria for virological failure/lack of response, and consequently wish to withdraw early from studies AVX-301 or AVX-302.

NCT00686270 HIV Infections Drug: apricitabine
MeSH: Infection HIV Infections

Exclusion Criteria: - Prior withdrawal from AVX-301 or AVX-302 - Current acute or chronic hepatitis B virus infection - Current treatment for hepatitis C virus infection - Renal Function not adequate HIV Infections Infection HIV Infections The clinical study AVX-301 studies the efficacy and safety of 800mg and 1200mg BID ATC in combination with an optimized background in patients who are HIV-1 infected and have failed treatment with emtricitabine or lamivudine and have confirmed M184V/I mutation. --- M184V ---

Primary Outcomes

Measure: The number, type and severity of SAEs occuring during the study

Time: Week 96

26 Phase 2B Safety and Effectiveness Study of Tenofovir 1% Gel, Tenofovir Disproxil Fumarate Tablet and Emtricitabine/Tenofovir Disoproxil Fumarate Tablet for the Prevention of HIV Infection in Women

A new approach to HIV prevention currently being studied includes the use of microbicides, substances that kill microbes. Tenofovir disoproxil fumarate (TDF) and emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) are oral, FDA-approved, anti-HIV drugs, and tenofovir gel is an experimental microbicide. The purpose of this study is to determine the safety and effectiveness of daily tenofovir 1% gel compared to a vaginal placebo gel, and the safety and effectiveness of oral TDF and oral FTC/TDF compared to an oral placebo in preventing HIV infection among women at risk for sexually transmitted infections.

NCT00705679 HIV Infections Drug: Emtricitabine/tenofovir disoproxil fumarate Drug: Emtricitabine/tenofovir disoproxil fumarate placebo Drug: Tenofovir disoproxil fumarate Drug: Tenofovir disoproxil fumarate placebo Drug: Tenofovir 1% vaginal gel Drug: Tenofovir placebo
MeSH: Infection HIV Infections Acquired Immunodeficiency Syndrome

The primary resistance mutations for the study were pre-defined as K65R and K70E (which confer resistance to TDF), and M184I and M184V (which confer resistance to FTC), for their potential to cause a decrease in susceptibility to the study drug. --- K65R --- --- K70E --- --- M184I --- --- M184V ---

The number of HIV-1 seroconverters while on study with the M184V resistance mutation are reported for this outcome measure.. Inclusion Criteria: - Willing to provide adequate locator information - Sexually active, defined as having vaginal intercourse at least once in the 3 months prior to screening - Agree to not participate in other research studies involving drugs, medical devices, or vaginal products for duration of study. --- M184V ---

Primary Outcomes

Description: Participants were followed for up to 30 months. Person-years measures the amount of time for each participant, in years, from the date of enrollment to the date of the first HIV-positive test result if HIV-infected during follow-up or to the date of the last HIV-negative test result on follow-up if not HIV-infected during follow-up.

Measure: Person-years of Follow-up of Tenofovir 1% Gel and Vaginal Placebo Gel Arms

Time: For up to 30 months of follow-up

Description: Participants were followed for up to 30 months. Participants were tested monthly for HIV-1 and positive rapid test results were confirmed by means of an enzyme-linked immunosorbent assay (EIA) and subsequent Western blotting (WB).

Measure: Number of HIV-1 Infections of Tenofovir 1% Gel and Vaginal Placebo Gel Arms

Time: For up to 30 months of follow-up

Description: This is the number of HIV-1 infections divided by the amount of person-years of follow-up time to HIV-1 infection status, multiplied by 100 (per 100 person-years).

Measure: Incidence Rate of HIV-1 Infections of Tenofovir 1% Gel and Vaginal Placebo Gel Arms

Time: For up to 30 months of follow-up

Description: Participants were followed for up to 30 months. Person-years measures the amount of time for each participant, in years, from the date of enrollment to the date of the first HIV-positive test result if HIV-infected during follow-up or to the date of the last HIV-negative test result on follow-up if not HIV-infected during follow-up. Note that the data for both of these arms were censored on the date when sites were asked to discontinue treatment in the oral TDF group.

Measure: Person-years of Follow-up of Oral TDF and Oral Placebo Arms

Time: For up to 30 months of follow-up

Description: Participants were followed for up to 30 months. Participants were tested monthly for HIV-1 and positive rapid test results were confirmed by means of an enzyme-linked immunosorbent assay (EIA) and subsequent Western blotting (WB).

Measure: Number of HIV-1 Infections of Oral TDF and Oral Placebo Arms

Time: For up to 30 months of follow-up

Description: This is the number of HIV-1 infections divided by the amount of person-years of follow-up time to HIV-1 infection status, multiplied by 100 (per 100 person-years).

Measure: Incidence Rate of HIV-1 Infections of Oral TDF and Oral Placebo Arms

Time: For up to 30 months of follow-up

Description: Participants were followed for up to 30 months. Person-years measures the amount of time for each participant, in years, from the date of enrollment to the date of the first HIV-positive test result if HIV-infected during follow-up or to the date of the last HIV-negative test result on follow-up if not HIV-infected during follow-up.

Measure: Person-years of Follow-up of Oral TDF-FTC and Oral Placebo Arms

Time: For up to 30 months of follow-up

Description: Participants were followed for up to 30 months. Participants were tested monthly for HIV-1 and positive rapid test results were confirmed by means of an enzyme-linked immunosorbent assay (EIA) and subsequent Western blotting (WB).

Measure: Number of HIV-1 Infections of Oral TDF-FTC and Oral Placebo Arms

Time: For up to 30 months of follow-up

Description: This is the number of HIV-1 infections divided by the amount of person-years of follow-up time to HIV-1 infection status, multiplied by 100 (per 100 person-years).

Measure: Incidence Rate of HIV-1 Infections of Oral TDF-FTC and Oral Placebo Arms

Time: For up to 30 months of follow-up

Description: This measure describes the number of participants with elevated serum creatinine levels, the only safety outcome of concern where a significant difference was detected between an active arm and the corresponding placebo arm.

Measure: Extended Safety of Daily Tenofovir 1% Gel, Oral TDF, and Oral FTC/TDF in Women at Risk for Sexually Transmitted HIV Infection Based on Occurrence of Grade 2, 3, and 4 Adverse Events

Time: Throughout study, up to 2.5 years

Secondary Outcomes

Description: The primary resistance mutations for the study were pre-defined as K65R and K70E (which confer resistance to TDF), and M184I and M184V (which confer resistance to FTC), for their potential to cause a decrease in susceptibility to the study drug. K65R, K70E, and M184I were not detected in HIV-1 from any HIV-1 seroconverters while on study product. The number of HIV-1 seroconverters while on study with the M184V resistance mutation are reported for this outcome measure.

Measure: Frequency of HIV-1 Drug Resistance in Women Who Acquire HIV-1 Infection While Using Study Product

Time: Throughout study, up to 2.5 years

27 A Multicenter, Randomized, Double-Blind, Double-Dummy, Phase 3 Study of the Safety and Efficacy of Ritonavir-Boosted Elvitegravir (EVG/r) Versus Raltegravir (RAL) Each Administered With a Background Regimen in HIV-1 Infected, Antiretroviral Treatment-Experienced Adults

The purpose of this study is to compare the safety, tolerability and efficacy of a regimen containing once-daily elvitegravir (EVG) versus twice-daily raltegravir (RAL) added to a background regimen (1 fully-active ritonavir (RTV)-boosted protease inhibitor (PI) plus 1 or 2 additional antiretroviral (ARV) agents) in HIV-1 infected, ARV treatment-experienced adults who have documented resistance, or at least six months experience prior to screening with two or more different classes of ARV agents. Participants will be randomized in a 1:1 ratio to receive EVG plus background regimen (Elvitegravir group), or raltegravir plus background regimen (Raltegravir group). Due to known drug interactions, participants in the Elvitegravir group receiving RTV-boosted atazanavir (ATV) or RTV-boosted lopinavir (LPV) as part of their background regimen will receive elvitegravir at a lower dose (85 mg).

NCT00708162 HIV Infection Drug: Elvitegravir Drug: Raltegravir Drug: EVG placebo Drug: RAL placebo Drug: Background regimen
MeSH: HIV Infections

If the M184V/I reverse transcriptase (RT) mutation is present on the screening genotype report and an NRTI is used as the second agent, then either FTC or LAM may be added as a third agent in the background regimen to maintain the M184V/I mutation. --- M184V ---

If the M184V/I reverse transcriptase (RT) mutation is present on the screening genotype report and an NRTI is used as the second agent, then either FTC or LAM may be added as a third agent in the background regimen to maintain the M184V/I mutation. --- M184V --- --- M184V ---

Primary Outcomes

Description: The percentage of participants achieving and maintaining confirmed HIV-1 RNA < 50 copies/mL at Week 48 was analyzed using the FDA-defined Time to Loss of Virologic Response (TLOVR) algorithm, which takes into account a patient's longitudinal viral load up to the predefined time point by considering patterns of suppression and rebounding.

Measure: Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 50 Copies/mL at Week 48

Time: Week 48

Secondary Outcomes

Description: The percentage of participants achieving and maintaining confirmed HIV-1 RNA < 50 copies/mL at Week 96 was analyzed using the FDA-defined TLOVR algorithm, which takes into account a patient's longitudinal viral load up to the predefined time point by considering patterns of suppression and rebounding.

Measure: Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 50 Copies/mL at Week 96

Time: Week 96

Description: The percentage of participants achieving and maintaining confirmed HIV-1 RNA < 400 copies/mL at Week 48 was analyzed using the FDA-defined TLOVR algorithm, which takes into account a patient's longitudinal viral load up to the predefined time point by considering patterns of suppression and rebounding.

Measure: Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 400 Copies/mL at Week 48

Time: Week 48

Description: The percentage of participants achieving and maintaining confirmed HIV-1 RNA < 400 copies/mL at Week 96 was analyzed using the FDA-defined TLOVR algorithm, which takes into account a patient's longitudinal viral load up to the predefined time point by considering patterns of suppression and rebounding.

Measure: Percentage of Participants Achieving and Maintaining Confirmed HIV-1 RNA < 400 Copies/mL at Week 96

Time: Week 96

Description: Virologic response at Week 48 (percentage of participants with HIV-1 RNA < 50 copies/mL) was analyzed using the FDA-defined Snapshot algorithm, which defines a patient's virologic response status using the viral load along with study drug discontinuation status at the predefined time point within an allowed window of time.

Measure: Virologic Response at Week 48 (HIV-1 RNA < 50 Copies/mL)

Time: Week 48

Description: Virologic response at Week 96 (percentage of participants with HIV-1 RNA < 50 copies/mL) was analyzed using the FDA-defined Snapshot algorithm, which defines a patient's virologic response status using the viral load along with study drug discontinuation status at the predefined time point within an allowed window of time.

Measure: Virologic Response at Week 96 (HIV-1 RNA < 50 Copies/mL)

Time: Week 96

Description: The percentage of participants with pure virologic failure (HIV-1 RNA cutoff at 50 copies/mL) up to Week 48 was estimated using the Kaplan-Meier method in the time to event analysis.

Measure: Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 50 Copies/mL) up to Week 48

Time: Baseline to Week 48

Description: The percentage of participants with pure virologic failure (HIV-1 RNA cutoff at 50 copies/mL) up to Week 96 was estimated using the Kaplan-Meier method in the time to event analysis.

Measure: Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 50 Copies/mL) up to Week 96

Time: Baseline to Week 96

Description: The percentage of participants with pure virologic failure (HIV-1 RNA cutoff at 400 copies/mL) up to Week 48 was estimated using the Kaplan-Meier method in the time to event analysis.

Measure: Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 400 Copies/mL) up to Week 48

Time: Baseline to Week 48

Description: The percentage of participants with pure virologic failure (HIV-1 RNA cutoff at 400 copies/mL) up to Week 96 was estimated using the Kaplan-Meier method in the time to event analysis.

Measure: Percentage of Participants With Pure Virologic Failure (HIV-1 RNA Cutoff at 400 Copies/mL) up to Week 96

Time: Baseline to Week 96

Description: The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 48 was analyzed using the missing = failure method, where participants with missing data were considered as having failed to meet the criteria for evaluation.

Measure: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48

Time: Week 48

Description: The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 96 was analyzed using the missing = failure method.

Measure: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 96

Time: Week 96

Description: The percentage of participants with HIV-1 RNA < 400 copies/mL at Week 48 was analyzed using the missing = failure method.

Measure: Percentage of Participants With HIV-1 RNA < 400 Copies/mL at Week 48

Time: Week 48

Description: The percentage of participants with HIV-1 RNA < 400 copies/mL at Week 96 was analyzed using the missing = failure method.

Measure: Percentage of Participants With HIV-1 RNA < 400 Copies/mL at Week 96

Time: Week 96

Description: The change from baseline in log10 HIV-1 RNA (copies/mL) at Week 48 was analyzed.

Measure: Change From Baseline in HIV-1 RNA at Week 48

Time: Baseline to Week 48

Description: The change from baseline in log10 HIV-1 RNA (copies/mL) at Week 96 was analyzed.

Measure: Change From Baseline in HIV-1 RNA at Week 96

Time: Baseline to Week 96

Description: The change from baseline in CD4 cell count (cells/mm^3) at Week 48 was analyzed.

Measure: Change From Baseline in CD4 Cell Count at Week 48

Time: Baseline to Week 48

Description: The change from baseline in CD4 cell count (cells/mm^3) at Week 96 was analyzed.

Measure: Change From Baseline in CD4 Cell Count at Week 96

Time: Baseline to Week 96

28 A Prospective, Randomized, Open Label Phase IV Study to Evaluate the Rationale of Switching From Fixed Dose Abacavir (ABC)/Lamivudine (3TC) to Fixed Dose Tenofovir DF (TDF)/Emtricitabine (FTC) in Virologically Suppressed, HIV-1 Infected Patients Maintained on a Ritonavir Boosted Protease Inhibitor Containing Antiretroviral Regimen

This protocol describes a prospective, randomized, open-label, multicenter study to evaluate the safety and efficacy of switching from fixed dose abacavir (ABC)/lamivudine (3TC) to fixed dose emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) in virologically suppressed, human immunodeficiency virus type 1 (HIV-1) infected subjects maintained on a ritonavir-boosted protease inhibitor (PI/r)-containing antiretroviral (ARV) regimen. Duration of treatment is 48 weeks.

NCT00724711 HIV Infection Drug: emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) Drug: abacavir (ABC)/lamivudine (3TC)
MeSH: HIV Infections

- Adequate renal function defined as a calculated CLcr greater than or equal to 50 mL/min according to the Cockcroft-Gault formula - Negative serum pregnancy test (females of childbearing potential only) - Hepatic transaminases alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 5 X upper limit of normal - Males and females (of childbearing potential, ie, a non-menopausal female or a female with menopause < 2 years, and who has not had a hysterectomy, bilateral oophorectomy, or medically documented ovarian failure; this definition includes a young woman who has not yet started menstruating), and must agree to avoid pregnancy by sexual abstinence, or utilization of a highly effective method of birth control throughout the study period and for 30 days following discontinuation of study drug - The ability to understand and sign a written informed consent form, which must be obtained prior to initiation of any study procedures Exclusion Criteria: - Subjects receiving ABC/3TC and a PI without ritonavir - Subjects receiving other ARV agents (eg, 2 protease inhibitors boosted with low-dose ritonavir (ie, "double-boosted PI regimens"), nonnucleoside reverse transcriptase inhibitors [NNRTIs], integrase inhibitors, TDF, or other nucleoside reverse transcriptase inhibitor [NRTIs]) in addition to ABC/3TC and a ritonavir-boosted protease inhibitor - Have known resistance to any of the study agents at any time in the past including NRTI resistance mutations (including but not limited to K65R, L74V/I, M184V/I, or thymidine analog mutations) and/or PI resistance mutations - A new acquired immunodeficiency syndrome (AIDS) defining condition diagnosed (with the exception of CD4 criteria) within 30 days of baseline - Previous therapy with agents with systemic myelosuppressive, pancreatoxic, hepatotoxic or cytotoxic potential within 3 months of study start or the expected need for such therapy at the time of enrollment - Proven or suspected acute hepatitis in the 30 days prior to study entry - Anticipated need to initiate drugs during the study that are contraindicated with protease inhibitors (except upon approval by Gilead) - Receiving ongoing therapy with any of the following (administration of any of the following medications must be discontinued at least 30 days prior to the Baseline visit and for the duration of the study period): - Nephrotoxic agents (aminoglycoside antibiotics, amphotericin B, cidofovir, cisplatin, foscarnet, intravenous pentamidine, other agents with significant nephrotoxic potential) - Adefovir dipivoxil - Probenecid - Systemic chemotherapeutic agents (ie, cancer treatment medications) - Systemic corticosteroids - Interleukin-2 (IL-2) - Investigational agents (except upon approval by Gilead) - Pregnant or lactating subjects - Evidence of a gastrointestinal malabsorption syndrome or chronic nausea or vomiting which may confer an inability to receive an orally administered medication - Current alcohol or substance abuse judged by the investigator to potentially interfere with subject adherence - Malignancy other than cutaneous Kaposi's sarcoma (KS) or basal cell carcinoma. --- K65R --- --- L74V --- --- M184V ---

Primary Outcomes

Description: The percentage of participants with HIV-1 RNA < 200 copies/mL based on TLOVR algorithm at Week 48 was summarized. Participants were considered nonresponders in the TLOVR analysis if they experienced virologic rebound prior to or at Week 48, discontinued study before Week 48, or added a new antiretroviral (ARV) agent prior to completion of the study. Virologic rebound was defined as 2 consecutive HIV-1 RNA values >= 200 copies/mL or the last HIV-1 RNA value >= 200 copies/mL followed by discontinuation from the study.

Measure: Percentage of Participants With HIV-1 Ribonucleic Acid (RNA) < 200 Copies/mL Through Week 48 Based on Time to Loss of Virologic Response (TLOVR) Algorithm

Time: Baseline to 48 weeks

Secondary Outcomes

Description: The percentage of participants with PVR for HIV-1 RNA cutoff at 200 copies/mL at Week 48 was summarized. Pure virologic response was the percentage of subjects who did not have a virologic rebound. Virologic rebound was defined as two consecutive HIV-1 RNA values >= 200 copies/mL or the last HIV-1 RNA value >= 200 copies/mL followed by discontinuation from the study.

Measure: Percentage of Participants With Pure Virologic Response (PVR) for HIV-1 RNA Cutoff at 200 Copies/mL Through Week 48

Time: Baseline to 48 weeks

Description: The percentage of participants with PVR for HIV-1 RNA cutoff at 50 copies/mL at Week 48 was summarized. Pure virologic response was the proportion of participants who did not have a virologic rebound. Virologic rebound was defined as two consecutive HIV-1 RNA values >= 50 copies/mL or the last HIV-1 RNA value >= 50 copies/mL followed by discontinuation from the study.

Measure: Percentage of Participants With Pure Virologic Response (PVR) for HIV-1 RNA Cutoff at 50 Copies/mL Through Week 48

Time: Baseline to 48 weeks

Description: The percentage of participants with HIV-1 RNA < 200 copies/mL at Week 48 was summarized.

Measure: Percentage of Participants With HIV-1 RNA < 200 Copies/mL at Week 48

Time: 48 weeks

Description: The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 48 was summarized.

Measure: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48

Time: 48 weeks

Description: Change = Week 48 value minus baseline value

Measure: Change From Baseline in Cluster Determinant 4 (CD4) Cell Count at Week 48

Time: Baseline to 48 weeks

Description: Change = Week 48 value minus baseline value

Measure: Change From Baseline Calculated Creatinine Clearance (CLcr) Using Ideal Body Weight by Cockcroft-Gault Method at Week 48

Time: Baseline to 48 weeks

Description: Change = Week 48 value minus baseline value

Measure: Change From Baseline Estimated Glomerular Filtration Rate (eGFR) by Modified Diet in Renal Disease (MDRD) at Week 48

Time: Baseline to 48 weeks

Description: Change = Week 48 value minus baseline value

Measure: Change From Baseline Fasting Glucose at Week 48

Time: Baseline to 48 weeks

Description: Change = Week 48 value minus baseline value

Measure: Change From Baseline Fasting Lipid Parameters at Week 48

Time: Baseline to 48 weeks

Description: Change = Week 48 value minus baseline value

Measure: Change From Baseline Ratio of Fasting Total Cholesterol Over High-density Lipoprotein (HDL) Cholesterol at Week 48

Time: Baseline to 48 weeks

Description: Change = Week 48 value minus baseline value

Measure: Change From Baseline C-Reactive Protein at Week 48

Time: Baseline to 48 weeks

Description: Change = Week 48 value minus baseline value

Measure: Change From Baseline Fibrinogen at Week 48

Time: Baseline to 48 weeks

Description: Change = Week 48 value minus baseline value

Measure: Change From Baseline Interleukin-6 (IL-6), Interleukin-10 (IL-10), and Tumor Necrosis Factor-alpha (TNF-alpha) at Week 48

Time: Baseline to 48 weeks

29 A Multicenter, Open-label, Randomized Study to Assess the Metabolics, Efficacy, and Safety of Once-daily Darunavir Versus Atazanavir in HIV-infected Treatment-naive Adult Patients

The purpose of this research study is to compare changes in triglyceride and other lipids (levels of fats found in the blood) from Baseline (Day 1) to Week 12 for darunavir/ritonavir 800/100 mg once daily versus atazanavir/ritonavir 300/100 mg once daily in combination with a fixed-dose background regimen consisting of emtricitabine [FTC]/tenofovir [TDF] 200/300 mg once daily). This study will also evaluate the safety (adverse events), effectiveness, and tolerability of darunavir/ritonavir and atazanivir/ritonavir over 48 weeks.

NCT00757783 HIV Drug: ritonavir Drug: ritonavir Drug: darunavir Drug: emtricitabine [FTC]/tenofovir [TDF] Drug: emtricitabine [FTC]/tenofovir [TDF] Drug: atazanavir

Number of participants with antiviral activity, HIV-1 RNA, missing values as treatment failure (Missing = Failure) were observed.. Change From Baseline in HIV-1 RNA Viral Load at Week 12 and 48.. the HIV-1 RNA viral load was calculated using Log Base 10 transformed HIV-1 RNA observed values.. Change From Baseline in CD4 Cell Count at Week 12 and 48, Observed Values.. Participants' Cluster of Differentiation (CD) 4 Cell Count were at baseline and the change values at Week 12 and 48 were observed.. Change From Baseline in Cluster of Differentiation (CD) 4 Cell Count at Week 12 and 48, Last Observation Carried Forward (LOCF).. Participants' Cluster of Differentiation (CD) 4 Cell Count were observed at baseline and the change values at Week 12 and 48 was calculated using LOCF.. Change From Baseline in Cluster of Differentiation (CD) 4 Percent at Week 12 and 48, Last Observation Carried Forward (LOCF).. Participants' Cluster of Differentiation (CD) 4 percent were observed at baseline and the change values at Week 12 and 48 was calculated using LOCF.. Inclusion Criteria: - HIV-1 RNA of 1000 copies/mL or more - No previous treatment with antiretroviral drugs for more than 10 days - Demonstrated sensitivity [Fold Change (FC) = lower Clinical Cut Off (CCO)] to tenofovir, darunavir and atazanavir - Demonstrated sensitivity to emtricitabine defined as absence of M184V/I mutation - Any CD4 (Cluster of Differentiation 4) cell count Exclusion Criteria: - Body mass index >30 kg/m2 - Laboratory parameters as follows: fasting glucose >110 mg/dL, Low-Density Lipoprotein (LDL) cholesterol >130 mg/dL, triglycerides >200 mg/dL - Presence of any currently active AIDS-defining illness - Treatment for primary HIV infection or postexposure prophylaxis for HIV - Patients with acute or chronic hepatitis A, B or C infection Inclusion Criteria: - HIV-1 RNA of 1000 copies/mL or more - No previous treatment with antiretroviral drugs for more than 10 days - Demonstrated sensitivity [Fold Change (FC) = lower Clinical Cut Off (CCO)] to tenofovir, darunavir and atazanavir - Demonstrated sensitivity to emtricitabine defined as absence of M184V/I mutation - Any CD4 (Cluster of Differentiation 4) cell count Exclusion Criteria: - Body mass index >30 kg/m2 - Laboratory parameters as follows: fasting glucose >110 mg/dL, Low-Density Lipoprotein (LDL) cholesterol >130 mg/dL, triglycerides >200 mg/dL - Presence of any currently active AIDS-defining illness - Treatment for primary HIV infection or postexposure prophylaxis for HIV - Patients with acute or chronic hepatitis A, B or C infection HIV The purpose of this study is to expand our understanding of the metabolic effects of darunavir/ritonavir (DRV/r) in HIV-infected patients. --- M184V ---

Number of participants with antiviral activity, HIV-1 RNA, missing values as treatment failure (Missing = Failure) were observed.. Change From Baseline in HIV-1 RNA Viral Load at Week 12 and 48.. the HIV-1 RNA viral load was calculated using Log Base 10 transformed HIV-1 RNA observed values.. Change From Baseline in CD4 Cell Count at Week 12 and 48, Observed Values.. Participants' Cluster of Differentiation (CD) 4 Cell Count were at baseline and the change values at Week 12 and 48 were observed.. Change From Baseline in Cluster of Differentiation (CD) 4 Cell Count at Week 12 and 48, Last Observation Carried Forward (LOCF).. Participants' Cluster of Differentiation (CD) 4 Cell Count were observed at baseline and the change values at Week 12 and 48 was calculated using LOCF.. Change From Baseline in Cluster of Differentiation (CD) 4 Percent at Week 12 and 48, Last Observation Carried Forward (LOCF).. Participants' Cluster of Differentiation (CD) 4 percent were observed at baseline and the change values at Week 12 and 48 was calculated using LOCF.. Inclusion Criteria: - HIV-1 RNA of 1000 copies/mL or more - No previous treatment with antiretroviral drugs for more than 10 days - Demonstrated sensitivity [Fold Change (FC) = lower Clinical Cut Off (CCO)] to tenofovir, darunavir and atazanavir - Demonstrated sensitivity to emtricitabine defined as absence of M184V/I mutation - Any CD4 (Cluster of Differentiation 4) cell count Exclusion Criteria: - Body mass index >30 kg/m2 - Laboratory parameters as follows: fasting glucose >110 mg/dL, Low-Density Lipoprotein (LDL) cholesterol >130 mg/dL, triglycerides >200 mg/dL - Presence of any currently active AIDS-defining illness - Treatment for primary HIV infection or postexposure prophylaxis for HIV - Patients with acute or chronic hepatitis A, B or C infection Inclusion Criteria: - HIV-1 RNA of 1000 copies/mL or more - No previous treatment with antiretroviral drugs for more than 10 days - Demonstrated sensitivity [Fold Change (FC) = lower Clinical Cut Off (CCO)] to tenofovir, darunavir and atazanavir - Demonstrated sensitivity to emtricitabine defined as absence of M184V/I mutation - Any CD4 (Cluster of Differentiation 4) cell count Exclusion Criteria: - Body mass index >30 kg/m2 - Laboratory parameters as follows: fasting glucose >110 mg/dL, Low-Density Lipoprotein (LDL) cholesterol >130 mg/dL, triglycerides >200 mg/dL - Presence of any currently active AIDS-defining illness - Treatment for primary HIV infection or postexposure prophylaxis for HIV - Patients with acute or chronic hepatitis A, B or C infection HIV The purpose of this study is to expand our understanding of the metabolic effects of darunavir/ritonavir (DRV/r) in HIV-infected patients. --- M184V --- --- M184V ---

Primary Outcomes

Description: Observed values.

Measure: Change From Baseline in Fasting Triglyceride (TG) Levels in the Lipid Evaluable (LE) Set at Week12

Time: Baseline, Week 12

Secondary Outcomes

Description: Observed Values

Measure: Change From Baseline in Total Cholesterol (TC) Levels in the LE Set at Week 12 and 48

Time: Baseline, Week 12 and 48

Description: Observed Values

Measure: Change From Baseline in Low Density Lipoprotein (LDL) Direct in the LE Set at Week 12 and 48.

Time: Baseline, Week 12 and 48

Description: Observed Values

Measure: Change From Baseline in High Density Lipoprotein (HDL) in the LE Set at Week 12 and 48.

Time: Baseline, Week 12 and 48

Description: Observed Values

Measure: Change From Baseline in Apolipoprotein A1 in the LE Set at Week 12 and 48.

Time: Baseline, Week 12 and 48

Description: Observed Values

Measure: Change From Baseline in Apolipoprotein B in the LE Set at Week 12 and 48.

Time: Baseline, Week 12 and 48

Description: Participants TC and HDL was analyzed at Baseline and Week 12 and 48. Change from Baseline at Week 12 and 48 was calculated as ratio using observed values.

Measure: Change From Baseline in TC/HDL Ratio in the LE Set at Week 12 and 48.

Time: Baseline, Week 12 and 48

Description: Participants glucose level was analyzed at Baseline and Week 12 and 48. Change from Baseline at Week 12 and 48 was reported.

Measure: Change From Baseline in Glucose at Week 12 and 48.

Time: Baseline, Week 12 and 48

Description: Participants insulin was analyzed at Baseline and Week 12 and 48 and change from Baseline at Week 12 and 48 were reported.

Measure: Change From Baseline in Insulin at Week 12 and 48.

Time: Baseline, Week 12 and 48

Description: Participants homeostasis model assessment-insulin resistance (HOMA-IR) were observed and change from Baseline were reported. HOMA-IR score was calculated as: (fasting plasma glucose*fasting serum insulin)/22.5. Low HOMA IR values indicate high insulin sensitivity and high HOMA IR values indicate low insulin sensitivity (insulin resistance).

Measure: Change From Baseline in Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) at Week 12 and 48.

Time: Baseline, Week 12 and 48

Description: Number of Participants with antiviral activity, human immunodeficiency virus Type 1 (HIV-1) RNA less than (<) 50 copies per milliliters (copies/mL) or < 400 copies/mL.

Measure: Antiviral Activity, Human Immunodeficiency Virus Type 1 (HIV-1) RNA.

Time: Week 12 and 48

Description: Number of participants with antiviral activity, HIV-1 RNA, missing values as treatment failure (Missing = Failure) were observed.

Measure: Number of Participants With Antiviral Activity, HIV-1 RNA, Missing Values as Treatment Failure (M=F)

Time: Week 12 and 48

Description: the HIV-1 RNA viral load was calculated using Log Base 10 transformed HIV-1 RNA observed values.

Measure: Change From Baseline in HIV-1 RNA Viral Load at Week 12 and 48.

Time: Baseline, Week 12 and 48

Description: Participants' Cluster of Differentiation (CD) 4 Cell Count were at baseline and the change values at Week 12 and 48 were observed.

Measure: Change From Baseline in CD4 Cell Count at Week 12 and 48, Observed Values.

Time: Baseline, Week 12 and 48

Description: Participants' Cluster of Differentiation (CD) 4 Cell Count were observed at baseline and the change values at Week 12 and 48 was calculated using LOCF.

Measure: Change From Baseline in Cluster of Differentiation (CD) 4 Cell Count at Week 12 and 48, Last Observation Carried Forward (LOCF).

Time: Baseline, Week 12 and 48

Description: Participants' Cluster of Differentiation (CD) 4 percent were observed at baseline and the change values at Week 12 and 48 was calculated using LOCF.

Measure: Change From Baseline in Cluster of Differentiation (CD) 4 Percent at Week 12 and 48, Last Observation Carried Forward (LOCF).

Time: Baseline, Week 12 and 48

30 Antiretroviral Activity and Tolerability of Once Daily Etravirine in Treatment-Naïve Adults With HIV-1 Infection

The main study is a single arm, open-label, prospective study to assess antiretroviral activity and tolerability of etravirine (TMC-125) 400 mg once daily, given with fixed-dose tenofovir/emtricitabine, in treatment-naïve HIV-1-infected men and women. There are also a genital secretions pharmacokinetic (PK) sub-study and a metabolic sub-study. The purpose of the genital secretions PK sub-study is to gain information about drug levels and HIV-1 RNA in genital secretions when subjects are taking etravirine. The purpose of the metabolic sub-study is to learn about the effects of etravirine on body composition, as well as lipid and glucose levels.

NCT00959894 HIV Infections Drug: Etravirine (Intelence) Drug: Truvada
MeSH: Infection Communicable Diseases HIV Infections Acquired Immunodeficiency Syndrome

2. Any of the following NRTI mutations: M184V/I, K70E/R, K65R, M41L, 69 insert, L210W, T215Y/F, K219Q/E, L74V. --- M184V ---

Primary Outcomes

Description: The primary study endpoint was the proportion of participants who achieved HIV-1 RNA <50 copies/ml at Week 24 of study participation. The per-protocol primary analysis was conducted intention-to-treat, with missing evaluations counted as failures. Achievement of HIV-1 viral load below 50 copies/ml was defined as having HIV-1 RNA <50 copies/ml during the Week 24 analysis window (>18 and <30 weeks post-entry).

Measure: The Antiretroviral Activity of Etravirine 400 mg Given Once Daily, With Fixed-dose Truvada Once Daily, Among Treatment-naïve HIV-1 Infected Adults as Measured by the Percentage of Participants With HIV RNA < 50 Copies/mL at Week 24

Time: 24 weeks

Secondary Outcomes

Description: This secondary outcome assessed the proportion of participants who achieved HIV-1 RNA <50 copies/ml at Week 48 of study treatment. The per-protocol analysis was conducted intention-to-treat, with missing evaluations counted as failures.

Measure: The Proportion of Participants With HIV RNA <50 Copies/mL at Week 48 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine

Time: 48 weeks

Description: This secondary outcome assessed the proportion of participants who achieved HIV-1 RNA <50 copies/ml at Week 96 of study treatment. The per-protocol analysis was conducted intention-to-treat, with missing evaluations counted as failures.

Measure: The Proportion of Participants With HIV RNA <50 Copies/mL at Week 96 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine

Time: 96 weeks

Description: This secondary outcome assessed the proportion of participants who achieved HIV-1 RNA <200 copies/ml at Week 24 of study treatment. The per-protocol analysis was conducted intention-to-treat, with missing evaluations counted as failures.

Measure: The Proportion of Participants With HIV RNA <200 Copies/mL at Week 24 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine

Time: 24 weeks

Description: This secondary outcome assessed the proportion of participants who achieved HIV-1 RNA <200 copies/ml at Week 48 of study treatment. The per-protocol analysis was conducted intention-to-treat, with missing evaluations counted as failures.

Measure: The Proportion of Participants With HIV RNA <200 Copies/mL at Week 48 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine

Time: 48 weeks

Description: This secondary outcome assessed the proportion of participants who achieved HIV-1 RNA 200 copies/ml at Week 96 of study treatment. The per-protocol analysis was conducted intention-to-treat, with missing evaluations counted as failures.

Measure: The Proportion of Participants With HIV RNA <200 Copies/mL at Week 96 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine

Time: 96 weeks

Description: The per-protocol analysis of change in CD4+ cell count from baseline to Week 24 was calculated using the measurement closest to schedule and within the analysis window, and quantified with an estimated median and distribution-free 95% confidence interval (CI).

Measure: Change in CD4+ Cell Count From Baseline to Week 24 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine

Time: Baseline to 24 weeks

Description: The per-protocol intention-to-treat analysis of change in CD4+ cell count from baseline to Week 48 was calculated using the measurement closest to schedule and within the analysis window, and quantified with an estimated median and distribution-free 95% CI.

Measure: Change in CD4+ Cell Count From Baseline to Week 48 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine

Time: Baseline to 48 weeks

Description: The per-protocol intention-to-treat analysis of change in CD4+ cell count from baseline to Week 96 was calculated using the measurement closest to schedule and within the analysis window, and quantified with an estimated median and distribution-free 95% CI.

Measure: Change in CD4+ Cell Count From Baseline to Week 96 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine

Time: Baseline to 96 weeks

Description: Per-protocol, genotype testing was conducted at confirmation of virologic failure if the confirmatory HIV-1 RNA was above the laboratory-specified threshold of 500 copies/mL. HIV-1 genotype was determined using the TRUGENE® HIV-1 assay (Siemens Healthcare Diagnostics, Tarrytown, NY)

Measure: Resistance Mutations in the Subset of Patients With Confirmed Virologic Failure Who Have HIV RNA >500 Copies/mL and Genotype Resistance Results

Time: 96 weeks

Description: The safety/tolerability endpoint was defined as the first grade 3 or higher sign, symptom or laboratory abnormality that was at least one grade higher than baseline among participants ever exposed to etravirine (regardless of treatment status), or permanent discontinuation of etravirine due to any toxicity (regardless of grade). Modification of tenofovir/emtricitabine was not a safety/tolerability event. The Kaplan-Meier method was used to estimate the proportion of participants ever exposed to etravirine who remained event-free through Week 96, with a 95% CI using Greenwood's variance estimate and a log-log transformation. Time was handled as continuous (weeks from treatment start to event or censoring).

Measure: Tolerability of Etravirine in HIV-1 Infected Adults Initiating Antiretroviral Therapy

Time: 96 weeks

Description: The Kaplan-Meier method was used to estimate the proportion of participants ever exposed to etravirine who remained event-free through Week 96, with a 95% CI using Greenwood's variance estimate and a log-log transformation. Time was handled as continuous (weeks from treatment start to event or censoring).

Measure: Probability of Remaining Free of a Safety/Tolerability Event at 96 Weeks

Time: 96 weeks

Description: Metabolic data analyses were conducted as-treated. Changes in total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and fasting blood glucose from baseline to follow-up were calculated using the value closest to schedule and within the analysis window, and were quantified with the median and inter-quartile range.

Measure: Change in the Lipid Profile and Glucose Metabolism, in a Subgroup of up to 40 Participants, From Baseline to Week 24 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine

Time: Baseline to 24 weeks

Description: Metabolic data analyses were conducted as-treated. Insulin resistance was estimated by the homeostasis model assessment of insulin resistance (HOMA-IR), and was calculated as [fasting insulin (µU/mL) × fasting glucose (mmol/L)]/22.5. Changes from baseline to follow-up were calculated using the value closest to schedule and within the analysis window, and were quantified with the median and inter-quartile range.

Measure: Change in Glucose Metabolism (Insulin Resistance), in a Subgroup of up to 40 Participants, From Baseline to Week 24 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine

Time: Baseline to 24 weeks

Description: Metabolic data analyses were conducted as-treated. Changes in total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and fasting blood glucose from baseline to follow-up were calculated using the value closest to schedule and within the analysis window, and were quantified with the median and inter-quartile range.

Measure: Change in the Lipid Profile and Glucose Metabolism, in a Subgroup of up to 40 Participants, From Baseline to Week 48 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine

Time: Baseline to 48 weeks

Description: Metabolic data analyses were conducted as-treated. Insulin resistance was estimated by the homeostasis model assessment of insulin resistance (HOMA-IR), and was calculated as [fasting insulin (µU/mL) × fasting glucose (mmol/L)]/22.5. Changes from baseline to follow-up were calculated using the value closest to schedule and within the analysis window, and were quantified with the median and inter-quartile range.

Measure: Change in Glucose Metabolism (Insulin Resistance), in a Subgroup of up to 40 Participants, From Baseline to Week 48 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine

Time: Baseline to 48 weeks

Description: Metabolic data analyses were conducted as-treated. Changes in total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and fasting blood glucose from baseline to follow-up were calculated using the value closest to schedule and within the analysis window, and were quantified with the median and inter-quartile range. Insulin resistance was estimated by the homeostasis model assessment of insulin resistance (HOMA-IR), and was calculated as [fasting insulin (µU/mL) × fasting glucose (mmol/L)]/22.5.

Measure: Change in the Lipid Profile and Glucose Metabolism, in a Subgroup of up to 40 Participants, From Baseline to Week 96 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine

Time: Baseline to 96 weeks

Description: Metabolic data analyses were conducted as-treated. Insulin resistance was estimated by the homeostasis model assessment of insulin resistance (HOMA-IR), and was calculated as [fasting insulin (µU/mL) × fasting glucose (mmol/L)]/22.5. Changes from baseline to follow-up were calculated using the value closest to schedule and within the analysis window, and were quantified with the median and inter-quartile range.

Measure: Change in Glucose Metabolism (Insulin Resistance), in a Subgroup of up to 40 Participants, From Baseline to Week 96 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine

Time: Baseline to 96 weeks

Description: Changes from baseline to follow-up in limb fat, trunk fat, total body fat, and lean mass were calculated. Whole body Dual X-ray Absorptiometry (DEXA) scans (Hologic Discovery W, Hologic Inc., Bedford, MA) were conducted at baseline, Week 24, and Week 96 to assess body fat distribution. Calculations of change from baseline to follow-up used the value closest to schedule and within the analysis window, and were quantified with the estimated median and distribution-free 95% CI.

Measure: Change in Limb and Trunk Fat Distribution as Measured by DEXA Scan, in the Same Subgroup of up to 40 Participants (as in Aim 8), From Baseline to Week 24 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine

Time: Baseline to 24 weeks

Description: Changes from baseline to follow-up in limb fat, trunk fat, total body fat, and lean mass were calculated. Whole body Dual X-ray Absorptiometry (DEXA) scans (Hologic Discovery W, Hologic Inc., Bedford, MA) were conducted at baseline, Week 24, and Week 96 to assess body fat distribution. Calculations of change from baseline to follow-up used the value closest to schedule and within the analysis window, and were quantified with the estimated median and distribution-free 95% CI.

Measure: Change in Limb and Trunk Fat Distribution as Measured by DEXA Scan, in the Same Subgroup of up to 40 Participants (as in Aim 8), From Baseline to Week 96 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine

Time: Baseline to 96 weeks

Description: Change from baseline to follow-up in fat mass ratio was calculated. Whole body Dual X-ray Absorptiometry (DEXA) scans (Hologic Discovery W, Hologic Inc., Bedford, MA) were conducted at baseline, Week 24, and Week 96 to assess body fat distribution. Fat mass ratio was calculated as the ratio of trunk fat percentage and lower limb fat percentage (% trunk fat mass / % lower limb fat mass). Calculations of change from baseline to follow-up used the value closest to schedule and within the analysis window, and were quantified with the estimated median and distribution-free 95% CI.

Measure: Change in Fat Mass Ratio as Measured by DEXA Scan, in the Same Subgroup of up to 40 Participants (as in Aim 8), From Baseline to Week 24 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine

Time: Baseline to 24 weeks

Description: This secondary outcome measure assessed the ratio of semen:plasma concentration of etravirine in paired semen and plasma samples collected from 14 male participants at Week 4 of treatment with etravirine and fixed dose tenofovir/emtricitabine.

Measure: Pharmacokinetics of Etravirine in Genital Secretions of up to 10 Men and up to 10 Women at Week 4 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine

Time: 4 weeks

Description: Change from baseline to follow-up in fat mass ratio was calculated. Whole body Dual X-ray Absorptiometry (DEXA) scans (Hologic Discovery W, Hologic Inc., Bedford, MA) were conducted at baseline, Week 24, and Week 96 to assess body fat distribution. Fat mass ratio was calculated as the ratio of trunk fat percentage and lower limb fat percentage (% trunk fat mass / % lower limb fat mass). Calculations of change from baseline to follow-up used the value closest to schedule and within the analysis window, and were quantified with the estimated median and distribution-free 95% CI.

Measure: Change in Fat Mass Ratio as Measured by DEXA Scan, in the Same Subgroup of up to 40 Participants (as in Aim 8), From Baseline to Week 96 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine

Time: Baseline to 96 weeks

Description: Population pharmacokinetics were calculated using sparse sampling. Plasma concentrations of etravirine measured in samples from participants who provided blood samples at multiple study visits, with variation in sampling times relative to dosing of etravirine used to cover the spectrum of the dosing schedule. Model simulations and fitting were performed with NONMEM ® 7.3. (ICON, plc) and model exploration was performed with Berkeley Madonna (Berkeley, CA, USA)

Measure: Population Pharmacokinetics of Etravirine 400 mg Once Daily, in Combination With Fixed-dose Emtricitabine-tenofovir Among Treatment-naïve HIV-1 Infected Adults

Time: At or after 4 weeks

Description: Population pharmacokinetics were calculated using sparse sampling. Plasma concentrations of etravirine measured in samples from participants who provided blood samples at multiple study visits, with variation in sampling times relative to dosing of etravirine used to cover the spectrum of the dosing schedule. Model simulations and fitting were performed with NONMEM ® 7.3. (ICON, plc) and model exploration was performed with Berkeley Madonna (Berkeley, CA, USA)

Measure: Population Pharmacokinetics of Etravirine 400 mg Once Daily, in Combination With Fixed-dose Emtricitabine-tenofovir Among Treatment-naïve HIV-1 Infected Adults: Etravirine AUC-24 Hours at Steady State

Time: At or after 4 weeks

31 Open Label, Randomized Trial of TDF/FTC+Raltegravir Vs. TDF/FTC+Efavirenz in HIV-1-Infected Women: Differential Effects on Viral Suppression/Reservoir, & Immune Parameters in Different Compartments, Including Gut & Genital Tract

Raltegravir not only has a unique mechanism of action, but may also have other unique effects on suppression of viral replication, viral reservoir, and immune reconstitution in blood and other important compartments. This may in part be due to the pharmacokinetics of Raltegravir in blood and gut tissue. Efavirenz will be the comparator antiretroviral drug in this study, with both drugs being used as part of a three-drug regimen with tenofovir and emtricitabine. The primary objectives are to determine differences in the effects of 2 anti-retroviral regimens, Raltegravir + Truvada versus Atripla, with respect to: 1. Viral load in plasma, genital tract (vaginal secretions), and gut (by in situ hybridization). 2. Latent viral reservoir (pro-viral DNA) in the peripheral blood and genital tract. 3. Immune effects (CD4/CD8 immunophenotypes) in gut and PBMCs and plasma cytokine profiles. The secondary objective is to determine the pharmacokinetics of Raltegravir in blood and gut tissue; relative tissue/compartment penetration compared to Efavirenz.

NCT00984152 HIV-1 Infections Drug: TDF/FTC Once-Daily + Raltegravir 400 mg Orally Twice-Daily Drug: TDF/FTC + Efavirenz (Atripla) Once-Daily

Exclusion Criteria: 1. Menopausal (may affect quantity of genital tract secretions) or any serious illness that requires treatment and/or hospitalization until the patient completes therapy 2. Any active infection, including co-infection with hepatitis B or C 3. Any neoplasm 4. Immunosuppressive therapy 5. Requirement for any medications that are prohibited by any of the study treatments 6. Significant liver or renal dysfunction 7. Baseline resistance to any of the study drugs by genotypic testing - NRTI: M41L, K65 R, D76N, T69D, K70R, L74V/I, y115F, Q151M, M184V, L210W, T215any, K219Q/E - NNRTI:L100I, K103N, V106A/M, V108I, Y181C/I, Y188C/L/H, G190anyA/S 8. Alcohol or substance abuse problems or psychiatric conditions that impair the ability of the subject to comply with the study protocol Inclusion Criteria: 1. Eligible subjects will be antiretroviral naïve (< 7 days of HAART at any time prior to entry) with plasma HIV-1 RNA > 50,000 copies/mL (obtained within 90 days prior to study entry by any laboratory that has a CLIA certification or its equivalent) and moderate immune suppression within 90 days prior to study entry. --- M41L --- --- D76N --- --- T69D --- --- K70R --- --- L74V --- --- Q151M --- --- M184V ---

Exclusion Criteria: 1. Menopausal (may affect quantity of genital tract secretions) or any serious illness that requires treatment and/or hospitalization until the patient completes therapy 2. Any active infection, including co-infection with hepatitis B or C 3. Any neoplasm 4. Immunosuppressive therapy 5. Requirement for any medications that are prohibited by any of the study treatments 6. Significant liver or renal dysfunction 7. Baseline resistance to any of the study drugs by genotypic testing - NRTI: M41L, K65 R, D76N, T69D, K70R, L74V/I, y115F, Q151M, M184V, L210W, T215any, K219Q/E - NNRTI:L100I, K103N, V106A/M, V108I, Y181C/I, Y188C/L/H, G190anyA/S 8. Alcohol or substance abuse problems or psychiatric conditions that impair the ability of the subject to comply with the study protocol HIV-1 Infections This is a phase III, prospective, randomized (1:1), multicenter, open label study comparing the effects of two HAART regimens: - Arm A: Raltegravir 400 mg PO BID + TDF/FTC (Truvada, 300/200 mg) One PO Daily - Arm B: Efavirenz + TDF/FTC (Atripla) Once PO Daily The following local sites: Mt. --- M41L --- --- D76N --- --- T69D --- --- K70R --- --- L74V --- --- Q151M --- --- M184V ---

Primary Outcomes

Measure: Viral load in plasma, genital tract (vaginal secretions), and gut (by in situ hybridization)

Time: 48 weeks

Measure: Latent viral reservoir (pro-viral DNA) in the peripheral blood and genital tract

Time: 48 weeks

Measure: Immune effects (CD4/CD8 immunophenotypes) in gut and PBMCs and plasma cytokine profiles

Time: 48 weeks

Secondary Outcomes

Measure: Determine the pharmacokinetics of Raltegravir in blood and gut tissue; relative tissue/compartment penetration compared to Efavirenz

Time: 48 weeks

32 Artery Elasticity After Switch From Epzicom to Truvada

Recent research as suggested that use of the HIV medication abacavir (Ziagen, or co-formulated with lamivudine as Epzicom) may increase risk for heart disease, though findings from multiple studies have been inconsistent. This pilot study will examine vascular function, a marker of heart disease risk, among patients taking abacavir as part of their HIV medications and are then randomized to: 1) switch to tenofovir, another HIV medication, or 2) continue to take abacavir.

NCT00998582 HIV Infections Drug: Tenofovir disoproxil
MeSH: HIV Infections

- Males and females (of childbearing potential) must agree to avoid pregnancy by sexual abstinence, or utilization of a highly effective method of birth control throughout the study period and for 30 days following discontinuation of study drug (refer to Appendix A for definitions of 'childbearing potential' and 'highly effective method of birth control') Exclusion Criteria: - Subjects with known resistance to abacavir, lamivudine, tenofovir DF, or emtricitabine at anytime in the past (including but not limited to K65R, L74V/I, M184V/I, or thymidine analog mutations). --- K65R --- --- L74V --- --- M184V ---

Primary Outcomes

Description: Small artery elasticity is a measure of vascular function, estimated through analysis of the blood pressure waveform. A sensor is placed on wrist over the radial pulse. The blood pressure waveform of the pulse is recorded and analyzed the elasticity, or compliance, of the small (and large) vasculature. Impaired artery elasticity, or increased stiffness, is an early sign of vascular disease that predicts risk for future cardiovascular events.

Measure: Change in Small Artery Elasticity (mL/mmHg x100) From Baseline to Week 24

Time: Change from baseline to 24 weeks

Description: Large artery elasticity is a measure of vascular function, estimated through analysis of the blood pressure waveform. A sensor is placed on wrist over the radial pulse. The blood pressure waveform of the pulse is recorded and analyzed the elasticity, or compliance, of the large (and small) vasculature. Impaired artery elasticity, or increased stiffness, is an early sign of vascular disease.

Measure: Outcome Was Change in Large Artery Elasticity (mL/mmHg x100) From Baseline to Week 24

Time: Change from baseline to 24 weeks

33 Treatment Outcomes and Plasma Level of Ritonavir-boosted Lopinavir Monotherapy Among HIV-infected Patients Who Had Non-nucleoside Reverse Transcriptase Inhibitor (NRTI) and NNRTI Failure: A Pilot Study

To assess 48-week treatment responses, tolerability, and steady-state minimum plasma concentrations of ritonavir-boosted lopinavir monotherapy for salvage therapy in HIV-1 infected patients who failed antiretroviral regimens containing NRTI and NNRTI.

NCT01002898 HIV Drug: lopinavir/ritonavir soft gel capsule

Inclusion Criteria: 1. HIV-1 infected patients >18 years of age, 2. failed NNRTI-based antiretroviral therapy with M184V, thymidine analogue mutations (TAMs) and NNRTI-associated mutations 3. had plasma HIV-1 RNA >1,000 copies/mL. --- M184V ---

On the other hand, previous studies showed that continuation of lamivudine after emerging of the M184V mutation had somewhat benefit on immunological response and clinical progression in patients who had limited options of salvage regimens. --- M184V ---

Primary Outcomes

Measure: To assess 48-week treatment responses of ritonavir-boosted lopinavir (LPV/r) monotherapy as salvage regimen.

Time: 48 weeks

34 A Phase 3, Randomized, Open Label, Controlled Study of Lopinavir/Ritonavir and Lamivudine Versus Standard Therapy in Naïve HIV-1 Infected Subjects.

The purpose of this study is designed to compare the safety, tolerability, antiviral activity and immunological effect of lopinavir/ritonavir plus lamivudine (3TC) versus standard therapy with 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) plus lopinavir/ritonavir in the treatment of naïve HIV-1 infected subjects.

NCT01237444 HIV Infection Drug: lopinavir/ritonavir plus one nucleoside Drug: lopinavir /ritonavir plus two nucleosides
MeSH: HIV Infections

2. The presence of any of the following major mutations: V32I; I47V / A; L76V; V82A/F/T/S or the presence of two or more minor mutations at positions:10,20,24,33,46,50,53,54,63,71,73,84,90 is considered resistance to lopinavir/ritonavir. 3. The presence of mutation M184V/I and/or K65R is considered resistance to 3TC or FTC. --- V32I --- --- I47V --- --- L76V --- --- V82A --- --- M184V ---

Primary Outcomes

Measure: • Proportion of patients with HIV-1 RNA levels of less than 50 copies/mL in an intent-to-treat analysis at week 48

Time: 48 and 96 weeks

Secondary Outcomes

Description: Proportion of patients with HIV-1 RNA levels of less than 50 copies/mL at week 24. Number and type of resistance mutations in case of virologic failure• CD4+ lymphocyte count and proportion evolution between baseline and week 24 and 48. Comparison of lipid profiles after 48 weeks Changes in quality of life, assessed by a validated questionnaire Treatment survival and interruptions. Frequency, type and severity of adverse events. Frequency of opportunistic infections (OI) and disease progression.

Measure: • Proportion of patients with HIV-1 RNA levels of less than 400 copies/mL at week 24 and at week 48

Time: 48 weeks

35 Evaluation of 3TC or FTC Mono-therapy Compared to Continuing HAART as a Bridging Antiretroviral Strategy in Persistently Non-adherent Children, Adolescents, and Young Adults Who Are Failing HAART and Have the M184V Resistance Mutation.

The purpose of this study was to compare the use of lamivudine (3TC) or emtricitabine (FTC) alone vs. continuing a failing highly active antiretroviral therapy (HAART) regimen in HIV infected children, adolescents and young adults. The study was to see if there were changes in the HIV virus and if there were differences in immune function, viral load and medication side effects between the two groups over 28 weeks. Participants were assigned to either take 3TC or FTC alone or continue on his/her current failing HAART regimen. During the first 28 weeks of this study, if the participant was randomized to the continue HAART arm, he/she was not switched to a different or new, potentially suppressive HAART regimen, but continued on the current failing HAART regimen. However, if continuing HAART, the participant might be switched to a new regimen if their provider felt that it was clinically needed or the participant met certain study endpoints (e.g., drop in CD4, increase in viral load). At the end of 28 weeks, the participant had the choice of remaining on the assigned study group medication(s) or starting a new HAART regimen prescribed by his/her doctor. Then, they would be followed for another 24 weeks to compare the difference in immune function, viral load and medication side effects between the different groups.

NCT01338025 HIV Disease Drug: HAART regimen Drug: 3TC or FTC monotherapy
MeSH: Acquired Immunodeficiency Syndrome HIV Infections

Evaluation of 3TC or FTC Mono-therapy Compared to Continuing HAART as a Bridging Antiretroviral Strategy in Persistently Non-adherent Children, Adolescents, and Young Adults Who Are Failing HAART and Have the M184V Resistance Mutation.. Evaluation of 3TC or FTC Mono-therapy Compared to Continuing HAART as a Bridging Strategy The purpose of this study was to compare the use of lamivudine (3TC) or emtricitabine (FTC) alone vs. continuing a failing highly active antiretroviral therapy (HAART) regimen in HIV infected children, adolescents and young adults. --- M184V ---

- CD4+ T cell count greater than or equal to 100 cells/mm3 (confirmed on at least two occasions within 6 months of study entry, including the screening value) - Documentation of the M184V mutation on genotypic testing at any time prior to study entry - In the best judgment of the clinical site team, concerns about the subject's ability to adhere made it unsuitable to initiate a new optimal HAART regimen for at least 6 months. --- M184V ---

Primary Outcomes

Description: Immunologic deterioration was declared for a participant if any one of the following conditions is observed within the first 28 weeks: greater than or equal to 30% decline in absolute CD4+ T cell count from entry, or development of CDC class C events. Results report number of participants with immunologic deterioration at week 28 calculated.

Measure: Number of Participants With Immunologic Deterioration

Time: From entry to week 28

Secondary Outcomes

Description: Change in CD4+ T cell count from entry to Week 28 (CD4+ at entry - CD4+ at Week 28).

Measure: Change in CD4+ T Cell Count

Time: Entry to week 28

Description: Change in HIV-1 RNA levels from Entry to Week 28

Measure: Change in HIV-1 RNA Levels

Time: 28 Weeks

Description: Number of participants reporting a missed medication dose in the past 3 days.

Measure: Number of Participants Non-adherent as Measured by 3-day Recall

Time: 28 Weeks

36 Multicenter Study of Options for Second-Line Effective Combination Therapy (SELECT)

The study was conducted on people who were taking their first anti-HIV drug regimen (including an Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI), a type of anti-HIV drug) but the drugs in this regimen were not doing a good job of fighting their HIV infection. The main purpose of this study was to compare two other anti-HIV drug regimens to see how well they fight HIV. The study also looked at how well participants tolerate the drug regimens and how safe they are. The study was designed to determine whether taking the combination of lopinavir/ritonavir (LPV/r) plus raltegravir (RAL) works as well as what is usually used for second-line therapy: LPV/r plus the best-available nucleoside (nucleotide) reverse transcriptase inhibitor (NRTI) combination. Testing a regimen that does not include any NRTIs was important because NRTIs may no longer work for patients who received them as part of their first treatment regimen.

NCT01352715 HIV-1 Infection Drug: Lopinavir/ritonavir Drug: Lopinavir/ritonavir Drug: Raltegravir Drug: Emtricitabine/tenofovir disoproxil fumarate Drug: Abacavir/lamivudine/zidovudine Drug: Abacavir/lamivudine Drug: Lamivudine/zidovudine Drug: Abacavir Drug: Zidovudine Drug: Lamivudine

The most significant of these mutations include M184V, thymidine analogue mutations (TAMs), Q151M complex, and K65R. --- M184V ---

Recent data suggest that patients with isolated M184V-related NRTI resistance who subsequently switch to a boosted PI plus lamivudine (3TC)- or emtricitabine (FTC)-based regimen may achieve HIV-1 RNA suppression without the need to switch to more complex regimens [1]. --- M184V ---

Detection of an isolated M184V NRTI mutation is possible when resources allow for early diagnosis of virologic failure. --- M184V ---

Primary Outcomes

Description: The primary endpoint was time to virologic failure. Virologic failure was defined as confirmed viral load >400 copies/mL at or after week 24. The Kaplan-Meier estimate of the cumulative probability of virologic failure by week 48 was used.

Measure: Cumulative Probability of Virologic Failure by Week 48

Time: From study entry to week 48

Secondary Outcomes

Description: Change in CD4+ cell count was calculated as CD4+ cell count at week 48 minus CD4+ cell count at study entry.

Measure: Change in CD4+ Cell Count From Baseline to Week 48

Time: Study entry and week 48

Description: Mutations were defined as major IAS mutations in the IAS-USA July 2014 list. New mutations were those detected at virologic failure but not at baseline.

Measure: Number of Participants With HIV-1 Drug Resistance Mutations in Protease, Reverse Transcriptase, and Integrase in Participants With Virologic Failure at Baseline and at Time of Virologic Failure

Time: From study entry through to week 96

Description: The DAIDS Adverse Event (AE) Grading Table, Version 1.0, December 2004 (Clarification, August 2009) was used for grading of AEs.

Measure: Number of Participants With Grade 3 or Higher Adverse Event (AE) at Least One Grade Higher Than Baseline

Time: From start of randomized treatment to off randomized treatment (up to 96 weeks)

Description: Discontinuation of randomized treatment for toxicity included participant decision to discontinue for low grade toxicity. Within class NRTI changes were not considered discontinuations.

Measure: Number of Participants Discontinuing Randomized Treatment for Toxicity

Time: From Start of Randomized Treatment to Off Randomized Treatment (up to 96 weeks)

Description: AIDS-defining events were those recognized by the Centers for Disease Control (CDC) and World Health Organization (WHO)

Measure: Number of Participants With a New AIDS-defining Events or Death

Time: From study entry throughout follow-up (up to 96 weeks)

Description: Serious non-AIDS diagnoses were based on ACTG Appendix 60 Diagnosis Codes

Measure: Number of Participants With a Targeted Serious Non-AIDS-defining Event or Death

Time: From study entry throughout follow-up (up to 96 weeks)

Description: The percentage of total study time that participants were in hospital.

Measure: Percentage of Time Spent in Hospital

Time: From study entry throughout follow-up (up to 96 weeks)

Description: Fasting was for 8 hours and the metabolic panel was drawn locally.

Measure: Changes in Fasting Total Cholesterol, High-density Lipoprotein (HDL) Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, Triglycerides, and Glucose From Baseline

Time: Study entry and week 48

37 Safety and Efficacy of Switching a Stable Combined Antiretroviral Therapeutic Regimen to Atazanavir With Ritonavir Plus Lamivudine in Treatment Experienced HIV Positive Patients With Full and Stable Virological Suppression

The purpose of this study is to evaluate the virological efficacy of maintenance therapy with atazanavir with ritonavir combined with lamivudine in treatment experienced HIV positive patients with full and stable virological suppression.

NCT01599364 Human Immunodeficiency Virus Drug: Atazanavir, ritonavir, lamivudine
MeSH: Acquired Immunodeficiency Syndrome HIV Infections

- Treated with a cART regimen containing atazanavir boosted with ritonavir since at least 3 months - With full virological suppression (VL<50 copies/mL) for a minimum of six months and in at least in two consecutive determination 3 months +/-2 weeks apart from each other - With CD4 cell count >200 since at least 6 months and without opportunistic infections or other AIDS-related events since at least one year before screening Exclusion Criteria: - Previous virological failure on a lamivudine- or PI-containing regimen or previous exposure to lamivudine-containing suboptimal antiretroviral regimens - Patients with at least a single viral load blip over 200 copies/mL - Patients with M184V or major atazanavir resistance mutation at previous genotypic resistance test (historical genotype) - Pregnancy or lactation, planned pregnancy in the short-term - Patients with HBsAg positive chronic HBV infection - Patients who experienced major toxicities related to any of the study drugs in the past - Patients with grade 4 laboratory abnormalities at baseline (excluding lipid profile and plasma bilirubin concentration). --- M184V ---

Lamivudine is a well tolerated NRTI which showed no significant toxicity in the short and long term and, together with its analog emtricitabine, is now a preferred option in most of the major international treatment guidelines; it has a good CNS penetration score and its only signature resistance mutation (M184V) deeply impairs the viral fitness and does not compromise the future treatment options. --- M184V ---

Primary Outcomes

Description: Proportion of patients with viral load < 50 copies/mL at week 48 at the intention-to-treat with switch = failure analysis

Measure: Proportion of patients with viral load < 50 copies/mL

Time: at week 48

Secondary Outcomes

Measure: Efficacy and the safety of atazanavir with ritonavir combined with lamivudine in treatment experienced HIV positive patients with full and stable virological suppression

Time: 48 and 96 weeks

38 An Open-Label Phase 3B Study in HIV-Infected Individuals With Viremia on or After Their First-Line Non-Nucleoside Reverse Transcriptase Inhibitor or Integrase Inhibitor-Based Regimen and Starting a Second-Line Regimen Consisting of ATV/RTV or DRV/RTV With an Optimized NRTI Backbone

The purpose of this study is to determine the proportion of subjects with HIV-1 RNA < 50 c/mL at Week 48 in patients who failed their first line therapy containing a non-nucleoside reverse transcriptase inhibitor (NNRTI) or an integrase inhibitor

NCT01605084 HIV Drug: Atazanavir Drug: Darunavir Drug: Ritonavir Drug: Optimized NRTI backbone

Proportion of subjects with HIV-1 RNA < 50 c/mL at Week 48 by baseline M184V presence or absence. --- M184V ---

Primary Outcomes

Measure: Proportion of subjects with Human immunodeficiency virus 1 (HIV-1) Ribonucleic Acid (RNA) < 50 c/mL

Time: At Week 48

Secondary Outcomes

Measure: Proportion of subjects with HIV-1 RNA < 50 c/mL

Time: At week 24

Measure: Change from baseline in CD4 cell count

Time: Baseline (Week 0) and at week 48

Measure: Incidence rates of serious adverse event (SAEs) and adverse events (AEs) leading to discontinuation

Time: up to week 48

Measure: Incidence rates of antiretroviral resistance measured by newly emergent genotypic substitutions and phenotypic resistance to study drugs for virologic failure

Time: up to week 48

Measure: Proportion of subjects with HIV-1 RNA < 50 c/mL at Week 48 by baseline M184V presence or absence

Time: Week 48

39 An Open Label Randomized Clinical Trial, to Evaluate the Treatment With Darunavir/Ritonavir + Lamivudine Once Daily Versus Continuing With Darunavir/Ritonavir Once Daily + Tenofovir/Emtricitabine or Abacavir/Lamivudine in HIV Infected Subject With Suppressed Plasma Viremia

This is an open label randomized clinial trial to evaluate the treatment with darunavir/ritonavir (800mg/100mg) plus lamivudine (300 mg) once daily versus continuing with darunavir/ritonavir (800mg/100mg) once daily plus tenofovir/emtricitabine (300mg/200mg) or abacavir/lamivudine (600mg/300mg) in HIV infected subject with suppressed plasma viremia.

NCT02159599 HIV Infection Drug: Darunavir/Ritonavir Drug: Lamivudine Drug: Emtricitabine/tenofovir or abacavir/lamivudine
MeSH: HIV Infections

3. Treatment with darunavir/ritonavir once a day and tenofovir/emtricitabine or abacavir/lamivudine during at least 4 weeks at the moment of the screening 4. Plasma HIV RNA levels below 50 copies / ml for at least 6 months (two separate measurements at least 6 months with viremia <50 copies / ml between both). 5. HbsAg negative Exclusion Criteria: 1. Pregnant or breastfeeding woman 2. Evidence of Lamivudine resistance (any previous genotype with mutation M184V/I or K65R) and/or to darunavir (population genotype show any of the following mutations: V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, T74P, L76V, I84V, L89V). --- M184V ---

Primary Outcomes

Description: Undetectable viral load <50 copies/ml according to the FDA snapshot algorithm

Measure: Proportion of patients with undetectable viral load

Time: week 48

Secondary Outcomes

Description: Undetectable viral load < 50 copies/ml according to the FDA snapshot algorithm

Measure: Proportion of patients with undetectable viral load

Time: Week 24

Description: Proportion of patients with viral load < 200 copies/ml according to FDA snapshot algorithm

Measure: Proportion of patients with viral load < 200 copies/ml

Time: week 48

Description: Viral load ≥ 50 copies/ml

Measure: Proportion of patients who present viral load ≥ 50 copies /ml one time

Time: From basal visit until week 48 visit

Description: Viral load ≥ 50 copies /ml

Measure: Proportion of patients who present viral load ≥ 50 copies /ml more tan two times

Time: From basal visit until week 48 visit

Description: Viral load < 50 copies/ml

Measure: Proportion of patients who maintained viral load < 50 copies/ml in all determinations

Time: week 48

Description: CD4/µl

Measure: Median of change cells CD4/µl count from basal to week 48

Time: week 48

Measure: Median of change in triglycerides , LDL-cholesterol, HDL-cholesterol and total cholesterol from basal to week 48

Time: week 48

Description: Change in glomerular filtration

Measure: Change in renal function

Time: week 48

Measure: Change in proportion of patients with renal tubular dysfunction

Time: week 48

Other Outcomes

Description: Mutations in patients viral failure

Measure: Proportion of genotypic resistance mutations

Time: Week 48

Measure: Change in proportion of genotypic resistance mutations

Time: week 48

40 A Randomized, Open Label, Phase 4 Study Evaluating the Renal Effect of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF or Other Tenofovir DF-containing Regimens (Ritonavir-boosted Atazanavir Plus Emtricitabine/Tenofovir DF or Efavirenz/Emtricitabine/Tenofovir DF) Compared to Ritonavir-boosted Atazanavir Plus Abacavir/Lamivudine in Antiretroviral Treatment-naïve HIV-1 Infected Adults With eGFR ≥70 mL/Min

The primary objective of this study is to assess glomerular function before and during administration of stribild (STB; elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF)) or a regimen containing TDF without cobicistat (COBI) as ritonavir (RTV)-boosted atazanavir (ATV/r) plus truvada (TVD; FTC/TDF) or atripla (ATR; efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF)) compared to a regimen containing neither TDF nor COBI as ATV/r plus abacavir/lamivudine (ABC/3TC) via determination of actual glomerular filtration rate (aGFR) using iohexol (a probe GFR marker) plasma clearance and estimated (calculated) glomerular filtration rate (eGFR).

NCT02246998 HIV-1 Infection Drug: STB Drug: TVD Drug: ATR Drug: RTV Drug: ATV Drug: ABC/3TC Drug: Iohexol

The most severe graded abnormality from all tests was counted for each participant.. Key Inclusion Criteria: - Treatment naïve - Plasma HIV-1 RNA levels ≥ 5,000 copies/mL at Screening - CD4 cell count > 200 cells/µL - Screening genotype report provided by the site must show sensitivity to FTC, TDF, EFV, ABC, 3TC, ATV and absence of study drug resistance mutations that include K65R, K70E and M184V in RT - Estimated GFR ≥ 70 mL/min - Hepatic transaminases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) ≤ 5 × upper limit of normal (ULN) - Total bilirubin ≤ 1.5 mg/dL (≤ 26 umol/L), or normal direct bilirubin - Adequate hematologic function (absolute neutrophil count ≥ 1,000/mm^3; platelets ≥ 50,000/mm^3; hemoglobin ≥ 8.5 g/dL) - Serum amylase ≤ 5 × ULN (individuals with serum amylase > 5 × ULN will remain eligible if serum lipase is ≤ 5 × ULN) - Normal electrocardiogram (ECG) or not clinically significant if abnormal ECG - Not pregnant or non-lactating females of non-childbearing potential. --- K65R --- --- K70E --- --- M184V ---

Key Inclusion Criteria: - Treatment naïve - Plasma HIV-1 RNA levels ≥ 5,000 copies/mL at Screening - CD4 cell count > 200 cells/µL - Screening genotype report provided by the site must show sensitivity to FTC, TDF, EFV, ABC, 3TC, ATV and absence of study drug resistance mutations that include K65R, K70E and M184V in RT - Estimated GFR ≥ 70 mL/min - Hepatic transaminases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) ≤ 5 × upper limit of normal (ULN) - Total bilirubin ≤ 1.5 mg/dL (≤ 26 umol/L), or normal direct bilirubin - Adequate hematologic function (absolute neutrophil count ≥ 1,000/mm^3; platelets ≥ 50,000/mm^3; hemoglobin ≥ 8.5 g/dL) - Serum amylase ≤ 5 × ULN (individuals with serum amylase > 5 × ULN will remain eligible if serum lipase is ≤ 5 × ULN) - Normal electrocardiogram (ECG) or not clinically significant if abnormal ECG - Not pregnant or non-lactating females of non-childbearing potential. --- K65R --- --- K70E --- --- M184V ---

Primary Outcomes

Measure: Actual Glomerular Filtration Rate (aGFR) Using Iohexol Plasma Clearance (CLiohexol) at Week 24

Time: Week 24

Description: GFR is a measure of the rate at which blood is filtered by the kidney. Cockcroft-Gault is an equation (calculation) used to estimate GFR based on serum creatinine, weight, and gender. eGFR = (140 - age) * (mass in kg) * (0.85 if female) divided by 72 * serum creatinine in mg/dL

Measure: Estimated GFR (eGFR) Calculated by Cockcroft-Gault Formula at Week 24

Time: Week 24

Description: MDRD is an equation (calculation) used to estimate GFR in participants with impaired renal function based on serum creatinine, age, race, and gender. eGFR (mL/min/1.73 m^2) = 186 * (Scr)^-1.154 * (Age)^(-0.203) * (0.742 if female) * (1.212 if black). Scr = serum creatinine in mg/dL

Measure: Estimated GFR Calculated by Modification of Diet in Renal Disease (MDRD) Formula at Week 24

Time: Week 24

Secondary Outcomes

Measure: Percentage of Participants Experiencing Treatment-Emergent Graded Laboratory Abnormality: Urine Glucose (by Dipstick)

Time: Up to 24 weeks plus 30 days

Measure: Percentage of Participants Experiencing Treatment-Emergent Graded Laboratory Abnormality: Serum Glucose (Fasting)

Time: Up to 24 weeks plus 30 days

Measure: Percentage Change From Baseline in Urine Albumin to Creatinine Ratio (mg/g) at Week 24

Time: Baseline; Week 24

Measure: Percentage Change From Baseline in Urine Protein to Creatinine Ratio (mg/g) at Week 24

Time: Baseline; Week 24

Measure: Percentage Change From Baseline in Urine β2-microglobulin to Creatinine Ratio (µg/g) at Week 24

Time: Baseline; Week 24

Measure: Percentage Change From Baseline in Urine Retinol Binding Protein (RBP) to Creatinine Ratio (µg/g) at Week 24

Time: Baseline; Week 24

Description: Cmax is defined as the maximum observed concentration of drug in plasma.

Measure: Pharmacokinetic (PK) Parameter: Cmax for COBI

Time: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24

Description: Tmax is defined as the time of Cmax.

Measure: PK Parameter: Tmax for COBI

Time: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24

Description: Clast is defined as the last observable concentration of drug.

Measure: PK Parameter: Clast for COBI

Time: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24

Description: Tlast is defined as the time of Clast. Plasma samples for PK analysis were collected out to 10 hours postdose, and the predose concentration was used as a surrogate for the 24 hour concentration for PK parameter generation.

Measure: PK Parameter: Tlast for COBI

Time: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24

Description: Ctau is defined as the observed drug concentration at the end of the dosing interval.

Measure: PK Parameter: Ctau for COBI

Time: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24

Description: λz is defined as the terminal elimination rate constant.

Measure: PK Parameter: λz for COBI

Time: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24

Description: AUCtau is defined as the concentration of drug over time (area under the plasma concentration versus time curve over the dosing interval).

Measure: PK Parameter: AUCtau for COBI

Time: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24

Description: t1/2 is defined as the estimate of the terminal elimination half-life of the drug.

Measure: PK Parameter: t1/2 for COBI

Time: Predose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24

Measure: PK Parameter: Cmax for RTV

Time: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24

Measure: PK Parameter: Tmax for RTV

Time: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24

Measure: PK Parameter: Clast for RTV

Time: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24

Description: Plasma samples for PK analysis were collected out to 10 hours postdose, and the predose concentration was used as a surrogate for the 24 hour concentration for PK parameter generation.

Measure: PK Parameter: Tlast for RTV

Time: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24

Measure: PK Parameter: Ctau for RTV

Time: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24

Measure: PK Parameter: AUCtau for RTV

Time: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24

Measure: PK Parameter: λz for RTV

Time: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24

Measure: PK Parameter: t1/2 for RTV

Time: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24

Measure: PK Parameter: Cmax for TFV

Time: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24

Measure: PK Parameter: Tmax for TFV

Time: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24

Measure: PK Parameter: Clast for TFV

Time: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24

Description: Plasma samples for PK analysis were collected out to 10 hours postdose, and the predose concentration was used as a surrogate for the 24 hour concentration for PK parameter generation.

Measure: PK Parameter: Tlast for TFV

Time: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24

Measure: PK Parameter: Ctau for TFV

Time: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24

Measure: PK Parameter: λz for TFV

Time: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24

Measure: PK Parameter: AUCtau for TFV

Time: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24

Measure: PK Parameter: t1/2 for TFV

Time: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24

Description: AUC inf is defined as the concentration of drug extrapolated to infinite time (area under the plasma concentration versus time curve extrapolated to infinite time).

Measure: PK Parameter: AUCinf for Iohexol

Time: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" on Day 1 and Weeks 4, 8, 16, and 24

Measure: Percentage of Participants With HIV-1 RNA < 50 Copies/mL Week 24 as Determined by Snapshot Algorithm

Time: Week 24

Measure: Change From Baseline in Cluster of Differentiation 4 Positive (CD4+) Cell Count at Week 24

Time: Baseline; Week 24

Description: Incidences of adverse events and laboratory abnormalities will be summarized.

Measure: Percentage of Participants Experiencing Adverse Events (AEs)

Time: Up to the last dose date plus 30 days (Up to 24 weeks plus 30 days)

Description: Graded laboratory abnormalities were defined as values that increased at least one toxicity grade from predose at any postdose up to the last dose date of study drug plus 30 days. The most severe graded abnormality from all tests was counted for each participant.

Measure: Percentage of Participants Experiencing Treatment Emergent (TE) Grade 3 or 4 Laboratory Abnormalities

Time: Up to the last dose date plus 30 days (Up to 24 weeks plus 30 days)

41 Management of Participants With Low-level Persistent Viremia (ANRS 161 L-VIR)

Management of participants with low-level persistent viremia

NCT02247687 HIV-1 Infection Treatment Resistant Disorders Viremia Drug: Protease inhibitor Drug: Isentress® (raltegravir) Other: Counseling arm
MeSH: Viremia

- Participant naïve to raltegravir (RAL) - failure of amplification or successful realization of genotypic resistance test without evidence for resistance mutations against current treatment (3TC/FTC accepted with M184V mutation) - creatinin < 3 Upper Limit normal (ULN) - Aspartate Amino Transférase (ASAT), Alanine Amino Transférase (ALAT) < 5 Upper Limit normal (ULN) - hemoglobin > 8 g/dL - platelets > 50 000/mm3 - In women, lack of current pregnancy verified by Beta Human Chorionic Gonadotropin (βHCG) at week -4 visit and use of a mechanical contraceptive method - Informed consent - Participants with an active health insurance coverage (article L1121-11 du Code de la Santé Publique) Exclusion Criteria: - HIV-2 infection, - severe medical condition in the last month (inclusion is possible for a stable condition at screening) - breastfeeding women, current pregnancy or planned pregnancy within 12 months. --- M184V ---

Primary Outcomes

Description: A virologic success is defined by a patient having plasma HIV-1 RNA levels <50 copies/ml at weeks 8 and 12.

Measure: Proportion of patients in Virologic success by week 12

Time: week 12

Secondary Outcomes

Measure: Proportion of participants with HIV-1 RNA < 50 copies/ml

Time: week 4, week 8, week 12, week 24, week 36, week 48

Measure: Proportion of participants with HIV-1 RNA < 20 copies/ml

Time: week 4, week 8, week 12, week 24, week 36, week 48

Measure: Proportion of participants with HIV-1 RNA <1copy/ml

Time: week 8, week 12, week 24, week 36, week 48

Description: •Change was calculated as the CD4 count at the corresponding week minus the baseline CD4 count

Measure: Change in CD4 cells count from baseline

Time: week 12, week 24, week 48 and end visit

Description: •resistance patterns at failure time compared with day 0, in HIV-DNA and in HIV-RNA

Measure: Number of Participants With Virologic Failure and Emergence of Resistance

Time: day 0 and visit at failure time

Description: Quantification of HIV DNA in PBMC at day 0 and its association with the proportion of success in each arm

Measure: Quantification of HIV DNA in peripheral blood mononucleated cell (PBMC)

Time: day 0

Description: •plasma concentrations of antiretroviral drugs and correlation with success or failure of the strategy

Measure: Levels of antiretroviral drugs in plasma

Time: day 0 and end visit

Description: •measurement of concentrations of antiretroviral drugs treatments in hair

Measure: Levels of antiretroviral drugs in hair

Time: day 0, week 12, week 24and end visit

Description: quantification of HIV RNA in seminal plasma

Measure: Levels of HIV-1 RNA in seminal plasma

Time: day 0, week 12, week 48 and end visit

Description: •proportion of participants who discontinued the strategy assigned by randomization at day 0 because of failure

Measure: Incidence of Study interruption

Time: From day 0 to week 24

Description: • proportions of participants experiencing a clinical or biological adverse events (ANRS scale)

Measure: Incidence of clinical and biological adverse events

Time: from day 0 to week 48

Description: •self-reported percentage of antiretroviral treatment participant had taken during the last 4 weeks

Measure: Self-reported adherence

Time: day 0, week 4, week 8, week 12, week 24, week 36, week 48 and end visit

42 Effect of SwitChing AtriPla to Eviplera on Neurocognitive and Emotional Functioning, ESCAPE Study

This study will evaluate the effects of switching Atripla to Eviplera on neurocognition measured by neuropsychological testing and functional MRI

NCT02308332 Neurocognitive Decline HIV Associated Neurocognitive Disorder Drug: Eviplera
MeSH: Neurocognitive Disorders

Differences in mean changes between baseline and end of study, as well as between the two study groups will be calculated using a paired T-test.. Inclusion Criteria: - Male, between 30 and 50 years - HIV-1 RNA < 50 copies/mL on screening visit - on Atripla continuously for ≥6 months preceding the screening visit - Have a HIV genotype prior to starting cART with Atripla with no known resistance to any of the study agents at any time in the past including, but not limited to RT mutations K65R, K101E/P, E138G/K/Q/R, Y181C/I/V, M184V/I and H221Y - Negative TPHA or VDRL < 12 months prior to the screening visit - no signs of an acute or chronic hepatitis C infection within the past 12 months before screening as defined in the Dutch guideline (Arends et al. --- K65R --- --- K101E --- --- E138G --- --- Y181C --- --- M184V ---

Inclusion Criteria: - Male, between 30 and 50 years - HIV-1 RNA < 50 copies/mL on screening visit - on Atripla continuously for ≥6 months preceding the screening visit - Have a HIV genotype prior to starting cART with Atripla with no known resistance to any of the study agents at any time in the past including, but not limited to RT mutations K65R, K101E/P, E138G/K/Q/R, Y181C/I/V, M184V/I and H221Y - Negative TPHA or VDRL < 12 months prior to the screening visit - no signs of an acute or chronic hepatitis C infection within the past 12 months before screening as defined in the Dutch guideline (Arends et al. --- K65R --- --- K101E --- --- E138G --- --- Y181C --- --- M184V ---

Primary Outcomes

Description: Patients will undergo a neuropsychological test battery where multiple standardized test will be undertaken to assess 7 different domains; Verbal Fluency, Executive Functioning, Speed of Information Processing, Learning, Memory, Attention/Working Memory, Motor skills. Raw scores can be calculated per domain and as a composite score. Differences in mean changes in composite score between baseline and end of study will be assessed with a paired T-test. A p-value <0.05 will be considered statistically significant. Within-arm changes will be assessed using Wilcoxon signed rank tests, and between-group comparisons will be evaluated with Wilcoxon rank sum tests. Multivariate analyses will be performed to analyse differences in the primary endpoints between the study groups.

Measure: To evaluate the neurocognitive performance as measured by neuropsychological test composite score after 12 weeks in stable HIV-infected patients switched from Atripla to Eviplera compared to a control group of patients on Atripla.

Time: 12 weeks

Secondary Outcomes

Description: The aim is to investigate if there is a correlation between improvement on neuropsychological test scores after 12 weeks of Eviplera therapy, and changes on fMRI after 12 weeks of Eviplera therapy. If there is a correlation, that means fMRI could be used to evaluate neurocognitive decline. Basically, we will asses if there is a correlation between ∆neuropsychological score and ∆fMRI-score. Because this is ordinal data, we will use a Spearman rank-order correlation to calculate a correlation-coefficient.

Measure: to assess the correlation between neurocognitive improvement (neuropsychological evaluation) and functional imaging (fMRI) after switching Atripla to Eviplera

Time: 12 weeks

Description: The aim is if an improvement in neuropsychological test scores after 12 weeks of Eviplera therapy is correlated with an improvement of quality of life. Basically, we will assess if there is a correlation between ∆neuropsychological score and ∆SF-36 total score. Because this is ordinal data, we will use a Spearman rank-order correlation to calculate a correlation-coefficient.

Measure: to evaluate correlation between neurocognitive performance and health related quality of life measured by SF-36 total score after switching from Atripla to Eviplera.

Time: 12 weeks

Measure: to assess the emotional functioning measured by HADS total score after switching Atripla to Eviplera by using a paired T-test to calculate differences in mean changes between baseline and end of study

Time: 12 weeks

Measure: to assess USER-P (total scores) after switching Atripla to Eviplera

Time: 12 weeks

Description: With this study, we want to investigate the effect of switching Efavirenz (as a component of Atripla) to Rilpivirine (as a component of Eviplera) on neurocognition. Our hypothesis is that neurocognition (as measured by neuropsychological testing scores) will improve when switching from Efavirenz (as a component of Atripla). If that is the case, hypothetically a lower or higher drug level of Efavirenz (as a component of Atripla) could have an effect on neurocognition (as measured by neuropsychological test scores). We will assess the correlation between drug level of Efavirenz or Rilpivirine and changes in neurocognitive function as measured by neuropsychological testing, and fMRI changes by regression analyses using drug levels as an independent variable and neuropsychological test scores as a dependent variable.

Measure: to assess drug levels of Efavirenz (as a component of Atripla) and Rilpivirin (as a component of Eviplera) in relation to changes in neurocognitive performance and fMRI in both patient groups.

Time: 12 weeks

Description: In our study, we will use the PROMIS instruments Anxiety, Depression, Sleep disturbance and Satisfaction with social roles and activities. These are all short forms containing 8 questions or statements. Patients are asked to rate the questions from 1-5 into which extent they believe them to be true; 1 being not at all and 5 being very much. For each short form, a score will be calculated by adding the values of the response to each question. PROMIS provides a score conversion table where the score can be translated into a T-score. This rescales the patient's score into a standardized score with a mean of 50 and a standard deviation of 10. In order to provide these results, PROMIS uses a calibration sample containing data from over 21000 respondents. Differences in mean changes between baseline and end of study, as well as between the two study groups will be calculated using a paired T-test.

Measure: to evaluate the usefulness of PROMIS instruments in HIV research

Time: 12 weeks

43 Comparing Type and Prevalence of HIV Drug Resistance in Treatment Experienced and naïve HIV-infected Adults in Uganda and Switzerland

The investigators aim to assess type and frequency of HIV drug resistance in adults presenting to the Infectious Diseases Institute (IDI) in Kampala, Uganda, and compare this data to patients from the Swiss HIV Cohort Study (SHCS). This study is a single-site, cross-sectional study. The Investigators' goal is to perform viral load measurements in 2750 HIV-infected patients who have been on ART for 6 months or more. Presuming a detectable viral load in 10%, resistance testing would then be performed in 250 patients on ART. All adult patients attending will be screened for enrollment. Furthermore, the investigators' goal is to perform resistance testing in 250 ART naive patients in order to detect transmitted resistance mutations. Investigators will therefore consecutively screen and enroll 250 ART naive patients who attend the clinic during the study period. For each participant, a case report form (CRF) form will be completed which includes social, as well as medical information. Investigators will ask each participant for permission to store plasma in case resistance testing must be repeated, and serum, in case of future research questions.

NCT02507921 HIV Drug Resistance

These analyses will be performed for all drug-resistance mutations pooled together (outcome-variable= patient has any drug resistance mutation), for drug resistance mutations against individual drug classes (outcome = patient has any drug resistance mutation to a particular drug class), and for the two resistance mutations (M184V and K103N) that have been most prevalent in previous studies in resource-limited settings. --- M184V ---

Primary Outcomes

Description: Type and frequency of transmitted HIV drug resistance mutations detected in treatment naive patients and comparison to naive patients in the Swiss HIV Cohort Study (SHCS) • Identification of risk factors associated with the occurrence of transmitted HIV drug resistance mutations in treatment-naive patients

Measure: HIV drug resistance in treatment-naive patients

Time: up to 12hrs

Description: • Type and frequency of HIV drug resistance mutations detected in patients on ART with virological failure and comparison to patients on treatment the Swiss HIV Cohort Study (SHCS) Identification of risk factors associated with the detection of HIV drug resistance mutations in treatment-experienced patients

Measure: HIV drug resistance in treatment-experienced patients

Time: up to 12hrs

Secondary Outcomes

Description: Proportion of HIV-infected patients with detectable viral load in the absence of immunological and/or clinical treatment failure

Measure: Viroligical failure

Time: up to 12hrs

Description: • Diagnostic performance of immunological/clinical criteria for the detection of treatment failure compared to virological testing (gold standard)

Measure: Viroligical failure

Time: up to 12hrs

Description: •Type and frequency of HIV drug resistance mutations detected in ART naive and experienced patients in Uganda and comparison to migrants from sub-Saharan Africa in the SHCS

Measure: Viroligical failure

Time: up to 12hrs

Description: •Assessment of local risk factors for treatment failure

Measure: Viroligical failure

Time: up to 12hrs

44 Safety and Efficacy of Emtricitabine/Tenofovir Alafenamide as Part of Salvage Antiretroviral Regimens in Patients With Uncontrolled Viremia and Drug-Resistant HIV Infection

Background: HIV attacks the immune system. Antiretroviral therapy (ART) is a combination of drugs used for treating HIV infection. For some people, ART drugs stop working against their HIV. Researchers want to see if a different form of the drug tenofovir (an ART drug currently approved by the FDA), combined with another drug, may help people whose HIV is resistant to ART. This combination pill is called F/TAF Objective: To study the safety and efficacy of the drug F/TAF, when used with other ART, for people whose HIV infection has been hard to control with available medicines. Eligibility: People age 14 years and older who have HIV infection and are enrolled in the DOTCOM (14-I-0009) protocol. Design: Participants will be screened with physical exam, medical history, and blood and urine tests. Participants will stay in the hospital for at least 10 days. For the first 9 days, they will take F/TAF by mouth along with their usual ART drugs. In the hospital, they will repeat the screening tests. Participants will have a DEXA scan, an x-ray that measures calcium and other minerals in the bones. Participants will lie on a soft table while the scanner passes over the lower spine and hips. Participants will get a supply of F/TAF and some new ART drugs to take at home. Participants will have follow-up visits in 1, 2, 4, 8, and 12 weeks. After the 12-week visit, they will come back about every 3 months for about 1 year. At these visits, participants will repeat the screening tests. They will discuss any problems taking their ART drugs. They may have another DEXA scan.

NCT02556333 HIV Drug: FTC/TAF

- Where neither TDF nor ABC are optimal NRTI options as defined by at least one of the following criteria: - Presence of the M184V mutation plus TDF-associated resistance mutations based on genotypic/phenotypic testing, specifically K65R alone, or with TAMs (such as 41L, 67N, 70R, 210W, 215Y/F, or 219Q/E) with or without other NRTI-associated mutations; or - FTC/TDF is not considered an option due to impaired renal function (eGFR by Cockroft-Gault equation [eGFR(CG)]=30-60 mL/min), or risk of renal impairment because of conditions such as uncontrolled hypertension, diabetes mellitus, or history of renal toxicity while receiving a TDF-based regimen; and where ABC/3TC is contraindicated (ie, presence of HLA B*5701 allele or history of hypersensitivity reaction to ABC), or is a suboptimal option (eg, presence of ABC-associated resistance mutation(s) or in patients with HBV co-infection). --- M184V ---

Primary Outcomes

Description: An HIV RNA decline of >=0.5 log by day 10 will be considered to be an adequate virologic response, to proceed to the second phase of the study.

Measure: HIV RNA Change From Baseline to Day 10

Time: 10 days

45 A Phase 3, Randomized, Open-Label Study to Evaluate the Safety and Efficacy of Switching From Regimens Consisting of Boosted Atazanavir or Darunavir Plus Either Emtricitabine/Tenofovir or Abacavir/Lamivudine to GS-9883/Emtricitabine/Tenofovir Alafenamide in Virologically Suppressed HIV-1 Infected Adults

The primary objective of this study is to evaluate the efficacy of switching to a fixed-dose combination (FDC) of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) versus continuing on a regimen consisting of boosted atazanavir (ATV) or darunavir (DRV) plus either emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) or abacavir/lamivudine (ABC/3TC) in HIV-1 infected adults who are virologically suppressed.

NCT02603107 HIV-1 Infection Drug: RTV Drug: ATV Drug: DRV Drug: COBI Drug: ATV/co Drug: DRV/co Drug: FTC/TDF Drug: ABC/3TC Drug: B/F/TAF

(If the lower limit of detection of the local HIV-1 RNA assay is < 50 copies/mL [e.g., < 20 copies/mL], the plasma HIV-1 RNA level cannot exceed 50 copies/mL on two consecutive HIV-1 RNA tests) - Have no documented or suspected resistance to FTC, tenofovir, ABC or 3TC, including but not limited to the reverse transcriptase resistance mutations K65R and M184V/I - No previous use of any approved or experimental integrase strand transfer inhibitor (INSTI) Key Exclusion Criteria: - An opportunistic illness indicative of stage 3 HIV diagnosed within the 30 days prior to screening - Individuals experiencing decompensated cirrhosis (eg, ascites, encephalopathy, or variceal bleeding) - Have been treated with immunosuppressant therapies or chemotherapeutic agents within 3 months of study screening, or expected to receive these agents or systemic steroids during the study (eg, corticosteroids, immunoglobulins, and other immune- or cytokine based therapies) - Current alcohol or substance use judged by the Investigator to potentially interfere with subject study compliance - A history of or ongoing malignancy (including untreated carcinoma in-situ) other than cutaneous Kaposi's sarcoma (KS), basal cell carcinoma, or resected, non-invasive cutaneous squamous carcinoma. --- K65R --- --- M184V ---

Primary Outcomes

Description: The percentage of participants with HIV-1 RNA ≥ 50 copies/mL at Week 48 was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status.

Measure: Percentage of Participants With HIV-1 RNA ≥ 50 Copies/mL at Week 48 as Determined by the FDA-Defined Snapshot Algorithm

Time: Week 48

Secondary Outcomes

Description: The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 48 was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status.

Measure: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 as Determined by the FDA-Defined Snapshot Algorithm

Time: Week 48

Measure: Change From Baseline in CD4 Cell Count at Week 48

Time: Baseline to Week 48

46 A Phase 3b, Randomized, Open-Label Study to Evaluate the Safety and Efficacy of Switching From Regimens Consisting of Abacavir/Lamivudine (ABC/3TC) Plus a Third Antiretroviral Agent to the Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) Fixed-Dose Combination (FDC) in Virologically-Suppressed HIV 1 Infected Adult Subjects

The primary objective of this study is to evaluate the efficacy of switching to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) fixed-dose combination (FDC) relative to continuing on a baseline regimen consisting of abacavir/lamivudine (ABC/3TC) plus a 3rd antiretroviral agent in HIV-1 infected participants.

NCT02605954 HIV-1 Infection Drug: E/C/F/TAF Drug: ABC/3TC Drug: Third Antiretroviral Agent
MeSH: Infection

- All documented historical plasma genotype(s) must not show resistance to tenofovir disoproxil fumarate (TDF) or emtricitabine (FTC), including, but not limited to the presence of reverse transcriptase resistance mutants K65R, K70E, M184V/I, or thymidine analog associated mutations (TAMs) (TAMs are: M41L, D67N, K70R, L210W, T215Y/F, K219Q/E/N/R). --- K65R --- --- K70E --- --- M184V ---

Primary Outcomes

Description: The percentage of participants achieving HIV-1 RNA < 50 copies/mL at Week 24 was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status.

Measure: Percentage of Participants Who Have HIV-1 RNA < 50 Copies/mL as Defined by the FDA Snapshot Algorithm at Week 24

Time: Week 24

Secondary Outcomes

Description: The percentage of participants achieving HIV-1 RNA < 50 copies/mL at week 12 was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status.

Measure: Percentage of Participants Who Have HIV-1 RNA < 50 Copies/mL as Defined by the FDA Snapshot Algorithm at Week 12

Time: Week 12

Description: The percentage of participants achieving HIV-1 RNA < 50 copies/mL at week 48 was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status.

Measure: Percentage of Participants Who Have HIV-1 RNA < 50 Copies/mL as Defined by the FDA Snapshot Algorithm at Week 48

Time: Week 48

Measure: Change From Baseline in CD4+ Cell Count at Week 24

Time: Baseline; Week 24

Measure: Change From Baseline in CD4+ Cell Count at Week 48

Time: Baseline; Week 48

47 A Phase 3b Open-Label Pilot Study to Evaluate Switching to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) Fixed Dose Combination (FDC) in Virologically-Suppressed HIV-1 Infected Adult Subjects Harboring the Archived Isolated NRTI Resistance Mutation M184V/M184I

This two part study will evaluate the efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) fixed-dose combination (FDC) after switching from a stable regimen consisting of emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) or abacavir/lamivudine (ABC/3TC) plus a third antiretroviral (ARV) agent in participants harboring the archived nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) resistance mutation M184V and/or M184I in HIV-1 reverse transcriptase. If the rate of virologic failure in Part 1 is deemed acceptable, once the internal data monitoring committee officially completes the interim review, the study will continue to Part 2.

NCT02616029 HIV-1 Infection Drug: E/C/F/TAF

A Phase 3b Open-Label Pilot Study to Evaluate Switching to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) Fixed Dose Combination (FDC) in Virologically-Suppressed HIV-1 Infected Adult Subjects Harboring the Archived Isolated NRTI Resistance Mutation M184V/M184I. --- M184V ---

Switching to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) Fixed Dose Combination (FDC) in Virologically-Suppressed HIV-1 Infected Adults Harboring the Archived Isolated NRTI Resistance Mutation M184V/M184I This two part study will evaluate the efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) fixed-dose combination (FDC) after switching from a stable regimen consisting of emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) or abacavir/lamivudine (ABC/3TC) plus a third antiretroviral (ARV) agent in participants harboring the archived nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) resistance mutation M184V and/or M184I in HIV-1 reverse transcriptase. --- M184V ---

Switching to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) Fixed Dose Combination (FDC) in Virologically-Suppressed HIV-1 Infected Adults Harboring the Archived Isolated NRTI Resistance Mutation M184V/M184I This two part study will evaluate the efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) fixed-dose combination (FDC) after switching from a stable regimen consisting of emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) or abacavir/lamivudine (ABC/3TC) plus a third antiretroviral (ARV) agent in participants harboring the archived nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) resistance mutation M184V and/or M184I in HIV-1 reverse transcriptase. --- M184V --- --- M184V ---

Key Inclusion Criteria: - Documented historical genotype report showing mutation M184V and/or M184I (mixtures are acceptable) in reverse transcriptase. --- M184V ---

- Proviral DNA test must not have additional exclusion resistance mutations against PIs, NRTIs and INSTIs - Part 1: Historical genotype report must show mutation M184V and/or M184I in reverse transcriptase WITHOUT any other NRTI resistance mutation (including thymidine analogue-associated mutations [TAMs] [TAMs are: M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E/N/R], K65R, K70E, T69 insertion, and Q151M mutation complex [A62V, V75I, F77L, F116Y, Q151M]) - Part 2 (after the interim efficacy review): Historical genotype report must show M184V and/or M184I in reverse transcriptase WITH or WITHOUT 1 or 2 TAMs. --- M184V ---

- Proviral DNA test must not have additional exclusion resistance mutations against PIs, NRTIs and INSTIs - Part 1: Historical genotype report must show mutation M184V and/or M184I in reverse transcriptase WITHOUT any other NRTI resistance mutation (including thymidine analogue-associated mutations [TAMs] [TAMs are: M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E/N/R], K65R, K70E, T69 insertion, and Q151M mutation complex [A62V, V75I, F77L, F116Y, Q151M]) - Part 2 (after the interim efficacy review): Historical genotype report must show M184V and/or M184I in reverse transcriptase WITH or WITHOUT 1 or 2 TAMs. --- M184V --- --- M184I --- --- M41L --- --- D67N --- --- K70R --- --- L210W --- --- T215Y --- --- K219Q --- --- K65R --- --- K70E --- --- Q151M --- --- A62V --- --- V75I --- --- F77L --- --- F116Y --- --- Q151M --- --- M184V ---

Primary Outcomes

Description: The percentage of participants with PVR for HIV-1 RNA cutoff at 50 copies/mL at Week 12 was summarized. PVR was the percentage of participants who did not have a confirmed virologic rebound. Virologic rebound was defined as 2 consecutive HIV-1 RNA values ≥ 50 copies/mL or the last available HIV-1 RNA value ≥ 50 copies/mL followed by discontinuation from the study.

Measure: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 12 as Defined by Pure Virologic Response (PVR)

Time: Week 12

Secondary Outcomes

Description: This outcome measure was planned to be assessed for any participant with any post Day 1 sample with HIV-1 RNA ≥ 50 copies/mL.

Measure: Percentage of Participants With Emergence of New Mutations in HIV-1 Reverse Transcriptase and Integrase

Time: Day 1 up to 48 weeks

Description: The percentage of participants with PVR for HIV-1 RNA cutoff at 50 copies/mL at Week 24 was summarized. PVR was the percentage of participants who did not have a confirmed virologic rebound. Virologic rebound was defined as 2 consecutive HIV-1 RNA values ≥ 50 copies/mL or the last available HIV-1 RNA value ≥ 50 copies/mL followed by discontinuation from the study.

Measure: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Weeks 24 Using PVR

Time: Week 24

Measure: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 Using PVR

Time: Week 48

Description: The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 12 was also analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. Week 12 window was between Day 71 and 98 (inclusive).

Measure: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 12 Using the FDA Snapshot Analysis

Time: Week 12

Description: The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 24 was also analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. Week 24 window was between Day 141 and 210 (inclusive).

Measure: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 Using the FDA Snapshot Analysis

Time: Week 24

Measure: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 Using the FDA Snapshot Analysis

Time: Week 48

Measure: Change From Day 1 in CD4+ Cell Count at Week 12

Time: Week 12

Measure: Change From Day 1 in CD4+ Cell Count at Week 24

Time: Week 24

Measure: Change From Day 1 in CD4+ Cell Count at Week 48

Time: Day 1, Week 48

48 A Phase 3b, Randomized, Open-Label Study to Evaluate Switching From a Tenofovir Disoproxil Fumarate (TDF) Containing Regimen to Elvitegravir/Cobicistat/Emtricitabine/ Tenofovir Alafenamide (E/C/F/TAF) Fixed-Dose Combination (FDC) in Virologically-Suppressed, HIV-1 Infected Subjects Aged ≥ 60 Years

The primary objective of this study is to evaluate the safety of elvitegravir/cobicistat/emtricitabine/ tenofovir alafenamide (E/C/F/TAF) relative to unchanged current antiretroviral therapy (ART) by assessing spine and hip bone mineral density (BMD) measured at Week 48 in virologically-suppressed, HIV-1 infected participants aged ≥ 60 years.

NCT02616783 HIV-1 Infection Drug: E/C/F/TAF Drug: TDF Drug: FTC Drug: FTC/TDF Drug: 3TC Drug: Third agent
MeSH: Infection

- Plasma HIV-1 RNA level < 50 copies/mL at screening visit - Adequate renal function - Estimated glomerular filtration rate ≥ 30 mL/min according to the Cockcroft-Gault formula (eGFRCG) and are on ARVs that are appropriately dose adjusted for renal function per package insert - All documented historical plasma genotype(s) must not show resistance to TDF or FTC, including, but not limited to the presence of reverse transcriptase resistance mutations K65R, K70E, M184V/I, or thymidine analog-associated mutations (TAMs) that include M41L, L210W, D67N, K70R, T215Y/F, K219Q/E/N/R. --- K65R --- --- K70E --- --- M184V ---

Primary Outcomes

Measure: Percent Change From Baseline to Week 48 in Spine BMD

Time: Baseline; Week 48

Measure: Percent Change From Baseline to Week 48 in Hip BMD

Time: Baseline; Week 48

Secondary Outcomes

Measure: Percent Change From Baseline to Week 24 in Spine BMD

Time: Baseline; Week 24

Measure: Percent Change From Baseline to Week 24 in Hip BMD

Time: Baseline; Week 24

Description: The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 24 was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status.

Measure: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 as Defined by the US FDA-Defined Snapshot Algorithm

Time: Week 24

Description: The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 48 was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status.

Measure: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 as Defined by the US FDA-Defined Snapshot Algorithm

Time: Week 48

Measure: Change From Baseline in CD4+ Cell Count at Week 24

Time: Baseline; Week 24

Measure: Change in Baseline in CD4+ Cell Count at Week 48

Time: Baseline; Week 48

49 A Phase 3b Randomized, Open-label, Controlled Study of the Efficacy, Safety and Tolerability of 12 Weeks of Ledipasvir/Sofosbuvir (LDV/SOF) Treatment for HIV/HCV Co-infected Subjects Who Switch to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) or Emtricitabine/Rilpivirine/Tenofovir Alafenamide (F/R/TAF) Prior to LDV/SOF HCV Treatment, the HIV/HCV Co-STARs Study (Co-infection Treatment With Single Tablet Antiviral Regimens)

This study will evaluate efficacy of ledipasvir/sofosbuvir (LDV/SOF) and safety and tolerability of switching to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) or emtricitabine/rilpivirine/tenofovir alafenamide (F/R/TAF) from the current antiretroviral (ARV) therapy and in virologically-suppressed, HIV-1/HCV co-infected participants.

NCT02707601 HIV-1 Infection HCV Infection Drug: E/C/F/TAF Drug: F/R/TAF Drug: LDV/SOF
MeSH: Infection Communicable Diseases Hepatitis C

- Plasma HIV-1 RNA level < 50 copies/mL at the screening visit - Have no documented resistance to any of the HIV study agents at time in the past, including but not limited to the reverse transcriptase resistance mutations K65R, K70E, K101E/P, E138A/G/K/R/Q, V179L, Y181C/I/V, M184V/I, Y188L, H221Y, F227C, M230I/L, the combination of K103N+L100I, or 3 or more thymidine analog associated mutations (TAMs) that include M41L or L210W (TAMs are M41L, D67N, K70R, L210W, T215Y/F, K219Q/E/N/R). --- K65R --- --- K70E --- --- K101E --- --- E138A --- --- V179L --- --- Y181C --- --- M184V ---

Primary Outcomes

Description: Sustained Virologic Response (SVR12) was defined as HCV RNA < the lower limit of quantitation (LLOQ) at 12 weeks after stopping LDV/SOF treatment.

Measure: Percentage of Participants With HCV RNA < LLOQ at 12 Weeks After Discontinuation of LDV/SOF Treatment (SVR12)

Time: HCV Posttreatment Week 12

Secondary Outcomes

Description: SVR4 was defined as HCV RNA < LLOQ at 4 weeks after stopping LDV/SOF treatment.

Measure: Percentage of Participants With HCV RNA < LLOQ at 4 Weeks After Discontinuation of LDV/SOF Treatment (SVR4)

Time: HCV Posttreatment Week 4

Description: The percentage of participants with HIV-1 RNA ≥ 50 copies/mL 24 weeks after start of the F/TAF-based regimen were analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status.

Measure: Percentage of Participants With HIV-1 RNA ≥ 50 Copies/mL (Virologic Failure) 24 Weeks After Start of the F/TAF-Based Regimen Using Modified FDA Snapshot Algorithm

Time: 24 weeks after start of HIV treatment

Measure: Percentage of Participants Experiencing Grades 1 Through 4 Adverse Events After Switch to E/C/F/TAF or F/R/TAF Throughout the Study and During Coadministeration With LDV/SOF Treatment

Time: Up to 32 weeks plus 30 days

50 A Phase 2b/3 Double Blind Safety and Efficacy Study of Injectable Cabotegravir Compared to Daily Oral Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC), For Pre-Exposure Prophylaxis in HIV-Uninfected Cisgender Men and Transgender Women Who Have Sex With Men

This study will evaluate the safety and efficacy of the injectable drug cabotegravir (CAB LA), for pre-exposure prophylaxis (PrEP) in HIV-uninfected cisgender men and transgender women who have sex with men (MSM and TGW).

NCT02720094 HIV Infections Drug: Cabotegravir tablets Drug: TDF/FTC tablets Drug: TDF/FTC placebo tablets Drug: CAB placebo tablets Drug: CAB LA Drug: Placebo for CAB LA
MeSH: HIV Infections

Incidence of resistance mutations to study products (including but not limited to K65R, M184V/I, Q148R) among seroconverters. --- K65R --- --- M184V ---

Primary Outcomes

Measure: Number of documented incident HIV infections in Steps 1 and 2

Time: Measured through participant's last study visit, up to 4 years after study entry

Measure: Number of Grade 2 or higher clinical and laboratory adverse events

Time: Measured through participant's last study visit, up to 4 years after study entry

Secondary Outcomes

Measure: Number of documented incident HIV infections in Step 2

Time: Measured through participant's last study visit, up to 4 years after study entry

Measure: Number of documented incident HIV infections in Steps 1, 2, and 3

Time: Measured through participant's last study visit, up to 4 years after study entry

Measure: Number of documented incident HIV infections in Step 3

Time: Measured through participant's last study visit, up to 4 years after study entry

Measure: Number of documented incident HIV infections in Step 2 and 3

Time: Measured through participant's last study visit, up to 4 years after study entry

Measure: Changes from baseline in creatinine and creatinine clearance levels

Time: Measured through participant's last study visit, up to 4 years after study entry

Description: (laboratory assessment of alanine aminotransferase (ALT), aspartate aminotransferase (AST), TBili, creatine phosphokinase (CPK), or clinical assessment of jaundice/icterus).

Measure: Number of Grade 3 or 4 liver-related adverse events (AEs)

Time: Measured through participant's last study visit, up to 4 years after study entry

Measure: Changes in Z-score from baseline and DXA criteria for osteopenia and osteoporosis

Time: Measured through participant's last study visit, up to 4 years after study entry

Measure: Incidence of resistance mutations to study products (including but not limited to K65R, M184V/I, Q148R) among seroconverters

Time: Measured through participant's last study visit, up to 4 years after study entry

Description: Based on physical examination

Measure: Changes in weight from baseline

Time: Measured through participant's last study visit, up to 4 years after study entry

Description: Based on physical examination

Measure: Changes in blood pressure from baseline

Time: Measured through participant's last study visit, up to 4 years after study entry

Description: Based on physical examination

Measure: Changes in pulse rate from baseline

Time: Measured through participant's last study visit, up to 4 years after study entry

Description: Based on laboratory evaluations

Measure: Changes in fasting glucose levels from baseline

Time: Measured through participant's last study visit, up to 4 years after study entry

Description: Based on laboratory evaluations

Measure: Changes in fasting lipid profile from baseline

Time: Measured through participant's last study visit, up to 4 years after study entry

51 A Phase 4, Randomized, Open Label, Controlled Study of Boosted Darunavir and Lamivudine Versus Boosted Darunavir and Emtricitabine/Tenofovir or Lamivudine/Tenofovir in Naïve HIV-1 Infected Subjects

The purpose of this study is to compare the safety and efficacy of a combination of a QD regimen consisting on ritonavir boosted darunavir (FDC) and lamivudine versus ritonavir boosted darunavir (FDC) plus co-formulated tenofovir and emtricitabine or co-formulated tenofovir/lamivudine in naïve HIV-1 infected patients. Subjects will be ARV-naïve HIV-1-infected patients eligible to start ARV therapy according to current guidelines.Subjects will be adults ≥ 18 years of age who meet all of the inclusion criteria and none of the exclusion criteria.

NCT02770508 HIV-1 Infection Drug: darunavir/ritonavir Drug: Lamivudine Drug: emtricitabine-tenofovir(FTC/TDF)

- Any of the following mutations will be considered resistance to 3TC or FTC : M184V/I and /or K65R and / or Q151M. --- M184V ---

Primary Outcomes

Description: The percentage of participants with Plasma Human Immunodeficiency Virus-1 (HIV-1) <50 c/mL at Week 48 will be assessed using Missing, Switch or Discontinuation = Failure (MSDF), as codified by the Food and Drug Administration (FDA) "snapshot" algorithm. This algorithm treated all participants without HIV-1 RNA data at Week 48 as nonresponders, Otherwise, virologic success or failure will be determined by the last available HIV-1 RNA assessment while the participant was on-treatment in the snapshot window (Week 48 +/- 6 weeks).

Measure: Percentage of patients with HIV-1 RNA levels of less than 50 copies/mL at week 48

Time: 48 weeks

Secondary Outcomes

Description: The percentage of participants with Plasma Human Immunodeficiency Virus-1 (HIV-1) <400 c/mL at Week 24 will be assessed using Missing, Switch or Discontinuation = Failure (MSDF), as codified by the Food and Drug Administration (FDA) "snapshot" algorithm.

Measure: Percentage of patients with HIV-1 RNA <400 copies/mL at week 24

Time: 24 weeks

Description: An genotiping test will be made at time to virological failure to detect mutation across reverse transcriptase (RT), and Protease (PRO). Protocol defined virological failure was defined as confirmed plasma HIV-1 RNA levels >=400 copies/mL on or after Week 24 or confirmed plasma HIV-1 RNA levels >=50 copies/mL at week 48

Measure: Number and type of resistance mutations in case of virologic failure

Time: from week 24 to week 48

Description: Change from Baseline in CD4+ cell counts will be assessed at Weeks 24 and 48.

Measure: CD4+ lymphocyte count and change between baseline (defined as the average between screening and baseline visit values) and weeks 24 and 48

Time: week 24 and 48

Description: Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment

Measure: Frequency, type and severity of adverse events and laboratory abnormalities.

Time: week 24 and 48

Description: Clinical disease progression (CDP) was assessed according to the Centers for Disease Control and Prevention (CDC) HIV-1 classification system. Category (CAT) A: one or more of the following conditions (CON), without any CON listed in Categories B and C: asymptomatic HIV infection, persistent generalized lymphadenopathy, acute (primary) HIV infection with accompanying illness or history of acute HIV infection. CAT B: symptomatic CON that are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or that are considered by physicians to have a clinical course or to require management that is complicated by HIV infection; and not included among CON listed in clinical CAT C. CAT C: the clinical CON listed in the AIDS surveillance case definition. Indicators of CDP were defined as: CDC CAT A at Baseline (BS) to a CDC CAT C event (EV); CDC CAT B at BS to a CDC CAT C EV; CDC CAT C at BS to a new CDC CAT C EV; or CDC CAT A, B, or C at BS to death.

Measure: Clinical disease progression (CDP)

Time: week 24 and 48

Description: The evaluation of quality of life will be done through two validated instruments: the Medical Outcomes Study HIV Health Survey ( MOS - HIV) and EuroQol 5D (EQ - 5D ) . Both instruments will be administered to patients at baseline , week 24 and week 48 .

Measure: Changes in quality of life

Time: baseline, week 24 and week 48

52 A Phase 2/3, Open-Label Study of the Pharmacokinetics, Safety, and Antiviral Activity of the GS-9883/Emtricitabine/Tenofovir Alafenamide (GS-9883/F/TAF) Fixed Dose Combination (FDC) in HIV-1 Infected Virologically Suppressed Adolescents and Children

Cohort 1 and 2: The primary objectives of this study are: Part A: - To evaluate the steady state pharmacokinetics (PK) of bictegravir (BIC) and confirm the dose of the bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) 50/200/25 mg fixed dose combination (FDC) in HIV-1 infected, virologically suppressed adolescents (12 to < 18 years of age) and children (6 to < 12 years of age) Parts A and B: - To evaluate the safety and tolerability of the adult strength B/F/TAF FDC through Week 24 in HIV-1 infected, virologically suppressed adolescents (12 to <18 years of age) and children (6 to <12 years of age) Cohort 3: The primary objectives of this study are: Part A: - To evaluate the steady state PK of BIC and confirm the dose of B/F/TAF 30/120/15 mg FDC in HIV-1 infected, virologically suppressed children ≥ 2 years of age weighing ≥ 14 to < 25 kg Parts A and B: - To evaluate the safety and tolerability of the low dose B/F/TAF FDC tablet through Week 24 in HIV-1 infected, virologically suppressed children ≥ 2 years of age weighing ≥ 14 to < 25 kg

NCT02881320 HIV-1 Infection Drug: B/F/TAF (Adult Strength) Drug: B/F/TAF (Low Dose)

m^2 according to the Schwartz Formula - No documented or suspected resistance to emtricitabine (FTC), tenofovir (TFV), or integrase strand transfer inhibitors (INSTIs) including, but not limited to, the reverse transcriptase resistance mutations K65R and M184V/I Note: Other protocol defined Inclusion/Exclusion criteria may apply. --- K65R --- --- M184V ---

Primary Outcomes

Description: AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).

Measure: PK Parameter: AUCtau of Bictegravir

Time: Week 2 (all Cohorts) or Week 4 (Cohort 1 and Cohort 2 Part A participants only)

Description: Ctau is defined as the observed drug concentration at the end of the dosing interval.

Measure: PK Parameter: Ctau of Bictegravir

Time: Week 2 (all Cohorts) or Week 4 (Cohort 1 and Cohort 2 Part A participants only)

Measure: Incidence of Treatment-Emergent Adverse Events (AEs) Through Week 24

Time: Up to 24 weeks

Measure: Incidence of Treatment-Emergent Laboratory Abnormalities Through Week 24

Time: Up to 24 weeks

Secondary Outcomes

Measure: Proportion of Participants with Plasma HIV-1 RNA < 50 copies/mL at Week 24 as Defined by the US FDA-Defined Snapshot Algorithm

Time: Week 24

Measure: Proportion of Participants with Plasma HIV-1 RNA < 50 copies/mL at Week 48 as Defined by the US FDA-Defined Snapshot Algorithm

Time: Week 48

Measure: Change from Baseline in CD4+ Cell Counts at Week 24

Time: Week 24

Measure: Change from Baseline in CD4+ Cell Counts at Week 48

Time: Week 48

Measure: Change from Baseline in CD4+ Cell Count Percentages at Week 24

Time: Week 24

Measure: Change from Baseline in CD4+ Cell Count Percentages at Week 48

Time: Week 48

Description: Tmax is defined as the time (observed time point) of Cmax.

Measure: PK Parameter: Tmax of Bictegravir

Time: Week 2 or Week 4

Description: Cmax is defined as the maximum observed concentration of drug.

Measure: PK Parameter: Cmax of Bictegravir

Time: Week 2 or Week 4

Description: AUClast is defined as the concentration of drug from time zero to the last observable concentration.

Measure: PK Parameter: AUClast of Bictegravir

Time: Week 2 or Week 4

Description: T1/2 is defined as the estimate of the terminal elimination half-life of the drug.

Measure: PK Parameter: T1/2 of Bictegravir

Time: Week 2 or Week 4

Description: CL is defined as the systemic clearance of the drug following study drug administration.

Measure: PK Parameter: Apparent Clearance (CL) of Bictegravir

Time: Week 2 or Week 4

Description: Vz is defined as the volume of distribution of the drug after study drug administration.

Measure: PK Parameter: Apparent Vz of Bictegravir

Time: Week 2 or Week 4

Description: AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).

Measure: PK Parameter: AUCtau of TAF and FTC

Time: Week 2 or Week 4

Description: AUClast is defined as the concentration of drug from time zero to the last observable concentration.

Measure: PK Parameter: AUClast of TAF and FTC

Time: Week 2 or Week 4

Description: Cmax is defined as the maximum observed concentration of drug.

Measure: PK Parameter: Cmax of TAF and FTC

Time: Week 2 or Week 4

Description: Ctau is defined as the observed drug concentration at the end of the dosing interval.

Measure: PK Parameter: Ctau of TAF and FTC

Time: Week 2 or Week 4

Description: Tmax is defined as the time (observed time point) of Cmax.

Measure: PK Parameter: Tmax of TAF and FTC

Time: Week 2 or Week 4

Description: T1/2 is defined as the estimate of the terminal elimination half-life of the drug.

Measure: PK Parameter: T1/2 of TAF and FTC

Time: Week 2 or Week 4

Description: CL is defined as the systemic clearance of the drug following study drug administration.

Measure: PK Parameter: Apparent CL of TAF and FTC

Time: Week 2 or Week 4

Description: Vz is defined as the volume of distribution of the drug after study drug administration.

Measure: PK Parameter: Apparent Vz of TAF and FTC

Time: Week 2 or Week 4

Measure: Percentage of Participants Experiencing Treatment-Emergent Adverse Events Through the Study

Time: Up to 48 weeks

Measure: Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities Through the Study

Time: Up to 48 weeks

Description: Participants will be asked if the study drug was palatable and if they were able to take the dosage form.

Measure: Acceptability and Palatability of B/F/TAF Formulation at Day 1 (All Cohorts)

Time: Day 1

Description: Participants will be asked if the study drug was palatable and if they were able to take the dosage form.

Measure: Acceptability and Palatability of B/F/TAF Formulation at Week 4 (All Cohorts)

Time: Week 4

Description: Participants will be asked if the study drug was palatable and if they were able to take the dosage form.

Measure: Acceptability and Palatability of B/F/TAF Formulation at Week 24 (Cohort 3)

Time: Week 24

Description: Participants will be asked if the study drug was palatable and if they were able to take the dosage form.

Measure: Acceptability and Palatability of B/F/TAF Formulation at Week 48 (Cohort 3)

Time: Week 48

53 Evaluation of a Simplified Strategy for the Long-term Management of HIV Infection: a Non-inferiority, Randomized, Controlled, Open-label Clinical Trial

The purpose of this study is to evaluate whether maintenance antiretroviral therapy could be simplified to DTG + FTC dual therapy and/or patient-centered monitoring once virological suppression is achieved. Using a factorial design, the study aims to assess the efficacy of DTG + FTC dual therapy to maintain virological suppression through 48 weeks of follow-up as well as the costs of a patient-centered ART laboratory monitoring.

NCT03160105 HIV-1-infection Antiretroviral Therapy Maintenance Therapy Drug: Switch to DTG + FTC Other: Patient-centered monitoring
MeSH: Infection Communicable Diseases HIV Infections

Note: patients with documented genotype(s) presenting only a M184V mutation remain eligible; 3. Creatinine clearance < 50ml/min; 4. ASAT or ALAT >2.5x upper limit of the norm; 5. Known hypersensitivity, intolerance or allergy to DTG or FTC; 6. Known or suspected non-adherence (defined as <80% adherence, i.e. missed doses > 1x/week) to current treatment in the last 6 months; 7. Concomitant use of drugs that decrease DTG blood concentrations including carbamazepine, oxcarbamazepine, phenytoin, phenobarbital, St John's wort and rifampicin; 8. Women who are pregnant or breast-feeding; 9. a. Presence of any INSTI-resistance. --- M184V ---

Primary Outcomes

Description: Proportion of patients maintaining HIV-RNA <100 copies/ml throughout 48 weeks

Measure: Efficacy of DTG-based maintenance therapy (< 100 copies/ml)

Time: 48 weeks

Description: Direct costs of the two study arms from the health care system perspective at week 48

Measure: Costs of a patient-centered ART monitoring

Time: 48 weeks

Secondary Outcomes

Description: Proportion of patients maintaining HIV-RNA <50 copies/ml throughout 48 weeks

Measure: Efficacy of DTG-based maintenance therapy (<50 copies/ml)

Time: 48 weeks

Description: Proportion of patients with HIV-RNA < 50 cp/ml at week 48

Measure: Efficacy of DTG-based therapy (<50 copies/ml) by FDA snapshot analysis

Time: 48 weeks

Description: defined as the first of the two-confirmed HIV-RNA >100 copies/ml (at least two weeks apart)

Measure: HIV-RNA >100 copies/ml as time to loss of virological response (TLOVR)

Time: 48 weeks

Description: from baseline to week 48

Measure: Change in CD4 cell count

Time: 48 weeks

Description: from baseline to week 48

Measure: Change in HIV-DNA

Time: 48 weeks

Description: from baseline to week 48

Measure: Change in lipidic profile

Time: 48 weeks

Description: from baseline to week 48

Measure: Change in glucose profile

Time: 48 weeks

Description: from baseline to week 48

Measure: Change in Framingham-calculated cardiovascular risk

Time: 48 weeks

Description: from baseline to week 48

Measure: Change in glomerular function rate

Time: 48 weeks

Description: throughout week 48

Measure: Proportion of patients with an adverse event

Time: 48 weeks

Description: throughout week 48

Measure: Proportion of patients with a severe adverse event

Time: 48 weeks

Description: throughout week 48

Measure: Proportion of patients with CNS adverse event

Time: 48 weeks

Description: at 2 and 6 week

Measure: Proportion of patients new to DTG with CNS symptoms

Time: 6 weeks

Description: from baseline to weeks 12 and 48

Measure: PROQOL questionnaire

Time: 48 weeks

Description: from baseline to weeks 24 and 48

Measure: Patient's monitoring satisfaction for pts in the patient-centered monitoring arm

Time: 48 weeks

Description: at week 48

Measure: Global satisfaction of the monitoring

Time: 48 weeks

Description: Monitoring satisfaction throughout 48 weeks

Measure: Proportion of patients in the patient-centered monitoring arm expressing willingness to change monitoring options

Time: 48 weeks

Description: at week 48

Measure: Patient's treatment satisfaction at week 48

Time: 48 weeks

Description: ART decided to be used in the post study period

Measure: ARV treatment in the post study

Time: 48 weeks

Description: at week 48

Measure: Study satisfaction

Time: 48 weeks

Description: at week 48

Measure: Cost-effectiveness of study arms

Time: 48 weeks

Description: from baseline to week 48

Measure: Change in patient weight

Time: 48 weeks

Description: Patient adherence to treatment throughout 48 weeks of follow-up

Measure: Adherence questions

Time: 48 weeks

Description: performed outside trial scheduled throughout 48 weeks

Measure: Number of study-related extra clinical visits

Time: 48 weeks

54 Antiretroviral Treatment Guided by Proviral Genotype: Pilot Trial of Proof of Concept.

Phase IIa, open clinical trial, pilot, single arm and proof of concept.

NCT03539224 HIV-1-infection Drug: Dolutegravir (DTG) Drug: Lamivudine (3TC)

For those included in group 1 (20 patients): No previous history of virological failure with ART regimen that included 3TC or FTC or previous virological failure had a population genotype without M184V/I or K65R/E/N mutations. --- M184V ---

For those included in group 2 (20 patients): previous history of virological failure with ART regimen that included 3TC or FTC and historical genotype with M184V/I or K65R/E/N mutations. --- M184V ---

Detection of any of the following mutations in proviral DNA in peripheral blood by conventional sequencing: M184V/I or K65R/E/N. --- M184V ---

Half of the participants will have history of failure with 3TC or FTC and M184V/I or K65R/E/N mutations in previous plasma genotypes, although to be eligible these mutations cannot be detectable at study entry in proviral DNA. --- M184V ---

Primary Outcomes

Description: - Efficacy: Proportion of patients with undetectable viral load (<50 copies / mL) at 48 weeks of follow-up, according to the FDA snapshot algorithm in the population "by intention to treat-exposed". The intention-to-treat population includes all patients who have received at least one dose of DTG and 3TC.

Measure: Proportion of patients with undetectable viral load (<50 copies / mL) at 48 weeks

Time: Week 48

Secondary Outcomes

Description: Proportion of patients with viral load <50 copies/ml at week 24, according to the FDA snapshot algorithm in the population "by intention to treat-exposed".

Measure: Proportion of patients with virological failure at 24 weeks

Time: Week 24

Description: Proportion of patients with virological failure at week 48 according to the FDA snapshot algorithm.

Measure: Proportion of patients with virological failure at 48 weeks

Time: Week 48

Description: Incidence of adverse events and discontinuation of treatment due to toxicity or intolerance.

Measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]

Time: Since baseline visits to week 48

Description: Incidence of genotypic resistance mutations in patients with virological failure at week 48. Description and frequency of genotypic resistance mutations.

Measure: Evaluation of the appearance of genotypic resistance mutations (1)

Time: Week 48

55 Effect of Reducing Nucleotide Exposure on Bone Health (ReNew)

This is an open-label, randomized pilot study to assess the effect on bone mineral density (BMD) of a switch from a tenofovir alafenamide-containing antiretroviral regimen to dolutegravir/lamivudine vs. a continuation of the tenofovir alafenamide-containing regimen.

NCT03549689 HIV/AIDS HIV-1-infection Osteopenia Drug: Dolutegravir (DTG) 50MG/lamivudine (3TC) 300MG FIXED DOSE COMBINATION (FDC) Drug: Current tenofovir alafenamide (TAF)-containing ART regimen
MeSH: Bone Diseases, Metabolic
HPO: Osteopenia

Any antiretroviral history (even before routine virologic monitoring became standard of care) that would suggest the presence of the M184V mutation should be considered exclusionary 7. ALT ≥5 X ULN, OR ALT ≥3xULN and bilirubin ≥1.5xULN (with >35% direct bilirubin) 8. Severe hepatic impairment (Child Pugh Class C) 9. Anticipated need for antiviral therapy for HCV 10. --- M184V ---

Primary Outcomes

Description: Compare the percentage change from entry to 96 weeks in lumbar spine BMD in those randomized to DTG/3TC vs. those continuing a TAF-based regimen

Measure: Percent change in lumbar spine Bone Mineral Density (BMD) at 96 weeks

Time: Baseline and 96 weeks

Secondary Outcomes

Description: Compare the percentage change from entry to 48 weeks in lumbar spine BMD in those randomized to DTG/3TC vs. those continuing a TAF-based regimen

Measure: Percentage change in lumbar spine BMD at 48 weeks

Time: Baseline and 48 weeks

Description: Compare the percentage change from entry to 48 weeks in total hip BMD in those randomized to DTG/3TC vs. those continuing a TAF-based regimen

Measure: Percentage change in total hip BMD at 48 weeks

Time: Baseline, 48 weeks

Description: Compare the percentage change from entry to 96 weeks in total hip BMD in those randomized to DTG/3TC vs. those continuing a TAF-based regimen

Measure: Percentage change in total hip BMD at 96 weeks

Time: Baseline, 96 weeks

Description: Compare the changes in CTX from entry to 12, 48, and 96 weeks

Measure: Change in CTX (a bone resorption marker)

Time: Baseline, 12 weeks, 48 weeks, and 96 weeks

Description: Compare the changes in P1NP from entry to 12, 48, and 96 weeks

Measure: Change in P1NP (a bone deposition marker)

Time: Baseline, 12 weeks, 48 weeks, and 96 weeks

Description: Compare the changes in urine β2-microglobulin from entry to 48 weeks and 96 weeks.

Measure: Change in urine β2-microglobulin (renal tubular marker)

Time: Baseline, 48 weeks, and 96 weeks

Description: Compare the changes in RBP from entry to 48 weeks and 96 weeks.

Measure: Change in urine RBP (renal tubular marker)

Time: Baseline, 48 weeks, and 96 weeks

Description: Compare the changes in protein from entry to 48 weeks and 96 weeks.

Measure: Change in urine protein

Time: Baseline, 48 weeks, and 96 weeks

Description: Compare the changes in urine albumin from entry to 48 weeks and 96 weeks.

Measure: Change in urine albumin

Time: Baseline, 48 weeks, and 96 weeks

Description: Compare the changes in fractional excretion of phosphate from entry to 48 weeks and 96 weeks.

Measure: Change in fractional excretion in phosphate

Time: Baseline, 48 weeks, and 96 weeks

Description: Compare the percentage change from entry to 48 weeks and 96 weeks in total lean mass (as measured by whole body DXA)

Measure: Percentage change in total lean mass

Time: Baseline, 48 weeks, and 96 weeks

Description: Compare the percentage change from entry to 48 weeks and 96 weeks in trunk fat (as measured by whole body DXA)

Measure: Percentage change in trunk fat

Time: Baseline, 48 weeks, and 96 weeks

Description: Compare the percentage change from entry to 48 weeks and 96 weeks in limb fat (as measured by DXA)

Measure: Percentage change in limb fat

Time: Baseline, 48 weeks, and 96 weeks

Description: Compare the levels of HIV RNA <50 copies/mL and below the limit of quantification (BLQ) at 48 weeks and 96 weeks using the FDA snapshot algorithm

Measure: Maintenance of HIV RNA level

Time: 48 weeks and 96 weeks

Description: Compare rates of grade 3 or 4 adverse events experienced by participants through 96 weeks

Measure: Grade 3 or 4 adverse events

Time: 96 weeks

Description: Compare treatment discontinuation of study medication due to adverse effect experienced by participants through 96 weeks

Measure: Treatment discontinuation of study medication due to adverse effect

Time: 96 weeks

Description: Compare changes in fasting lipids (total cholesterol, LDL, HDL, and triglycerides) at entry, 48 weeks, and 96 weeks

Measure: Change in fasting lipids

Time: Entry, 48 weeks, and 96 weeks

56 A Phase 3b, Multicenter, Open-Label Study to Evaluate Switching From a Regimen of Two Nucleos(t)Ide Reverse Transcriptase Inhibitors (NRTI) Plus a Third Agent to a Fixed Dose Combination (FDC) of Bictegravir/Emtricitabine/Tenofovir Alafenamide (B/F/TAF), in Virologically-Suppressed, HIV-1 Infected African American Participants

The primary objective of this study is to evaluate the efficacy of switching from a regimen of 2 nucleos(t)ide reverse transcriptase inhibitors (NRTIs) and a third agent to a fixed dose combination (FDC) of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) versus continuing their baseline regimen in HIV-1 infected, virologically suppressed African American participants.

NCT03631732 HIV-1 Infection Drug: B/F/TAF Drug: NRTIs Drug: Third Agent

- History of 1-2 thymidine analogue mutations (TAMs), M184V/I, and any other RT substitutions are allowed, with the following exceptions: History of 3 or more TAMs (M41L, D67N, K70R, L210W, T215F/Y, and K219Q/E/N/R), T69-insertions, or K65R/E/N in RT will be excluded. --- M184V ---

Primary Outcomes

Measure: Proportion of Participants with HIV-1 RNA ≥ 50 copies/mL at Week 24 as Defined by the US FDA-Defined Snapshot Algorithm

Time: Week 24

Secondary Outcomes

Measure: Proportion of Participants with HIV-1 RNA ≥ 50 copies/mL at Week 48 as Defined by the US FDA-Defined Snapshot Algorithm

Time: Week 48

Measure: Proportion of Participants with HIV-1 RNA < 50 copies/mL at Week 24 as Defined by the US FDA-Defined Snapshot Algorithm

Time: Week 24

Measure: Proportion of Participants with HIV-1 RNA < 50 copies/mL at Week 48 as Defined by the US FDA-Defined Snapshot Algorithm

Time: Week 48

Measure: Change From Baseline in CD4+ Cell Count at Week 24

Time: Baseline; Week 24

Measure: Change From Baseline in CD4+ Cell Count at Week 48

Time: Baseline; Week 48

57 Phase I/II Study of the Pharmacokinetics, Safety, and Tolerability of Abacavir/Dolutegravir/Lamivudine Dispersible and Immediate Release Tablets in HIV-1-Infected Children Less Than 12 Years of Age

The purpose of this study is to examine the pharmacokinetics, safety, and tolerability of abacavir/dolutegravir/lamivudine dispersible and immediate release tablets in HIV-1-infected children less than 12 years of age.

NCT03760458 HIV Infections Drug: Abacavir (ABC)/Dolutegravir (DTG)/Lamivudine (3TC) Dispersible Tablets Drug: Abacavir (ABC)/Dolutegravir (DTG)/Lamivudine (3TC) Immediate Release Tablets (Immediate release)
MeSH: HIV Infections

- Based on parent or guardian report at entry, child is expected to be available for 48 weeks of follow-up - Parent or legal guardian is willing and able to provide written informed consent for child's study participation and, when applicable per local institutional review board/ethics committee (IRB/EC) policies and procedures, child is willing and able to provide written informed assent for study participation Exclusion Criteria: - Documented resistance to ABC, DTG, or 3TC - Note: Testing to rule out resistance is not required, and the M184V resistance mutation is not exclusionary. --- M184V ---

Primary Outcomes

Description: Based on analysis of intensive PK samples collected at Week 1 and compared within each weight band to the PK targets specified in the study protocol

Measure: Geometric mean area under the plasma concentration-time curve over 24 hours at steady-state (AUC0-24h) for ABC, DTG, and 3TC

Time: Measured at Week 1

Description: Based on analysis of intensive PK samples collected at Week 1

Measure: Geometric mean maximum plasma concentration (Cmax) for ABC, DTG, and 3TC

Time: Measured at Week 1

Description: Based on analysis of intensive PK samples collected at Week 1 and compared within each weight band to the PK targets specified in the study protocol

Measure: Geometric mean concentration at 24 hours post-dose (C24h) for ABC, DTG, and 3TC

Time: Measured at Week 1

Description: Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017

Measure: Number of participants who had adverse events

Time: Measured through Week 24

Description: Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017

Measure: Number of participants who had Grade 3 or Grade 4 adverse events assessed as related to study drug

Time: Measured through Week 24

Description: Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017

Measure: Number of participants who had Grade 5 adverse events assessed as related to study drug

Time: Measured through Week 24

Description: Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017

Measure: Number of participants who had life-threatening adverse events assessed as related to study drug

Time: Measured through Week 24

Description: Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017

Measure: Number of participants who had serious adverse events assessed as related to study drug

Time: Measured through Week 24

Description: Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017

Measure: Number of participants who had adverse events assessed as related to study drug that lead to permanent discontinuation of study drug

Time: Measured through Week 24

Secondary Outcomes

Description: Derived from population PK modeling with sampling

Measure: Area under the plasma concentration-time curve over 24 hours at steady-state (AUC0-24h) for ABC, DTG, and 3TC

Time: Measured through Week 48

Description: Derived from population PK modeling with sampling

Measure: Concentration at time 0 (pre-dose) (C0h) for ABC, DTG, and 3TC

Time: Measured through Week 48

Description: Derived from population PK modeling with sampling

Measure: Concentration at 24 hours post-dose (C24h) for ABC, DTG, and 3TC

Time: Measured through Week 48

Description: Derived from population PK modeling with sampling

Measure: Maximum plasma concentration (Cmax) for ABC, DTG, and 3TC

Time: Measured through Week 48

Description: Derived from population PK modeling with sampling

Measure: Time to maximum concentration (Tmax) for ABC, DTG, and 3TC

Time: Measured through Week 48

Description: Derived from population PK modeling with sampling

Measure: Apparent oral clearance (CL/F) for ABC, DTG, and 3TC

Time: Measured through Week 48

Description: Derived from population PK modeling with sampling

Measure: Half-life (t1/2) for ABC, DTG, and 3TC

Time: Measured through Week 48

Description: Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017

Measure: Number of participants who had adverse events

Time: Measured through Week 48

Description: Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017

Measure: Number of participants who had Grade 3 or Grade 4 adverse events assessed as related to study drug

Time: Measured through Week 48

Description: Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017

Measure: Number of participants who had Grade 5 adverse events assessed as related to study drug

Time: Measured through Week 48

Description: Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017

Measure: Number of participants who had life-threatening adverse events assessed as related to study drug

Time: Measured through Week 48

Description: Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017

Measure: Number of participants who had serious adverse events assessed as related to study drug

Time: Measured through Week 48

Description: Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017

Measure: Number of participants who had adverse events assessed as related to study drug that lead to permanent discontinuation of study drug

Time: Measured through Week 48

Description: Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017

Measure: Number of participants who had adverse events

Time: Measured through Week 144

Description: Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017

Measure: Number of participants who had Grade 3 or Grade 4 adverse events assessed as related to study drug

Time: Measured through Week 144

Description: Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017

Measure: Number of participants who had Grade 5 adverse events assessed as related to study drug

Time: Measured through Week 144

Description: Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017

Measure: Number of participants who had life-threatening adverse events assessed as related to study drug

Time: Measured through Week 144

Description: Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017

Measure: Number of participants who had serious adverse events assessed as related to study drug

Time: Measured through Week 144

Description: Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017

Measure: Number of participants who had adverse events assessed as related to study drug that lead to permanent discontinuation of study drug

Time: Measured through Week 144

Description: Based on laboratory evaluations

Measure: Proportion of participants with HIV-1 RNA levels meeting virologic response criteria

Time: Measured through Week 48

Description: Based on laboratory evaluations

Measure: Proportion of participants with HIV-1 RNA levels meeting virologic response criteria

Time: Measured through Week 144

Description: Based on laboratory evaluations

Measure: Number of participant with HIV-1 RNA greater than or equal to 200 copies/mL at Weeks 4, 24, and 48 (snapshot algorithm)

Time: Measured through Week 48

Description: Based on laboratory evaluations

Measure: Number of participants with HIV-1 RNA greater than or equal to 50 copies/mL at Weeks 4, 24, and 48 (snapshot algorithm)

Time: Measured through Week 48

Description: Based on laboratory evaluations

Measure: Median changes (with IQR) in CD4+ cell count and percentage at Weeks 4, 24, and 48

Time: Measured through Week 48

Description: Based on laboratory evaluations

Measure: Median changes (with IQR) in CD4+ cell count and percentage through Week 144

Time: Measured through Week 144

Description: Based on laboratory evaluations

Measure: Median changes (with IQR) in total cholesterol, HDL, LDL, and triglycerides at Weeks 24 and 48

Time: Measured through Week 48

Description: Based on questionnaire responses

Measure: Aggregated data on parent/guardian reported adherence to study drug at Weeks 4, 24, and 48

Time: Measured through Week 48

Description: Based on questionnaire responses

Measure: Aggregated data on parent/guardian reported tolerability (i.e., palatability and acceptability) of study drug at Weeks 4, 12, 24, and 48

Time: Measured through Week 48

Description: Based on laboratory evaluations

Measure: ARV resistance mutations at time of virologic failure (and at entry for children with resistance identified at time of virologic failure)

Time: Measured through Week 48

58 A Phase 1b, Open-label Study to Evaluate the PK, Safety and Efficacy of B/F/TAF in HIV-1 Infected, Virologically Suppressed, Pregnant Women in Their Second and Third Trimesters

The primary objective of this study is to evaluate the steady state pharmacokinetics of bictegravir (BIC) and confirm the dose of BIC/emtricitabine/tenofovir alafenamide (B/F/TAF) 50/200/25 mg fixed dose combination (FDC) in HIV-1 infected, virologically suppressed pregnant women in their second and third trimesters.

NCT03960645 HIV-1-infection Drug: B/F/TAF

Key Inclusion Criteria: - The ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures - With singleton pregnancy, at least 12 weeks but not more than 31 weeks pregnant at the time of screening - Agree not to breastfeed for the duration of the study - Currently on a stable antiretroviral regimen for ≥ 6 months preceding the screening visit - Documented plasma HIV-1 RNA levels of < 50 copies/mL for ≥ 6 months preceding the screening visit and have HIV-1 RNA < 50 copies/mL at the screening visit - Have no documented or suspected resistance to FTC, Tenofovir (TFV), or integrase strand-transfer inhibitors (INSTIs) including, but not limited to, the reverse transcriptase resistance mutations K65R or M184V/I - Historic genotype reports will be collected if available - Have a normal ultrasound, completed locally prior to the Day 1 visit, with no evidence of any fetal malformation or structural abnormality affecting either fetus or placenta - Normal maternal alfa-fetoprotein level at the screening visit Key Exclusion Criteria: - Have chronic hepatitis B virus (HBV) - Have active hepatitis C virus (HCV) infection - An opportunistic illness indicative of stage 3 HIV diagnosed within the 30 days prior to screening Note: Other protocol defined Inclusion/Exclusion criteria may apply. --- K65R --- --- M184V ---

Primary Outcomes

Description: AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).

Measure: Pharmacokinetic (PK) Parameter: AUCtau of BIC

Time: Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose

Secondary Outcomes

Description: AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).

Measure: PK Parameter: AUCtau of emtricitabine (FTC) and tenofovir alafenamide (TAF)

Time: Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose

Description: AUClast is defined as the concentration of drug from time zero to the last observable concentration.

Measure: PK Parameter: AUClast of BIC, FTC, and TAF

Time: Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose

Description: Cmax is defined as the maximum observed concentration of drug during the dosing interval.

Measure: PK Parameter: Cmax of BIC, FTC, and TAF

Time: Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose

Description: Ctau is defined as the observed drug concentration at the end of the dosing interval.

Measure: PK Parameter: Ctau of BIC and FTC

Time: Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose

Description: Clast is defined as the last observable concentration of drug.

Measure: PK Parameter: Clast of BIC, FTC, and TAF

Time: Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose

Description: Tmax is defined as the time (observed time point) of Cmax.

Measure: PK Parameter: Tmax of BIC, FTC, and TAF

Time: Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose

Description: t1/2 is defined as the estimate of the terminal elimination half-life of the drug.

Measure: PK Parameter: t1/2 of BIC, FTC, and TAF

Time: Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose

Description: CL/F is defined as the apparent oral clearance following administration of the drug.

Measure: PK Parameter: CL/F of BIC, FTC, and TAF

Time: Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose

Description: Vz/F is defined as the apparent volume of distribution of the drug.

Measure: PK Parameter: Vz/F of BIC, FTC, and TAF

Time: Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose

Description: λz is defined as the terminal elimination rate constant, estimated by linear regression of the terminal elimination phase of the log plasma concentration of drug versus time curve of the drug.

Measure: PK Parameter: λz of BIC, FTC, and TAF

Time: Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose

Measure: Proportion of Participants With HIV-1 RNA < 50 Copies/mL Using the Missing = Excluded Approach

Time: At the Time of Delivery

59 Zidovudine, Lamivudine and Dolutegravir (AXD) Relative to Tenofovir, Lamivudine and Dolutegravir (TXD) In Second Line Antiretroviral Therapy (ARTIST) Trial: a Randomised Controlled Trial

The strategy to support virological suppression on second-line antiretroviral treatment (ART) includes the provision of ART that has a low pill burden, good tolerability, low toxicity, is easily monitored, has a high barrier to resistance and that is low cost. The fixed dose combination of tenofovir, lamivudine and dolutegravir offers significant advantage as a potential second-line regimen compared to the World Health Organization standard of care second-line regimen of zidovudine, lamivudine and dolutegravir, in terms of cost, tolerability and monitoring requirements. The ARTIST study will be a randomised, open-label, active-controlled trial with 48 weeks of follow up, and will evaluate the viral load suppression achieved by participants taking the fixed dose combination of tenofovir, lamivudine and dolutegravir or zidovudine, lamivudine and dolutegravir as second-line therapy. There is evidence to suggest that even in the presence of resistance mutations to tenofovir and lamivudine (K65R or M184V/I), using this backbone with dolutegravir will provide an effective second-line regimen in patients who have failed a first line regimen that includes a tenofovir and lamivudine or emtricitabine backbone and a non-nucleoside reverse transcriptase inhibitor (NNRTI). The trial will comprise two stages: the first will evaluate the viral suppression in 65 participants produced by the fixed dose combination of tenofovir, lamivudine and dolutegravir with a supplementary dose of dolutegravir for the first 14 days to mitigate the NNRTI effect in reducing dolutegravir concentrations when switching antiretrovirals. The study will progress to the second stage if this proves effective, and 130 participants will then be randomised to receive the fixed dose combination of tenofovir, lamivudine and dolutegravir (without a supplementary dose of dolutegravir) or the WHO standard of care second-line regimen of zidovudine, lamivudine and dolutegravir. The primary endpoint is viral suppression (viral load<50 copies/mL) at 24 weeks. A Pharmacokinetic sub-study will be conducted on 12 participants in stage 1 and in 12 patients in stage 2 who are randomised to the intervention arm, to assess the trough concentrations of dolutegravir and off-treatment concentrations of efavirenz at day 3, 7, 14, and 28. This is to evaluate the need for the lead in supplementary dose of dolutegravir.

NCT03991013 HIV Infections Drug: TLD: fixed dose combination of tenofovir, lamivudine and dolutegravir antiretroviral therapy Drug: ALD: combination of zidovudine, lamivudine and dolutegravir antiretroviral therapy
MeSH: HIV Infections

There is evidence to suggest that even in the presence of resistance mutations to tenofovir and lamivudine (K65R or M184V/I), using this backbone with dolutegravir will provide an effective second-line regimen in patients who have failed a first line regimen that includes a tenofovir and lamivudine or emtricitabine backbone and a non-nucleoside reverse transcriptase inhibitor (NNRTI). --- K65R --- --- M184V ---

Primary Outcomes

Description: VL< 50 copies/mL in the participants overall and stratified by presence or absence of resistance mutations at baseline, in stage 1

Measure: Virological suppression in stage 1

Time: 24 weeks

Description: VL< 50 copies/mL in the participants overall and stratified by presence or absence of resistance mutations at baseline, in stage 2

Measure: Virological suppression in stage 2

Time: 24 weeks

Secondary Outcomes

Description: To determine the proportion of patients who develop dolutegravir resistance mutations and new nucleoside reverse transcriptase inhibitors on second-line treatment

Measure: Proportion new ARV resistance

Time: 48 weeks

Description: To evaluate the trough concentrations (ng/mL) of dolutegravir in the period after switching regimens

Measure: PK trough DTG

Time: first 28 days

Description: To evaluate the residual concentrations (ng/mL) of efavirenz in the period after switching regimens

Measure: PK residual EFV

Time: first 28 days

Description: To evaluate the proportion of patients with dolutegravir trough concentrations above the PA-IC90 value at all PK time points.

Measure: PK DTG above PA-IC90

Time: first 28 days

Description: To describe tenofovir-diphosphate concentration (ng/mL - marker of adherence) in those with virological failure at 24 and 48 weeks by treatment arm and to compare to a group of matched controls.

Measure: Adherence in failures stage 1

Time: 24 and 48 weeks

Description: To describe dolutegravir concentration (ng/mL - marker of adherence) in those with virological failure at 24 and 48 weeks by treatment arm and to compare to a group of matched controls.

Measure: Adherence in failures stage 2

Time: 24 and 48 weeks

Description: To describe adverse events among the study cohort in stage one and in stage two by treatment arm

Measure: Description of adverse events

Time: 48 weeks

Description: To describe all-cause mortality among the study cohort in stage one and in stage two by treatment arm

Measure: Description of all cause mortality

Time: 48 weeks

60 Switch to Tenofovir Alafenamide (TAF), Emtricitabine (FTC), Bictegravir (BIC)(Biktarvy®) in HIV-1-infected Patients Over 65 Years Old at Risk of Polymedication

Patients infected and living with HIV are getting older and have more and more non-HIV co-morbidities. These expose them to polypharmacy that increases the risk of pharmacological interaction. Bictegravir, co-formulated with emtricitabine (FTC) and tenofovir alafenamide (TAF) (BIKTARVY) a new generation integrase inhibitor with a high genetic barrier and had no drug interaction may be a treatment of choice for participant over 65 years old who are HIV infected . BIKTARVY improve adherence and quality of life; and on the other hand it would limit the risks of pharmacological interaction. In addition, the use of TAF reducing the risk of long-term renal toxicity and adverse effects on bone would be of interest in this aging population and more at risk of osteoporosis.

NCT04222283 HIV Infections Drug: BIKTARVY 50Mg-200Mg-25Mg Tablet
MeSH: HIV Infections

The reverse transcriptase resistant mutations M184V plus one TAM are allowed. --- M184V ---

- If no genotype is available, DNA genotype will be performed at screening visit: no resistance mutation to integrase inhibitors, the reverse transcriptase resistant mutations M184V plus one TAM are allowed. --- M184V ---

Primary Outcomes

Description: The primary outcome is the proportion of patients with virological failure at Week 24.

Measure: Virological failure is defined by plasma HIV RNA > 50 cps/mL on 2 following samples at 2 to 4 weeks apart

Time: Week 24

Secondary Outcomes

Description: • Assessment of co morbidities and frailty

Measure: Charlson and Fried Score

Time: Day 1, Week 24 and Week 48

Description: • Assessment of cardio vascular risk

Measure: DAD Score

Time: Day 1,Week 24 and Week 48

Description: • Assessment of polymedication and potential drug-drug interactions

Measure: polymedication

Time: Baseline, Week 24 and Week 48

Description: • Change of drug-drug interactions

Measure: drug interactions

Time: Baseline To Week 48

Description: Rate of participants withdrawn from the study for grade 3 or 4 adverse event

Measure: • adverses events

Time: Baseline To Week 48

Description: • Rate of therapeutic success

Measure: therapeutic success

Time: Week 24 and Week 48

Description: • Rate of participants with detectable signal in case viral load is less than 20 c/ml threshold (Cobas/TaqmanHIV-1 Roche Diagnostics) at W24 and W48

Measure: Viral load detectable

Time: From Baseline to Week 48

Description: • Rate of participants with a blip

Measure: Blip detectable

Time: Baseline to Week 48

Description: • Emergence of resistance mutations at time of virological failure

Measure: mutation

Time: Day 1 to Week 48

Description: • Change of CD4 and CD8 cell count from BSL,

Measure: immunology parameters

Time: Baseline, to Week 24 and Week 48

Description: • Evolution of lipid parameters

Measure: lipid parameters

Time: Baseline, Week 24, Week 48

Description: Renal glomerular filtration, creatinine clearance

Measure: Renal parameters

Time: Baseline,Week 4,Week 12,Week 24 and Week 48 ;

Description: • Plasma levels of antiretroviral drugs (TAF, FTC, BIC)

Measure: pharmacology

Time: Baseline, Week 12, Week 24, Week 48

Description: • Adherence to treatment: self-administered questionnaire

Measure: Addherence

Time: Baseline, Week 24 and Week 48

Description: • Tolerance to treatment: questionnaire

Measure: Tolerance

Time: Week 4, Week 24 and Week 48

Description: urine albumin, urine creatinine, urine protein, beta-2-microglobulin and retinol binding protein

Measure: Renal parameters (Urine)

Time: Baseline, Week 24, Week 48


HPO Nodes


Osteopenia
Genes 256
SNORD116-1 GTF2H5 FAT4 POLR3H IER3IP1 GORAB HPGD COL1A1 BAZ1B PRKAR1A ERCC2 TMEM67 RPL11 NAGA NSMF SLC34A1 TRPS1 OTX2 AGPAT2 P4HB CTC1 ATP6V0A2 TARS1 MMP2 TCIRG1 RFC2 SGMS2 ANTXR2 STAT3 PLEKHM1 UROS FGF8 MKRN3 MMP14 PTH1R IRX5 B4GALT7 FAT4 LRP5 ZMPSTE24 GTF2IRD1 PROP1 SLC39A8 HESX1 GNRH1 PMM2 NPR2 FKBP14 PDE11A TAC3 GFI1 FGF17 BSCL2 CDH23 RNF113A GBA SH3PXD2B ATP6V0A2 SPRY4 PMM2 SPIDR COL7A1 GATA1 CREB3L1 PWRN1 SBDS FOXA2 ADAMTS2 FSHR GPR35 STAT1 IGF1 ANTXR2 HECW2 FBN2 IL17RD ALDH18A1 SEC24D PSMC3IP SLC7A7 PHGDH SEC23A TMEM38B TAPT1 GNPTAB MLXIPL BRAF CDH23 CLIP2 IFITM5 GPAA1 FARSB ELN GLIS3 PYCR1 DNAJC21 SMARCAL1 PROK2 CAVIN1 SMPD1 FGFR2 GNRHR KISS1R HS6ST1 LRP5 RSPRY1 FUT8 SLC34A1 TBL2 KRAS AIP DCAF17 SNORD115-1 SLC17A5 ESR1 ELN MST1 DUSP6 CCND1 WDR11 NOTCH2 NRAS COG1 POLE SLC39A13 SKI CRTAP MMP1 MRPS22 MTAP CAVIN1 HSD17B4 EIF2AK3 HERC2 ATP7A LIFR CYP19A1 CHD7 SNRPN GTF2I TACR3 MGAT2 EED ANO5 IARS2 SERPINH1 B4GALT7 IPW PROP1 MPLKIP FOS MBTPS2 MAFB NPAP1 LMNA GEMIN4 FGFR1 DUSP6 SRP54 PIGT TAF1 NUP107 MEN1 CAV1 MMP2 LHX4 GLI2 DCHS1 EFL1 TRPS1 GCM2 PRLR ADAMTSL2 POLR3A POU1F1 COG1 RNU4ATAC PDGFRB ADAMTS2 NOTCH2 SLC39A8 DDOST ADCY10 ANOS1 DCHS1 HRAS GCM2 ERCC3 LIMK1 RNF125 P3H1 AVP BMP15 GPAA1 CHST3 ANO5 FLRT3 STAT1 SLC35A2 PSMB8 KCNJ1 NDN FBN1 MAGEL2 PLOD2 PLOD3 SOX3 MKRN3-AS1 PRKACA PWAR1 SCARB2 STN1 MEN1 SLC12A1 LMNA SMARCD2 GNPAT GTF2E2 TCF4 CDC73 KISS1 ZMPSTE24 PSAT1 SRP54 FGFR1 NR5A1 ESR1 RECQL4 PSAP PIGY PLS3 LMNA FGF17 ELANE UNC80 USP9X COL1A1 UROS FKBP14 CRIPT GZF1 STAT3 FKBP10 TRPV6 PROKR2 XYLT2 GNAS SKI KISS1R DPM2 PPARG SLC39A13 COX4I2 SLC9A3R1 B3GAT3 TONSL
Immunodeficiency
Genes 257
LETM1 NFKB2 EPG5 BCL10 AK2 MS4A1 RTEL1 IFNGR2 LIG4 NFKB1 AGPAT2 FCGR3A NFKB2 RNF168 TERT ZBTB24 CHD1 ATRX ANTXR2 PKP1 WIPF1 NOP10 GATA2 HYOU1 XRCC4 SDHD NHP2 IRAK4 CORO1A TBX1 RBCK1 MALT1 TNFRSF4 LAT CD247 IL2RG PARN EPG5 BSCL2 PARN AK2 IRF7 ICOS GATA1 TNFSF12 USB1 ACTB SMARCAL1 UNG TYK2 IL21R TTC7A IL2RB STAT1 IKBKG FGFRL1 FOXN1 HIRA CCDC47 CLCA4 ACD TNFRSF13B MYC AICDA IRAK4 CD3G FCN3 CYBA CTBP1 CHD1 LAMTOR2 LIG4 CAVIN1 SIK3 IL7R LCK ICOS NPM1 MYD88 ORAI1 RAG2 CARD11 PTEN IGHM PTPRC LAMTOR2 RAG1 PGM3 ARVCF TNFRSF1B TNFRSF13C IRF8 SEC24C IL2RG COG6 IKBKG CD28 DKC1 POLE CR2 ADA JMJD1C TCF3 AP3D1 MBTPS2 SHANK3 HELLS COMT UFD1 RAG2 TTC37 IFNGR1 BCL11B CD19 CARD9 BLNK PRKDC CR2 BUB1B MEIS2 RAG1 SDHC NSD2 CTPS1 DOCK2 CDCA7 LMNB2 IRF2BP2 CD79B TERC LYST CD19 FOS CD3E TFRC NCF1 NHEJ1 IRF8 CTC1 LYST LRBA DNMT3B CAV1 CRKL STX1A MAGT1 CPLX1 TNFRSF13B MMUT DCLRE1C RMRP GP1BB CTLA4 DCLRE1C SKIV2L LRRC8A CD81 ICOS TGFB1 XIAP XRCC4 IL7R TTC7A SKIV2L TBCE RTEL1 IGLL1 NCF2 IL21 UNC119 SIN3A WHCR TNFRSF13C ISG15 JAK3 CD79A RAG1 USP8 CD19 CR2 STAT1 CD3D CFTR CYBB IL12RB1 WAS AKT1 IL2RA HBB IKBKB ATM STAT1 STK4 PRKCD ACP5 IKBKG SH2D1A MTHFD1 CDC42 ADA2 PGM3 RAG1 XIAP MAPK1 PIK3R1 SLC46A1 CHD7 MS4A1 FOXN1 RREB1 CDH23 KLLN WRAP53 CD40LG SEC23B ZBTB24 PIK3CA BTK FRAS1 TINF2 RAC2 IKZF1 RAB27A DKC1 DCTN4 TINF2 CD81 DKC1 RAG2 PRPS1 NFKB1 IKBKG IL2RG BCR UROS TNFRSF13C POLE SPATA5 TNFSF12 SDHB ADA CUL4B PIK3R1 STIM1 PIK3CD IL12B SP110 NFE2L2 PPARG TBX1 RNF168 AGL RTEL1 RMRP TERT CD40 DNMT3B