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Diagnosis of hepatitis C can be done with the help of blood tests that determines HCV antibodies in the blood.
A diagnosis of hepatitis C does not really mean that a patient needs hepatitis C treatment. Interferon is given by injection and has certain side effects which include flu-like symptoms such as headaches, fatigue, loss of appetite, nausea, depression, vomiting, fever and thinning of hair. This blog will help the Hepatitis C to cope with most clinical situations related to the abdominal and alimentary tract in patients with FMF. Hepatitis C is an Infectious virus which is carried from the blood stream to the liver resulting in inflammation of the liver. The major cause of spreading this deadly disease is blood to blood contact from an infected person to a healthy person. In a study of 10 cases of chronic Hepatitis C, who were found positive for Hepatitis C virus with raised liver disease enzymes (ALT, AST) and increased viral Hepatitis C load, were treated with combination of alternative treatment for Hepatitis C with Dr. Most infants and children with the HCV virus never develop signs and symptoms of Hepatitis C.
Hepatitis C is an infectious disease caused by a virus of the flavoviridae family that can infect and damage the liver. People become infected with hepatitis because of blood-to-blood contact associated with intravenous drug use, poorly sterilized medical equipment and transfusions. In an estimated one in five cases of hepatitis C, the immune system will successfully eliminate the virus and the person will have no further symptoms (unless they become infected again). Depending on other risk factors, such as alcohol use, between 10% and 40% of people with untreated chronic hepatitis C will go on to develop scarring of the liver ( cirrhosis ), often more than twenty years after first catching the virus.
In general, treatment is recommended for those with proven HCV infection liver abnormalities; treatments consisted of a combination of pegylated interferon alpha (polyethylene glycol is added to make the interferon last longer in the body) and the antiviral drug ribavirin for a period of 24 or 48 weeks, depending on HCV genotype. Although the results has been encouraging, this treatment can cause cause severe nausea and depression, and other debilitating symptoms such as itchy skin, rash, tiredness, nausea, anemia, neutropenia.
Emergence of new drug-resistant virus strains are rare also because the virus does not have an animal reservoir, meaning that it is not harboured by other animals, and it is not easily spread between people, except through blood.
In December 2013, US Food and Drug Administration (FDA) approved a new drug , Sofosbuvir (brand name, SOVALDI™) from Gilead Sciences in Foster City, California for Hepatitis C treatment.
Sofosbuvir and other nucleotide inhibitors of the HCV RNA polymerase exhibit a very high barrier to resistance development. From December 2013, Sofosbuvir is a component of the first all-oral, interferon-free regimen approved for treating chronic hepatitis; interferon-free therapy for treatment of hepatitis C reduces the side effects associated with use of interferon. The FDA approved Sofosbuvir in combination with ribavirin (RBV) for oral dual therapy of HCV genotypes 2 and 3, and for triple therapy with injected pegylated interferon (pegIFN) and RBV for treatment-naive patients with HCV genotypes 1 and 4. As Sofosbuvir is always combined with other drugs such as ribavirin and interferon, only the adverse effects of these combinations have been evaluated. Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP).
The intracellular metabolic activation pathway of Sofosbuvir is mediated by generally low affinity and high capacity hydrolase and nucleotide phosphorylation pathways that are unlikely to be affected by concomitant drugs. Sofosbuvir will cost $84,000 for 12 weeks of treatment used for genotype 1 and 2, and $168,000 for the 24 weeks used for genotype 3. Sofosbuvir was approved by the European Medicines Agency (EMA) in January 2014; marketing of Sofosbuvir, authorized in all the 28 country of European Union, will be in 400 mg tablets for once-a-day oral administration, in association with other antiviral agents, while mono therapy is not recommended. The authorization was supported by five “Phase 3” studies data, NEUTRINO , FISSION , POSITRON , FUSION and VALENCE . Nowadays, Sofosbuvir has been approved in USA, Canada, Europe; authorization is on examination in Australia, New Zealand, Switzerland and Turkey. Hepatitis C virus is a single-stranded RNA virus, and its open-reading frame encodes ten structural proteins (viral capsid and envelope) and non-structural proteins (required for viral replication).
The effect of sofosbuvir 400 and 1200 mg on QTc interval was evaluated in a randomized, single-dose, placebo-, and active-controlled (moxifloxacin 400 mg) four period crossover thorough QT trial in 59 healthy subjects.
The pharmacokinetic properties of sofosbuvir and the predominant circulating metabolite GS-331007 have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C.
Relative to fasting conditions, the administration of a single dose of SOVALDI with a standardized high fat meal did not substantially affect the sofosbuvir Cmax or AUC0-inf. Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the dose was greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine, feces, and expired air, respectively.
Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polyme-rase, which is essential for viral replication.
HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. In a pooled analysis of 982 subjects who received SOVALDI in Phase 3 trials, 224 subjects had post-baseline NS5B genotypic data from next generation nucleotide sequencing (assay cutoff of 1%). Treatment-emergent substitutions L159F (n= 6) and V321A (n= 5) were de-tected in post-baseline samples from GT3a-infected subjects across the Phase 3 trials. In the trial done in subjects with hepatocellular carcinoma awaiting liver transplantation where subjects received up to 48 weeks of sofosbuvir and ribavirin, the L159F substitution emerged in multiple subjects with GT1a or GT2b HCV who experienced virologic failure (breakthrough and relapse). HCV replicons expressing the sofosbuvir-associated resistance substitution S282T were susceptible to NS5A inhibitors and ribavirin.
In the FISSION study, 499 treatment-naive patients with genotype 2 or 3 HCV were randomized to sofosbuvir 400 mg plus ribavirin for 12 weeks or peginterferon plus ribavirin for 24 weeks in a noninferiority trial. The NEUTRINO study was a 12-week open label study of sofosbuvir plus ribavirin in treatment naive patients with HCV genotype 1, 4, 5 or 6 (of whom 98% had genotype 1 or 4).
POSITRON evaluated sofosbuvir plus ribavirin compared with placebo in patients with genotype 2 and 3 HCV in whom interferon was not an option (previously intolerant of interferon, unwilling or unable to take interferon).
The FUSION study was a blinded, active-control study involving patients with genotype 2 or 3 HCV who had not had a response to prior treatment with an interferon-containing regimen. One obvious clinical need is for data regarding safety and efficacy of sofos-buvir in patients who have decompensated chronic liver disease, are peri-transplant or post-liver-transplant. The US FDA has recently (6 December, 2013) approved sofosbuvir under the brand name Sovaldi for the treatment chronic HCV infection under a breakthrough therapy designation, because it has shown a substantial improvement over the other available therapies. Although sofosbuvir is by no means one of the first DAA drugs to reach phase III clinical trials, the collective trial data for sofosbuvir do represent a significant paradigm shift in the management of HCV infection. During its October 2013 meeting, the CHMP gave an opinion on the conditions under which early access to sofosbuvir, in combination with other medicines, could be given in compassionate-use programmes, for patients with chronic hepatitis C infection before or after liver transplantation.
Such programmes, set up at the national level (in italy as well), are intended to give patients with a life-threatening, long-lasting or seriously disabling disease who have no available treatment options access to treatments that are still under development and that have not yet been authorised. During its November meeting, the CHMP also provided an opinion on the use of a combination of sofosbuvir with the antiviral daclatasvir in certain patients with chronic hepatitis C virus (HCV) infection, in a compassionate-use programme.
From the above discussion, it seems that sofosbuvir is a promising therapy for chronic HCV infection, as it offers several advantages over the existing therapies, particularly in dealing with patients with decompensated liver disease and patients who cannot tolerate interferon-containing therapies.


It should be kept in mind regarding diagnosis of hepatitis C that this test is not a part of routine physical examination and people should ask the doctor for hepatitis C test, if better hepatitis C treatment is required. Hepatitis C is symptomatic in the beginning, although chronic infection results in scarring of liver and later leads to cirrhosis of liver, Hepatocellular Carcinoma (HCC) and fatty liver.
Even a tiny drop of infected blood is capable of causing Hepatitis C, like using contaminated injecting equipment, sharing needles and blood contact on open wounds. Karun Verma’s award winning alternative treatment of Hepatitis C is highly effective Hepatitis C treatment in India with no side effects. Karun Verma’s Hepatitis C treatment in India were assessed on the basis on symptomatic relief, levels of serum glycolytic enzymes (AST, ALT) and HCV viral load only. In most cases, hepatitis C causes no noticeable symptoms until the liver has been significantly damaged.
Around one in five people with cirrhosis will then develop liver failure, and one in 20 will develop liver cancer, both of which can be fatal.
This treatment was shown to cure rates of between 70 and 80% for genotype 2 and 3, and 45 to 70% for other genotypes.
Improved screening of blood supplies used for transfusions and better patient-screening techniques have already greatly cut transmission rates over the last 15 years. The major point of this decision was a study in which it was shown that if taken in combination with ribavirin, the treatment eliminates hepatitis C in around 80% of people. The triphosphate acts like a substrate for the viral RNA polymerase, and inhibites of viral RNA synthesis. This is an important advantage relative to HCV drugs that target other viral enzymes such as the protease, for which rapid resistance development has proved to be an important cause of therapeutic failure. Sofosbuvir treatment regimens last 12 weeks for genotypes 1, 2 and 4, and 24 weeks for treatment of genotype 3. The price has moved controversy, with critics contending the drug is unaffordable and supporters suggesting that the drug brings price savings relative to older treatments associated with severe side effects, lengthy treatment, and low cure rates. The uridine nucleotide analog sofosbuvir is a phosphoramidate prodrug that has to be triphosphorylated within the cells to produce its action. At a dose three times the maximum recommended dose, SOVALDI does not prolong QTc to any clinically relevant extent.
Following oral administration of SOVALDI, sofosbuvir was absorbed with a peak plasma concentration observed at ~0.5-2 hour post-dose, regardless of dose level.
The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalyzed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway.
The majority of the sofosbuvir dose recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir. Sofosbuvir is a nucleotide pro-drug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. Reduced susceptibility to sofosbuvir was associated with the primary NS5B substitution S282T in all replicon genotypes examined. No detectable shift in the phenotypic susceptibility to sofosbuvir of subject isolates with L159F or V321A substitutions was seen. HCV replicons expressing the ribavirin-associated substitutions T390I and F415Y were susceptible to sofosbuvir.
It has the key function of replicating the HCV's viral RNA by using the viral positive RNA strand as its template and catalyzes the polymerization of ribonucleoside triphosphates (rNTP) during RNA replication.
In this trial, despite a marked difference in the RVR rates (99% versus 67%, respectively), the SVR12 rates were identical at 67% [Lawitz et al. SVR12 rates of 90% were observed overall, with 81% response rates in genotype 1 with cirrhosis. Patients were randomly assigned to either 12 weeks of sofosbuvir and ribavirin followed by 4 weeks of matching placebo, or 16 weeksof sofosbuvir and ribavirin. The excellent safety data to date and the lack of significant drug interactions makes sofosbuvir an appealing choice to be studied in these groups. The most interesting feature of this approval lies in the fact that this drug can be administered without the need of interferon therapy.
With sofosbuvir-based regimens, successful interferon-free treatment of HCV is now achievable across multiple genotypes, but different patterns of genotypic response to treatment have emerged compared with those seen in traditional interferon-based therapy. On account of its excellent performance in clinical trials, this drug has got FDA approval on 6 December, 2013, under the breakthrough therapy designation. In case if the initial test is found to be positive, a second test is referred to confirm the diagnosis of hepatitis C and liver enzymes. The herbal treatment of Hepatitis C is a ray of hope for those patients who are unable to tolerate, afford or not eligible for Interferon and Ribavirin therapy. After eight weeks of this Hepatitis C treatment in India, there was a significant decline in level of serum glycolytic enzymes in almost all cases. Hepatitis C symptoms usually appear four to six weeks after you’re infected and can range from mild to severe. When symptoms do occur, they are often vague and can be easily mistaken for another condition.
But researchers has been studying new treatments to increase cure rates, to avoid collateral effects and to eliminate latent form of the virus. Also in another study, a combination of Sofosbuvir and Simeprevir in 197 people with HCV who had either not responded to interferon or who had advanced liver fibrosis caused by the virus cleared the virus in more than 90% of participants. Prior to the discovery of Sofosbuvir, a variety of nucleoside analogs had been examined as anti-hepatitis C treatments, but these exhibited relatively low potency.
Most side effects are significantly more common in interferon containing regimens as compared to interferon-free ones. John's wort) may decrease Sofosbuvir plasma concentration leading to reduced therapeutic effect of it and thus should not be used with. There is also concern that patients in developing countries may not have sufficient access due to high prices; a key issue is that there are no international agencies or groups that purchase hepatitis C drugs for distribution to poor countries. The required enzymes for its activation are present in the human hepatic cells, therefore, it is converted to its active metabolite during the first-pass metabolism, directly at the desired site of action: The liver. After a single 400 mg dose of [14C]-sofosbuvir in healthy subjects, the blood to plasma ratio of 14C-radioactivity was approximately 0.7.
Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-HCV activity in vitro. An M289L substitution developed along with the S282T substitution in genotype 2a, 5 and 6 replicons. The sofosbuvir-associated resistance substitution S282T was not detected at baseline or in the failure isolates from Phase 3 trials.
In addition, S282R and L320F substitutions were detected on-treatment by next generation sequencing in a subject infected with GT1a HCV with a partial treatment response. Several crystal structures of NS5B polymerase in several crystalline forms have been determined based on the same consensus sequence BK (HCV-BK, genotype 1).


These cirrhotic patients also had extremely low rates of treatment discontinuation of only 2%, suggesting that this combination is safe and extremely well tolerated even in cirrhotic patients [Lawitz et al. Degree of liver fibrosis did not appear to significantly influence outcomes in genotype 2 patients (94% SVR12 even in those with cirrhosis), but in genotype 3 patients, SVR12 rates were low at 21% in patients with cirrhosis [Jacobson et al.
To date there is one case report published of a patient with severe recurrent cholestatic hepatitis C, 6 months post-transplant, who was effectively rescued and achieved SVR with treatment with sofosbuvir and daclatasvir in combination [Fontana et al. It is now clear that in the current DAA era, genotypes 2 and 3 should be evaluated quite separately, as SVR rates in genotype 3 patients are significantly lower than those seen in genotype 2 [Jacobson et al. This drug is effective against all HCV genotypes, has a better safety profile, and low risk of development of resistance; however, careful clinical use and monitoring is still essential, to gather more data on this drug. A liver biopsy is done to identify the degree and type of liver damage and for less complication in the hepatitis C treatment.
However, the success rate of this therapy is less than 50%, also resulting in lack of immunity, and at times unaffordable. This alternative treatment for Hepatitis C brought about a significant decline in HCV virus load in majority chronic cases of Hepatitis C treatment in India. If symptoms do occur, they develop about 7-8 weeks after being exposed to the virus and may include: feeling sick, vomiting and feeling generally unwell. Only around 15% of cases shows symptoms during the first six months of a hepatitis C infection: this stage is known as acute hepatitis C.
This low potency originates in part because the enzymatic addition of the first of the three phosphate groups of the triphosphate is slow. For example, fatigue and headache are nearly cut in half, influenza-like symptoms are reduced to 3–6% as compared to 16–18%, and neutropenia is almost absent in interferon-free treatment. Sofosbuvir should not be taken in association with anticonvulsants, antimycobacterials, HIV protease inhibitors. Doctors of the world and other association wrote an essay to stress the inability of most of common people and country to cope with such high prices.
The median terminal half-lives of sofosbuvir and GS-331007 were 0.4 and 27 hours, respectively.
Site-directed mutagenesis of the S282T substitution in replicons of 8 genotypes conferred 2- to 18-fold reduced susceptibility to sofosbuvir and reduced the replication viral capacity by 89% to 99% compared to the corresponding wild-type.
However, an S282T substitution was detected in one genotype 2b subject who relapsed at Week 4 post-treatment after 12 weeks of sofosbuvir monotherapy in the Phase 2 trial P7977-0523 [ELECTRON]. Notably, in this study there was a marked difference in response rates between patients with genotype 2 (97% SVR 12) and genotype 3 (56% SVR12) HCV, and between cirrhotic (47% SVR12) and noncirrhotic (72% SVR12) patients.
Overall rates of SVR were significantly higher in the 16-week arm (73%) than in the 12-week arm (50%), and again the genotype 2 patients had higher SVR rates (86% and 94% for 12 and 16 weeks, respectively) than genotype 3 patients (30% and 62% respectively for 12 and 16 weeks) [Jacobson et al.
Earlier it was under the FDA's priority review program (an expedited review of drugs useful for serious conditions, which, after their approval, would provide significant improvement in safety or effectiveness). Data on the effectiveness of this combination in cirrhotic genotype 1 null responders is awaited. Large post-marketing studies, including pharmacoepidemiological and pharmacovigilance studies, can solve many unanswered questions for the future of this novel drug. There is a new treatment for hepatitis C which includes a longer acting form of interferon which cures more patients having fewer side effects.
Some patients opt for liver transplant, though there is always a chance for HCV virus to recur post liver transplant.
The symptoms may include high temperature, tiredness, loss of appetite and they occur a few weeks after infection. Some of the most commonly reported symptoms of hepatitis C include: tiredness, headaches, depression, problems with short-term memory, concentration and completing relatively complex mental tasks, joint and muscle aches and pain, itchy skin, flu-like symptoms, like those that occur in the acute phase of the infection, abdominal pain, pain in the liver area (which is located in the right upper side of abdomen). The design of Sofosbuvir avoids this slow step by building the first phosphate group into the structure of the drug during synthesis. This analog then mimics the physiological nucleotide and competitively blocks the NS5B polymerase, thus inhibiting the HCV-RNA synthesis by RNA chain termination.
Relative to healthy subjects administered sofosbuvir alone (N = 272), the sofosbuvir AUC0-24 was 39% higher and GS-331007 AUC0-24 was 39% lower, respectively, in HCV-infected subjects. Evaluation of sofosbuvir in combination with interferon alpha or ribavirin showed no antagonistic effect in reducing HCV RNA levels in replicon cells. The isolate from this subject displayed a mean 13.5-fold reduced susceptibility to sofosbuvir.
The encircled active site, unique to NS5B, is contained within the palm structure of the protein.
This is promising, and results of future trials of sofosbuvir in these types of patient groups are awaited with interest. Positive results from major clinical trials, plus a demonstration of efficacy in patients who cannot tolerate interferon-based regimens and in patients with liver cancer undergoing liver transplantation, make this drug a valuable and very useful therapy for these patient populations. A new era of successful interferon-free DAA therapy for HCV is emerging, with potential to broaden treatment of HCV to include patient groups who have either avoided or not been suitable for previous interferon- based therapy, and it is likely that sofosbuvir will form the backbone of this treatment approach.
As of now, sofosbuvir is among the most promising agents available for the treatment of chronic HCV infection. No significant side effects (like headache, dizziness, digestive disturbances, fever, alopecia, lethargy or depression etc. Additional groups are attached to the phosphorus to temporarily mask the two negative charges of the phosphate group, thereby facilitating entry of the drug into the infected cell.
The catalytic site of the enzyme is also highly conserved across all the HCV genotypes, accounting for pan-genotypic efficacy of sofosbuvir.
Sofosbuvir and GS-331007 AUCs are near dose proportional over the dose range of 200 mg to 1200 mg. For this subject,the S282T substitution was no longer detectable at Week 12 post-treatment by next generation sequencing with an assay cut off of 1%. Recent studies on NS5B protein genotype 1b strain J4’s (HC-J4) structure indicate a presence of an active site where possible control of nucleotide binding occurs and initiation of de-novo RNA synthesis. Cirrhosis was associated with a decreased rate of SVR, particularly in genotype 3 receiving 12 weeks of therapy rather than 16 weeks (SVR 19% versus 61%). In genotype 2 patients SVR rates ranged from 60% to 78% in cirrhotic patients, and up to 100% in noncirrhotic patients without cirrhosis who were treated for 16 weeks.
In contrast, the presence of advanced liver fibrosis has a significant detrimental effect on SVR rates in genotype 3 patients when a 12-week regimen is used. Current research attempts to bind structures to this active site to alter its functionality in order to prevent further viral RNA replication.
The other strategy that could be considered is addition of another DAA to the regimen, but until these data are available to clarify the optimal interferon-free treatment of genotype 3 HCV patients with advanced fibrosis or previous treatment failure, there may be an initial role for continuing to use peginterferon together with sofosbuvir in this group of patients.



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