Author: admin | 17.08.2014

Researchers may just have come one step closer to finding a possible cure for genital herpes, a common yet incurable sexually transmitted infection.
The drug, called pritelivir, curbs "viral shedding," or the amount of time the virus was active and potentially transmissible to the sexual partners of people with genital herpes.
This was discovered in a small preliminary study, which was funded by AiCuris, the pharmaceutical company that is developing pritelivir.
At the end of four weeks, researchers found that patients who were on a daily dose of 75 milligrams of pritelivir demonstrated the biggest response to the medication. The occurrence of genital lesions also decreased to 1.2 percent of days among those who took pritelivir, compared to 9 percent of days for those who took a placebo. Genital herpes is caused by the herpes simplex virus, specifically the strain called HSV-2. In many cases the virus causes mild to no symptoms, so those infected but show none of the symptoms, are not even aware that they need treatment. Enter the email associated with your account and we will send you an email with a link to reset it. An investigational drug (pritelivir), with a novel mechanism of action, reduced the rate of viral shedding in patients with genital herpes simplex virus-2 infection.Note that the rate of adverse events was not elevated in any of the groups receiving different dosages compared with placebo. An investigational drug with a novel mechanism of action reduced the rate of viral shedding in patients with genital herpes simplex virus-2 (HSV-2) infection, researchers reported. In a small, double-blind, placebo-controlled study, the drug, dubbed pritelivir, also reduced the number of days patients had genital lesions, according to Anna Wald, MD, of the University of Washington in Seattle, and colleagues. The effect was dose-dependent, and the rate of adverse events was similar among treatment groups, Wald and colleagues reported in the Jan. Although several drugs are licensed to treat HSV-2, they are all nucleoside analogs that block the action of the viral DNA polymerase, Wald and colleagues noted. Also, while they "ameliorate" clinical disease, they do not reduce viral shedding and only partly block sexual transmission.
Pritelivir is the first in a new class of HSV drugs that blocks replication by targeting the viral helicase-primase enzyme complex, which works with the polymerase to direct HSV DNA synthesis.
In pre-clinical research, the drug was potent against HSV-1 and HSV-2 isolates and was efficacious in animals, while phase I trials in humans did not raise any safety concerns.
To test the efficacy of the drug and to find the best dose, Wall and colleagues studied outcomes in 156 people who took pritelivir either daily or weekly for 28 days. The primary endpoint was comparison with placebo in the proportion of days in which viral shedding was seen, but the researchers also looked at the number of days in which lesions were observed as well as safety. The bottom line, Wald and colleagues reported, was that a daily dose of 75 mg of the drug led to an 87% reduction in the relative risk of viral shedding. That's important, commented Jeffrey Klausner, MD, of the University of California Los Angeles, because shedding is linked to transmission of the virus. The approved drugs "decrease lesions but not shedding," commented Richard Pollard, MD, of the University of California Davis.
Other findings, Wald and colleagues reported, include: Viral shedding was reduced 68%, compared with placebo, with a weekly dose of 400 mg. The findings are an important step toward better treatment for herpes infections, which can be life threatening, commented Richard Whitley, MD, and Mark Prichard, PhD, both of the University of Alabama Birmingham. In an accompanying editorial, they noted that the drug has the potential to be an alternative that will allow treatment in cases where resistance to approved drugs has developed.
And, they added, it opens the door to combination therapies, since pritelivir has a different target than the nucleoside analogs, such as acyclovir. Other experts agreed that the potential for combining the drug with earlier medications is an exciting aspect of the research. And, even though, like the earlier medications, the drug targets DNA replication, it "acts by a different mechanism," commented Betsy Herold, MD, of Albert Einstein College of Medicine in New York City. Among other things, she told MedPage Today, that means it would be active against virus that is resistant to acyclovir and similar drugs.
On the other hand, combination treatment is not a slam-dunk, commented Subhakar Mutyala, MD, of Scott & White Healthcare in Temple, Texas. The next step for the research ought to be a trial comparing pritelivir with one or more of the approved drugs, several experts commented. Indeed, Herold noted that such a study was started but has been placed on hold by the FDA because of unexplained dermal and hematologic toxicity in monkeys. Wald and colleagues noted in the journal that the animals were given very high doses -- more than 70 times the 75-mg dose in the current study. MedPageToday is a trusted and reliable source for clinical and policy coverage that directly affects the lives and practices of health care professionals. Physicians and other healthcare professionals may also receive Continuing Medical Education (CME) and Continuing Education (CE) credits at no cost for participating in MedPage Today-hosted educational activities. 6 months were twice as likely to shed asymptomatically compared to those diagnosed for more than 6 months [11].
Richard Whitley, a professor of pediatric infectious diseases at the University of Alabama at Birmingham.
Because the virus hides in nerve cells and reactivates periodically, there is no cure for genital herpes. The percentage of days with genital lesions was 9% in the placebo group and 1.2% in both the 75-mg-a-day group and those getting 400 mg weekly. Wald reported financial links with Amgen, Vical, Agenus, Genentech, Genocea, and Gilead.Whitley and Prichard had no relevant disclosures. 52 subjects had at least one PCR measurement in both treatment periods and comprised the primary efficacy population.

In addition, sexual transmission of HSV can occur during asymptomatic periods, and asymptomatic viral shedding is most frequent during the first 12 months after acquiring HSV-2 (5). Centers for Disease Control and Prevention (CDC), about 16 percent of Americans aged 14-49 are infected with HSV-2. However, medication can be taken to treat its symptoms and suppress the outbreak of new symptoms. Several investigations have supported the effect of suppressive antiviral therapy on the reduction of viral shedding in patients with an established recurrence pattern [9, 11, 14–17].
Viral isolates from cultures were confirmed and typed with monoclonal antibodies at Quest Diagnostics.
These results are similar to those of the first two studies [12, 13] noted above except that the proportion of days with shedding while on placebo was slightly higher in the current study.
Two recent studies have shown that suppressive therapy with valacyclovir in subjects with newly diagnosed HSV-2 genital herpes has clinical efficacy in reducing outbreaks, similar to that seen in persons with established recurrent disease [18, 19].
Interestingly, those who received the drug in 400 mg dosage on a weekly basis, showed shedding on 5.3 percent of the days. The material on this site is for informational purposes only, and is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.
More recent studies have shown that suppressive antiviral therapy is as effective at controlling symptomatic disease in recently infected persons as it is in those with prevalent infection [18, 19].
It is not clear if that difference is meaningful, but it could be because our subjects were recently infected and these persons shed virus more frequently than those with established disease [8, 9]. The current study extends those findings by showing that the impact of suppressive valacyclovir on viral shedding is also similar to that found in persons with established recurrent genital herpes.
One group was given placebo pills, while the other four were given different doses of pritelivir. This is significant because if once a week dosage is effective, treatment among patients would be more acceptable and convenient. Because clinical and subclinical reactivation of HSV may result in the sexual transmission of HSV to a partner, suppressing viral shedding is important at both the individual and population level [12]. Taken together, these studies suggest that there is no reason to wait until a person with newly diagnosed genital herpes establishes a recurrence pattern to consider suppressive therapy. Robinson, “Age-specific prevalence of infection with herpes simplex virus types 2 and 1: a global review,” Journal of Infectious Diseases, vol. The current study was conducted to provide additional natural history data in individuals who have been given a new diagnosis of genital herpes, and to provide the first evaluation of the efficacy of valacyclovir 1 g once daily in reducing HSV-2 shedding in this population.
However, the proportional reduction of shedding in subjects on suppression in our study was similar to that reported by Gupta et al. To allow for dropouts, a sample size of 66 subjects was chosen.The populations considered in the overall analysis included the Intent-to-Treat (ITT) exposed, consisting of all subjects who received at least one dose of investigational product. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.AbstractObjective.
DesignThis was a double-blind, randomized, multicenter, two-way crossover study conducted at 14 centers in the United States (US) between February and November 2006.
Genital herpes (GH) recurrences and viral shedding are more frequent in the first year after initial HSV-2 infection. Subjects were randomized to receive valacyclovir 1 g or matching placebo once daily for 60 days in each of two treatment periods in a two-way crossover design. Also considered was the Intent-to-Treat Crossover (ITTC) population consisting of all ITT subjects who had at least one PCR result in each treatment period. These subjects clearly had new HSV-2 infections while the remaining study subjects had been infected long enough to mount an antibody response by the time they enrolled in the study.
Corey, “Development of clinically recognizable genital lesions among women previously identified as having “asymptomatic” herpes simplex virus type 2 infection,” Annals of Internal Medicine, vol.
The objective of this study was to provide the first evaluation of valacyclovir 1 g once daily compared to placebo in reducing viral shedding in subjects newly diagnosed with GH. In our study, the term VAL-PBO is used to describe the treatment order for subjects randomized to receive valacyclovir in the first treatment period followed by placebo in the second treatment period; the term PBO-VAL is used to describe the treatment order for subjects randomized to receive placebo in the first treatment period followed by valacyclovir in the second treatment period. This provided us with the opportunity to explore the differences in viral shedding between those with and without antibodies to HSV-2 in the group randomized to placebo treatment in the first study period. Handsfield, “Genital herpes and public health: addressing a global problem,” Journal of the American Medical Association, vol. The First Period Efficacy population consisted of all patients with efficacy data in the ITT-Exposed, with the exception of 2 subjects whose data was compromised (see Section 3). As was previously reported in a study that evaluated viral shedding by culture in initially HSV-2 seronegative subjects [23], asymptomatic shedding was extremely common.
Fife receives research support from Antigenics, Astellas, Gilead, GlaxoSmithKine, Novartis and Wyeth, and is a member of the Speaker’s Bureau for Merck. 70 subjects were randomized to receive valacyclovir 1 g daily or placebo in a crossover design for 60 days with a 7-day washout period.
This was the primary population for assessing efficacy in the first treatment period.The treatment comparison for continuous endpoints, including the primary endpoint, was tested using nonparametric crossover analysis methods in the ITTC population [21].
Our post-hoc analysis showed shedding rates 4-to5-fold higher among those initially HSV-2 seronegative subjects compared to the broader group of subjects who were newly diagnosed but already HSV-2 seropositive. The primary endpoint was the percent of all days with any HSV-2 viral shedding over 60 days defined, for each subject as the percent of all days with PCR data for which HSV-2 shedding was detected by a positive PCR result.
The test of treatment difference was preceded by a test of carryover effect using a Wilcoxon rank-sum test at the 5% level of significance [21]. Given the limited number of patients in the HSV-2 seronegative subset, the viral shedding results in this cohort must be interpreted with caution, yet the observation suggests the potential importance of early treatment in persons with new HSV-2 infection.

If this test was significant, then the treatment comparison would be tested using The First Period Efficacy population only. Study PopulationEligible subjects were diagnosed with a first recognized episode of herpes at the screening visit or within 4 months of randomization. Subjects were required to have documented signs and symptoms of genital HSV-2 infection, as well as laboratory confirmation (positive culture, PCR, or type-specific serology) of HSV-2 infection to be eligible for the study.
Time to first genital recurrence was evaluated with Kaplan-Meier estimates and log-rank test using the First Period Efficacy population and data in treatment period 1. Ashley, “Recurrence rates in genital herpes after symptomatic first-episode infection,” Annals of Internal Medicine, vol.
It was accepted that a subject’s first recognized episode of genital herpes might not represent new infection as prior episodes may have escaped detection. Subject CharacteristicsSeventy subjects from 14 centers in the United States were randomized into the study, 35 subjects to the VAL-PBO treatment sequence, and 35 subjects to the PBO-VAL treatment sequence. Kottiri, et al., “Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States,” Journal of the American Medical Association, vol. ProceduresA subject’s participation in the study included a screening evaluation, a randomization visit, and eight study visits (four visits per treatment period, with a 15-day interval between each visit). During the course of routine monitoring, errors in sample identification were discovered for two subjects at one site.
The error was felt to compromise the integrity of the data; therefore, swab samples from two subjects in the VAL-PBO sequence group were excluded from the efficacy analysis. These three subjects had some swabbing samples but all PCR assay results were missing, leaving 65 subjects in the First Period Efficacy population.
Once randomized, subjects attended the clinic for additional visits if they suspected they had a genital herpes recurrence. Twenty of the 70 (29%) subjects in the ITT population prematurely withdrew from the study (11 while receiving valacyclovir, 9 while receiving placebo). Cates Jr., “Estimates of the incidence and prevalence of sexually transmitted diseases in the United States,” Sexually Transmitted Diseases, vol. A genital examination was conducted at the screening visit for subjects who presented with genital herpes signs or symptoms.
Genital examinations also were conducted at the randomization and genital herpes recurrence visits for all subjects. Corey, “Virologic characteristics of subclinical and symptomatic genital herpes infections,” The New England Journal of Medicine, vol. On Day 1 of a genital herpes recurrence, swabs of the lesion also were collected in the clinic for HSV-2 detection by culture and PCR. During a documented recurrence, a subject temporarily discontinued blinded study medication and received open-label episodic treatment with valacyclovir 500 mg twice daily for 3 days, after which double-blind therapy resumed. Subjects used a telephonic, interactive voice response system daily to capture information on genital lesions, genital symptoms, and oral outbreaks. Adverse events, concomitant medications, and treatment compliance information were collected at each clinic visit, based on recall and discussion with the subject as well as pill counts. Blood and urine samples were collected for hematology, clinical chemistry, and urinalysis at the screening visit and at the end of each treatment period. Laboratory MethodsThe HerpeSelect ELISA glycoprotein G-based assay (Focus Diagnostics, Cypress, Calif, USA) was used to detect the presence of HSV-1 and HSV-2 antibodies at screen (Quest Diagnostics, Van Nuys, Calif, USA). Zeh, “Frequent genital herpes simplex virus 2 shedding in immunocompetent women: effect of acyclovir treatment,” The Journal of Clinical Investigation, vol. Corey, “Clinical reactivation of genital herpes simplex virus infection decreases in frequency over time,” Annals of Internal Medicine, vol.
Krantz, et al., “Valacyclovir and acyclovir for suppression of shedding of herpes simplex virus in the genital tract,” Journal of Infectious Diseases, vol.
Patel, et al., “Once-daily valacyclovir to reduce the risk of transmission of genital herpes,” The New England Journal of Medicine, vol. Patel, “Asymptomatic shedding of herpes simplex virus from the genital tract: uncertainty and its consequences for patient management,” International Journal of STD and AIDS, vol. Caissie, “Detection of viral DNA to evaluate outcome of antiviral treatment of patients with recurrent genital herpes,” Journal of Clinical Microbiology, vol. Hallahan, “Acyclovir suppresses subclinical shedding of herpes simplex virus,” Annals of Internal Medicine, vol.
Phillips, “Suppressive therapy with valacyclovir in early genital herpes: a pilot study of clinical efficacy and herpes-related quality of life,” Sexually Transmitted Diseases, vol.
Heitman, “An international, randomized, double-blind, placebo-controlled, study of valacyclovir for the suppression of herpes simplex virus type 2 genital herpes in newly diagnosed patients,” Sexually Transmitted Diseases, vol. Corey, “Development of a high-throughput quantitative assay for detecting herpes simplex virus DNA in clinical samples,” Journal of Clinical Microbiology, vol. Koch, “The use of non-parametric methods in the statistical analysis of the two-period change-over design,” Biometrics, vol. Senn, Crossover Trials in Clinical Trial Research, John Wiley & Sons, London, UK, 2nd edition, 2002. Corey, “Asymptomatic reactivation of herpes simplex virus in women after the first episode of genital herpes,” Annals of Internal Medicine, vol.

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