Valacyclovir and Acyclovir for Suppression of Shedding of Herpes Simplex Virus in the Genital Tract

Department of Medicine, University of Washington, Seattle, Washington 98122, USA. .
The Journal of Infectious Diseases (Impact Factor: 6). 11/2004; 190(8):1374-81. DOI: 10.1086/424519
Source: PubMed


Valacyclovir exhibits better oral absorption and higher, more prolonged serum concentrations than oral acyclovir. The efficacy of valacyclovir and acyclovir on genital herpes simplex virus (HSV) shedding was assessed in a double-blind, 3-period crossover trial.
Sixty-nine immunocompetent participants with genital HSV-2 received oral valacyclovir, acyclovir, and matching placebo in random order for 7-week periods. Participants provided daily genital mucosal swabs for HSV detection by viral culture and polymerase chain reaction (PCR).
HSV was detected at least once in 62 (90%) participants by culture and in 68 (98%) by PCR. During placebo, the total HSV shedding rate was 15.4% of days by culture (PCR, 40.2%); the subclinical shedding rate was 6.6% by culture (PCR, 27.1%). Both antivirals were associated with lower HSV shedding by culture (relative risk [RR], 0.03 [95% confidence interval [CI], 0.01-0.07] for valacyclovir and RR, 0.05 [95% CI, 0.03-0.10] for acyclovir) and PCR (RR, 0.18 [95% CI, 0.12-0.26] for valacyclovir and RR, 0.20 [95% CI, 0.15-0.28] for acyclovir), compared with placebo. No significant differences in frequency and quantity of HSV were detected by PCR between the valacyclovir and acyclovir arms.
Although the suppression of viral replication is not complete, valacyclovir and acyclovir are highly effective in suppressing the frequency and quantity of genital HSV shedding.

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    • "Rates of infection are even higher among women, owing to the greater efficiency of male-to-female (MTF) transmission [6, 7]. While multiple variables factor into the high prevalence rate at the population level, the fact that most sexual transmissions occur in the absence of clinically identifiable genital lesions likely plays a major role [8, 9]. While antiviral drugs have proven effective to reduce viral transmission [6, 8, 10], they are not curative. "
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    ABSTRACT: The global impact of sexually transmitted infections (STIs) is significant. The sexual transmission of viruses such as herpes simplex virus type-2 (HSV-2) and the human immunodeficiency virus type-1 (HIV-1), has been especially difficult to control. To date, no effective vaccines have been developed to prevent the transmission of these STIs. Although antiretroviral drugs have been remarkably successful in treating the symptoms associated with these viral infections, the feasibility of their widespread use for prevention purposes may be more limited. Microbicides might provide an attractive alternative option to reduce their spread. In particular, topically applied small inhibitory RNAs (siRNAs) have been shown to not only block transmission of viral STIs to mucosal tissues both in vitro and in vivo, but also confer durable knockdown of target gene expression, thereby circumventing the need to apply a microbicide around the time of sexual encounter, when compliance is mostly difficult. Despite numerous clinical trials currently testing the efficacy of siRNA-based therapeutics, they have yet to be approved for use in the treatment of viral STIs. While several obstacles to their successful implementation in the clinic still exist, promising preclinical studies suggest that siRNAs are a viable modality for the future prevention and treatment of HSV and HIV.
    Infectious Diseases in Obstetrics and Gynecology 01/2014; 2014:125087. DOI:10.1155/2014/125087
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    • "Although most HSV-2 seropositive individuals are asymptomatic, more than three-quarters shed virus, and it is during periods of subclinical shedding in the source partner when most sexual transmission of HSV-2 takes place [12, 41–43]. Prophylactic ACV or VACV has been shown to reduce both viral shedding and sexual transmission of HSV-2 [23, 25, 28, 44] and does not lead to drug resistance in immunocompetent patients [28]. "
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    ABSTRACT: Following initial infection, herpesviruses retreat into a permanent latent state with periodic reactivation resulting in an enhanced likelihood of transmission and clinical disease. The nucleoside analogue acyclovir reduces clinical symptoms of the three human alpha herpesviruses, HSV-1, HSV-2, and VZV. Long-term administration of acyclovir (ACV) can reduce the frequency and severity of reactivation, but its low bioavailability and short half-life require a daily drug regimen. Our lab is working to develop a subcutaneous delivery system to provide long-lasting, sustained release of ACV. Previously, we demonstrated that an implantable silicone (MED-4050) device, impregnated with ACV protected against HSV-1 both in vitro and in vivo. Here, we extend our in vitro observations to include protection against both HSV-2 and VZV. We also demonstrate protection against HSV-2 in vitro using MED-4750, a silicone polymer designed for long-term use in humans. When release of ACV from MED-4750 is quantitated on a daily basis, an initial burst of 5 days is observed, followed by a long period of slow release with near-zero-order kinetics, with an average daily release of 1.3923 ± 0.5908 μ g ACV over days 20-60. Development of a slow-release implant has the potential to significantly impact the treatment of human alpha herpesvirus infections.
    Advances in Pharmacological Sciences 08/2013; 2013:915159. DOI:10.1155/2013/915159
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    • "In one natural history study, women who acquired genital herpes within a year before enrollment had more frequent shedding compared to women who had been infected for one year or more [8]. Another study found that individuals diagnosed for ≤6 months were twice as likely to shed asymptomatically compared to those diagnosed for more than 6 months [11]. Collectively, higher viral shedding and recurrence rates in subjects with newly acquired infection may translate to an increased risk of transmitting virus to uninfected sex partners. "
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    ABSTRACT: Genital herpes (GH) recurrences and viral shedding are more frequent in the first year after initial HSV-2 infection. 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. 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. A daily swab of the genital/anal-rectal area was self-collected for HSV-2 detection by PCR. Subjects attended the clinic for routine study visits and GH recurrence visits. Treatment differences were assessed using a nonparametric crossover analysis. 52 subjects had at least one PCR measurement in both treatment periods and comprised the primary efficacy population. Valacyclovir significantly reduced HSV-2 shedding during all days compared to placebo (mean 2.9% versus 13.5% of all days (P < .01), a 78% reduction). Valacyclovir significantly reduced subclinical HSV-2 shedding during all days compared to placebo (mean 2.4% versus 11.0% of all days (P < .01), a 78% reduction). However, 79% of subjects had no GH recurrences while receiving valacyclovir compared to 52% of subjects receiving placebo (P < .01). In this study, the frequency of total and subclinical HSV-2 shedding was greater than reported in earlier studies involving subjects with a history of symptomatic genital recurrences. Our study is the first to demonstrate a significant reduction in viral shedding with valacyclovir 1 g daily compared to placebo in a population of subjects newly diagnosed with HSV-2 infection.
    Infectious Diseases in Obstetrics and Gynecology 02/2009; 2009:105376. DOI:10.1155/2009/105376
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