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Valacyclovir and Acyclovir for Suppression of Shedding of Herpes Simplex Virus in the Genital Tract
  The Journal of Infectious Diseases Oct 15, 2004;190:1374-1381
Rachna Gupta,1 Anna Wald,1,2,3,4 Elizabeth Krantz,3 Stacy Selke,3 Terri Warren,5 Mauricio Vargas-Cortes,6,a Gerri Miller,6 and Lawrence Corey1,3,4
Departments of 1Medicine, 2Epidemiology, and 3Laboratory Medicine, University of Washington, and 4Program in Infectious Diseases, Fred Hutchinson Cancer Center, Seattle; 5Westover Heights Clinic, Portland, Oregon; 6GlaxoSmithKline, Research Triangle Park, North Carolina
Background. 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.
Methods. 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).
Results. 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.
Conclusions. 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.
Most sexual transmission of herpes simplex virus (HSV) type 2 occurs on days without genital lesions in the source partner. Acyclovir reduces both clinical and subclinical shedding of HSV-2 in the genital tract; however, the virus can still be detected by DNA polymerase chain reaction (PCR) on 8% of the days during suppressive therapy. Valacyclovir is a prodrug of acyclovir that has better oral absorption and, at high doses, can provide serum levels of acyclovir that are comparable to those of intravenous administration. The projected area under the curve of a 500-mg twice-a-day dose of valacyclovir is 〜3 times greater than that of a 400-mg twice-a-day dose of oral acyclovir. Studies in patients with symptomatic recurrent genital herpes have shown that valacyclovir has comparable efficacy to acyclovir. To investigate the efficacy of valacyclovir on the shedding of HSV from genital mucosa, we compared the effect of valacyclovir and acyclovir on viral shedding in persons with recently acquired or frequently recurring genital HSV-2 infection.
The present results demonstrate several issues about the natural history of HSV reactivation in the genital tract and the effects of antiviral therapy on reactivation. HSV reactivation in both men and women is frequent, especially when measured by quantitative PCR. Treatment with valacyclovir or acyclovir is effective in reducing subclinical and total HSV shedding. The frequency of both total and subclinical shedding decreased with antiviral therapy by 91%--97% when measured by culture and by 76%--82% when measured by PCR. This effect was seen at all anatomic sites and in both men and women. Additionally, the quantity of HSV shed and the number of recurrences were also significantly reduced.
The subclinical reactivation of HSV accounted for a large proportion of total HSV shedding observed during the study. While subjects were receiving placebo, nearly one-third of all days with positive HSV cultures occurred on days without any reported lesions. Using the more-sensitive PCR method, one-half of the total days with HSV DNA detected while subjects were receiving placebo occurred in the absence of lesions. While subjects were receiving therapy with acyclovir or valacyclovir, most of the culture- and PCR-positive days were subclinical in nature.
The magnitude of effect of therapy on genital HSV suppression with valacyclovir was comparable to that achieved with acyclovir. We chose the dose of valacyclovir 500 mg twice daily, because our study was initiated before studies that established the clinical efficacy of once-daily therapy, and our goal was to maximize the potential advantage of valacyclovir over acyclovir. Valacyclovir is rapidly converted to acyclovir after absorption and achieves higher plasma levels of acyclovir than oral preparations of acyclovir. The present study data show that neither valacyclovir nor acyclovir leads to 100% suppression of HSV detection on mucosal surfaces. Nonetheless, the clinical and virological effect of both antivirals is pronounced.
For total, subclinical, and lesional shedding (measured by the number of culture- and PCR-positive days), there was a trend in favor of valacyclovir—patients who received valacyclovir shed virus on a smaller percentage of days than when they received acyclovir. However, the observed difference of 5% in subclinical shedding rates by PCR was small and was far below the hypothesized 50% reduction on which we calculated our sample size. Whether a much larger study would show better suppression with valacyclovir versus acyclovir is unknown. It is unclear why occasional episodes of high copy numbers of HSV DNA shedding were seen while subjects were receiving daily therapy. A detailed analysis of compliance showed no association between missed pill use (which was very infrequent) and breakthrough shedding. Whether the limits of suppression that we have described can be further reduced by higher doses of drug or the addition of compounds with alternative mechanisms of action (e.g., helicase inhibitors) are questions that remain unanswered.
The subclinical shedding rate of this cohort was 6.6% by culture, which is higher than the rates of 1%--4% in immunocompetent hosts that have been described elsewhere. This rate likely reflects the high risk factors of this cohort, recent HSV-2 acquisition, and frequent recurrences. The study population was specifically chosen to be "high shedders," to facilitate the detection of potential differences between the antiviral agents. The frequency of HSV reactivation, as defined by lesions and the degree of reduction in genital lesions by valacyclovir and acyclovir, was similar to previous studies of these medications in persons with frequently recurring genital herpes.
The effect of antiviral treatment on shedding has a time lag. Viral suppression is not immediate and takes 5 days to achieve. After the cessation of therapy, the suppression effect lingers and returns to pretreatment levels in 5 days. This lag may reflect the inhibition of viral replication that occurs not only at the mucosal but also at the neuronal level. Of interest, reactivation of HSV-2 on buttock sites after ultraviolet light exposure occurs after 〜5 days, which suggests that this is the time required for the virus to become evident at the mucosa after reactivation.
Our results help elucidate the dynamics of mucosal HSV detection. Both clinical and subclinical reactivation of HSV in an individual may result in the sexual transmission of HSV to their partner. Subclinical reactivation is unrecognized and may occur sporadically and frequently; hence, it is felt to be the major mode of HSV transmission. The significance of suppressing HSV shedding with antiviral medication was recently demonstrated in a large international, randomized, placebo-controlled trial. In that study of >1400 heterosexual, HSV-2 antibody--discordant couples, once-daily valacyclovir (500 mg) reduced the risk of transmitting symptomatic genital herpes by 75% and overall acquisition of HSV-2 by 48%. A shedding substudy (n = 89 subjects) that used a similar protocol indicated that once-daily valacyclovir also reduced the frequency of viral shedding as measured by PCR by 73%, a rate similar to that observed in the present study. It is unclear whether there are any definitive correlates between frequency of reduction in subclinical shedding and transmission. Developing such a surrogate measurement for transmission requires more study. However, it is reassuring to see that a reduction in transmission is associated with a reduction in viral shedding on mucosal surfaces.
The strengths of the present study include the large number of participants for an investigation of this type; daily sample collection, which provided >20,000 specimens for analysis; a low attrition rate; and a high rate of adherence to study drug and procedures. In addition, the majority of genital lesions were confirmed by a clinician, which minimized the misclassification of lesional days of shedding as subclinical days. Our study population was highly selected for interest in such a labor-intensive study and was mostly white. The effect of race on HSV reactivation has not been evaluated. Although a history of recognized genital herpes is found less frequently among African Americans with HSV-2 antibody in the United States, shedding has not been systematically studied in other populations. Preliminary data from Africa, focusing on HIV seropositive women, suggest that HSV reactivation is common in that population as well.
In summary, we found that valacyclovir and acyclovir are highly effective in suppressing the frequency and quantity of HSV shedding. Current antivirals do not achieve an absolute cessation of shedding, but the effect on HSV shedding is sustained beyond the half-life of the drug.
Subjects and setting. Healthy men and women who were seropositive for HSV-2 were considered for enrollment. Patients were eligible if they had a diagnosis of a first episode of genital HSV-2 infection <6 months before enrollment. Alternatively, patients were eligible if they had longstanding genital herpes infection and a recurrence rate of >6 episodes during the preceding year. Patients who had been receiving recent suppressive therapy were eligible if they reported >recurrences/year before initiating suppressive therapy. Suppressive therapy was stopped for at least 1 month before enrollment, and at least 1 recurrence was required during that time. Subjects were excluded if they were immunocompromised, HIV positive, had abnormal renal or hepatic function, or had a history of malabsorption or of ocular HSV. Women of childbearing potential had to use an effective method of contraception throughout the study. Study participants were recruited by newspaper advertisements, flyers, and local health clinics at 2 centers: the University of Washington (UW) Virology Research Clinic in Seattle and the Westover Heights Clinic in Portland, Oregon. Enrollment took place between August 1995 and July 1996. The protocol was approved by human subjects review committees, and all subjects gave written, informed consent.
Study design. The study was a randomized, double-blind, placebo-controlled, 3-period, crossover trial. Sixty-nine subjects received oral acyclovir 400 mg twice a day, valacyclovir 500 mg twice a day, and placebo twice a day, in random order. After 7 weeks of receiving the initial treatment, each participant crossed over to the second treatment for 7 weeks and then to the third treatment for the final 7 weeks. A 1-week washout period of placebo followed the first 2 treatment arms. Participants were stratified by the duration of their HSV-2 infection and sex and were then randomized by blocks at entry. One stratum was composed of patients with a diagnosis of a first episode of genital herpes infection <6 months before randomization. The other stratum was composed of patients diagnosed with genital herpes >6 months before randomization and who had a history of >recurrences/year in the absence of suppressive therapy. At the time of enrollment, participants were taught to recognize clinical episodes of HSV, and they visited the clinic every 2 weeks thereafter. During HSV recurrences, participants continued their assigned study treatment and reported to the clinic within 24 h of an outbreak for evaluation.
Throughout the 161 study days, participants collected daily swabs of genital secretions, as described elsewhere. Women swabbed the cervicovaginal, vulvar, and perianal areas, and men swabbed the penile skin and perianal area. Participants also collected a daily mixed swab of the entire genital area and were asked to collect additional swabs of genital lesions during a recurrence, in addition to the regular daily swabs. Each area was swabbed with 2 Dacron swabs held together; 1 was placed in viral culture media and the second in PCR buffer. Samples were collected by courier 3 times/week for delivery to the virology laboratory. Participants maintained a daily diary of medication use, adverse experiences, genital symptoms, and the presence of lesions.
The primary end points of the study were to evaluate the efficacy of valacyclovir and acyclovir for the suppression of subclinical HSV shedding in immunocompetent subjects as measured by culture and PCR, to evaluate the effect of valacyclovir and acyclovir on the amount and distribution of the number of HSV DNA copies detected by quantitative PCR and to evaluate the safety and tolerance of valacyclovir and acyclovir. Secondary end points were to evaluate the efficacy of valacyclovir and acyclovir for the suppression of total (subclinical and lesional) shedding by culture and PCR and to evaluate the efficacy of valacyclovir and acyclovir for the suppression of recurrences.
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