Sexually Transmitted Diseases:
Comparative Efficacy of Famciclovir and Valacyclovir for Suppression of Recurrent Genital Herpes and Viral Shedding
Wald, Anna MD, MPH*†‡; Selke, Stacy MS‡; Warren, Terri RN, ANP§; Aoki, Fred Y. MD∥; Sacks, Stephen MD¶; Diaz-Mitoma, Francisco MD, PhD#; Corey, Lawrence MD*‡**
From the *Departments of Medicine, †Epidemiology, and ‡Laboratory Medicine, School of Medicine and School of Public Health and Community Medicine, University of Washington, Seattle, Washington; §Westover Heights Clinic, Portland, Oregon; ∥Viridae Clinical Sciences Inc., Vancouver, BC, Canada; ¶Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada; #Department of Pathology and Laboratory Medicine, University of Ottawa, Ontario, Canada; and the **Fred Hutchinson Cancer Research Center, Seattle, Washington
Funding for the studies was provided by SmithKline Beecham. Dr. Sacks died before completion of this manuscript but was an active researcher in the study. Other investigators in these studies included V. Beltrani, Poughkeepsie, NY; W. Coxwell, Austell, GA; M. Drehobl, San Diego, CA; K. Fife, Indianapolis, IN; S. Kraus, Atlanta, GA; T. Kurtz, Des Moines, IA; M. Lassonde, Montreal, PQ, Canada; L. Marr, Portland, OR; J. Nahlik, St. Louis, MO; J. Pickens, Memphis, TN; B. Romanowski, Edmonton, AB, Canada; T. Russell, Milwaukee, WI; J. Shupack, New York, NY; G. Trono, Hartford, CT; R. Tucker, Wenatchee, WA; S. Tyring, Naussau Bay, TX; M. Weinstein, Bryan, TX.
Conflict of interest: All authors received research grants from SmithKline Beecham for the conduct of the studies. Dr. Wald is a consultant to Novartis, current proprietors of famciclovir.
Correspondence: Anna Wald, MD, MPH, University of Washington Virology Research Clinic, 600 Broadway, Suite 400, Seattle, WA 98122. E-mail: email@example.com
Background: Daily antiviral therapy with famciclovir and valacyclovir has been shown to be effective in reducing both symptomatic and asymptomatic reactivation of herpes simplex virus type 2 (HSV-2) when compared to placebo. However, few comparative studies between the 2 antivirals have been performed.
Objectives: To compare the clinical and virologic effects of famciclovir and valacyclovir administered as daily suppressive therapy for persons with genital herpes.
Study Design: Two randomized, double-blind, placebo-controlled studies comparing daily famciclovir 250 mg bid with valacyclovir 500 mg qd were performed. Study 1 randomized 320 participants and compared the clinical effect of the drugs given for 16 weeks, and study 2 enrolled 70 HSV-2 seropositive subjects and compared the virologic effect of the drugs given for 10 weeks.
Results: In study 1, the time to first recurrence was similar in famciclovir and valacyclovir recipients, hazard ratio (HR) 1.17 (95% CI, 0.78–1.76), but time to first virologically confirmed recurrence was shorter among famciclovir recipients, HR = 2.15 (95% CI, 1.00–4.60). In study 2, HSV was detected on 3.2% of days among famciclovir recipients and 1.3% of days among valacyclovir recipients, relative risk 2.33 (95% CI, 1.18–4.89).
Conclusion: Valacyclovir appear to be somewhat better than famciclovir for suppression of genital herpes and associated shedding. Further comparative trials of antiviral drugs for various indications should be performed as acyclovir and penciclovir appear to have different ability to abrogate HSV reactivation.
THREE ANTIVIRALS ARE CURRENTLY available for chronic suppressive therapy of herpes simplex virus infections.1 Acyclovir, valacyclovir, and famciclovir have been shown to be clinically effective in the treatment of mucocutaneous herpes simplex virus type 2 (HSV-2) infection in the immunocompetent host.2 All 3 have been shown to be effective in reducing the signs and symptoms of recurrent episodes of genital herpes. When used on a daily basis, all reduce the frequency of clinical recurrences of infection and reduce viral shedding. Although many trials have demonstrated the efficacy of these agents as compared with placebo, few studies that directly compare the antiviral drugs have been performed.
In 1997, SmithKline Beecham Company initiated 2 separate trials to evaluate the comparative efficacy of famciclovir and valacyclovir in the suppression of genital herpes. Despite study completion, the data from these 2 trials were not made available until the product was bought by Novartis Corp. This report describes the results of these 2 trials, which were designed to define if famciclovir reduced symptomatic and asymptomatic reactivation of HSV-2 better than valacyclovir. The first study examined the effect of the 2 medications on the suppression of clinical genital herpes recurrences among persons with frequent recurrences. The second study measured viral shedding on the genital mucosa as measured by HSV DNA polymerase chain reaction (PCR) of genital secretions collected daily for 10 weeks.
Study Participants and Study Design
Study 1 was a randomized, double-blind, double-dummy comparison of oral famciclovir 250 mg bid and oral valacyclovir 500 mg q am on suppression of clinical genital herpes recurrences. The study was conducted between February and October 1997 and was conducted at 22 centers in the United States and Canada. Men and women were eligible to enroll if they were at least 18 years of age, had a history of recurrent genital herpes with at least 6 recurrences during the past year, and lacked kidney impairment, liver disease, and human immunodeficiency virus (HIV) infection. Additional exclusion criteria included pregnancy, receipt of other investigational drugs, sensitivity to nucleoside analogues, or history of acyclovir or penciclovir-resistant HSV. Persons receiving suppressive antiviral therapy were eligible if they had a history of frequent recurrences before initiation of suppressive therapy and discontinued suppressive therapy at least 2 months before receiving study medication. For patients who did not have a previous HSV-2 culture from genital secretions or a serologic test, Western blot was done at the University of Washington for antibodies to HSV-1 and HSV-2. Participants with HSV-1 antibody only were eligible for participation if they met the criteria for frequency of recurrences.
Participants returned to clinic every 4 weeks after enrollment and within 24 hours if they had a recurrence. During the visit, study medication was dispensed and adverse events assessed. The study lasted 16 weeks.
Study 2 was a randomized, double-blind, double-dummy comparison of the effect of oral famciclovir 250 mg bid and oral valacyclovir 500 mg qd on HSV shedding from the genital area. The therapy was administered for 10 weeks. Three centers participated in the study. Eligible participants were enrolled between December 1997 and May 1998. All had a clinical history of at least 6 episodes of recurrent genital herpes in the last 12 months or, if receiving suppressive therapy, had to have such history in the 12 months before initiation of the suppressive regimen. At the screening, general health was assessed, and participants with liver or kidney disease, HIV, receiving immunosuppressive therapy, or recently received investigational new drug were excluded. Persons receiving suppressive therapy for HSV infection had to agree to discontinue it at least 14 days before the screening visit.
Following enrollment, participants were seen at weeks 2, 4, 7, and 10. At each visit, study medication was dispensed and adverse events were assessed. Throughout the 10-week study, participants collected swabs daily from genital secretions, as previously described.3,4 The swabs were kept in the patient's home refrigerator and brought to the clinic at each visit. In both studies, local institutional review boards reviewed and approved the study, and all participants signed informed consent forms.
The serologic and PCR studies were done at the University of Washington. HSV serologic status was determined by Western blot.5 For study 1, swabs of lesions were sent to SmithKline Beecham Clinical Laboratory for HSV isolation in tissue culture. For study 2, HSV DNA PCR was done by the real-time quantitative PCR assay as published.6 All laboratory studies were performed by technicians masked to the patient code or therapy. Data for each assay were sent to a centralized database.
Both study 1 and study 2 were developed with a superiority trial design, i.e., the hypothesis was that daily famciclovir would be better than valacyclovir.
The primary endpoint was the proportion of patients who had a clinically confirmed recurrence during the study. The secondary efficacy endpoints included the proportion of patients who had a virologically confirmed recurrence, time to first clinically confirmed recurrence, and time to first virologically confirmed recurrence. Differences in time to recurrence were analyzed using Cox regression, so that a higher hazard ratio for recurrence indicates a shorter time to recurrence for that treatment group relative to the other. Additionally, mean frequency of lesional episodes is computed as the number of episodes observed out of the number of person-months contributed. Lesions that developed within the first 5 days of initiating study drug were excluded from efficacy analysis.
A total of 120 evaluable participants per treatment group was calculated to be sufficient to detect an 18% difference between treatment groups in the proportion of patients with a clinically confirmed recurrence during the study, with 80% power and 5% significance (2-tailed). To allow for dropouts, 150 patients per study arm were planned for enrollment.
The primary endpoint of the study was the proportion of days with HSV detected by PCR in the swabs of genital area. The secondary endpoints were the proportion of subclinical shedding days, as defined by days without genital lesions; the proportion of the lesional HSV shedding days; time to first HSV shedding; time to first subclinical HSV shedding; and time to first lesional HSV shedding. Baseline characteristics were summarized by treatment group and compared using a 2-sample t-test for continuous variables and Fisher exact test for categorical variables. All randomized patients who received at least 1 dose of the study drug were included in the analyses. The proportion of days with HSV shedding was analyzed using a Poisson regression model including treatment, gender, and center as covariates. The relative risk (RR) and the 95% confidence interval for the RR were presented using valacyclovir group as the reference. The variances of the estimates were adjusted to account for potential overdispersion in the data. All statistical tests were 2 sided.
Study 2 planned to enroll 70 patients with genital HSV-2 infection: 30 evaluable in each treatment arm and additional subjects to allow for dropouts. This number was based on an 8% rate of viral shedding in the famciclovir group and a 14% rate of viral shedding in the valacyclovir group, a 43% relative reduction at 5% significance, and a power of 90%.
Three hundred twenty participants were enrolled; 159 were randomized to receive famciclovir and 161 were randomized to receive valacyclovir. Twenty-two centers participated, with median enrollment of 16.5 subjects (range, 10–24). Of these, 146 (91.8%) famciclovir and 142 (88.2%) valacyclovir recipients completed the entire 16 weeks of study. Demographic and clinical characteristics at study entry are summarized in Table 1 and demonstrate that participants were well randomized by gender, race, serostatus, and clinical history. Thirty-one percent of participants were enrolled on the basis of previous laboratory-confirmed diagnosis of genital herpes; the remaining 222 participants were enrolled on the basis of their HSV antibody status. Two hundred fourteen of these 222 persons had HSV-2 antibodies by Western blot. Eight subjects (4 in each arm) had recurrent genital HSV-1 infection. Among the participants, 25% of the famciclovir and 29% of valacyclovir recipients reported more than 10 recurrences per year before study entry.
Two famciclovir- and 3 valacyclovir-treated participants developed a genital herpes recurrence within 5 days of study entry and were excluded from efficacy analyses. The proportion of participants that developed a clinically confirmed recurrence was similar in both groups, 34% among the famciclovir recipients and 28% among the valacyclovir recipients (RR = 1.10; 95% CI, 0.94–1.28; Table 2). Slightly more patients randomized to famciclovir had a virologically confirmed recurrence than patients randomized to valacyclovir, 13% versus 6% (RR = 1.08; 95% CI, 1.01–1.16). Time to first clinical recurrence of genital herpes was similar in both groups, hazard ratio (HR) = 1.17 (95% CI, 0.78–1.76) for famciclovir compared with valacyclovir, but time to first virologically confirmed recurrence was shorter in the famciclovir group, HR = 2.15, (95% CI, 1.00–4.60). Overall, the mean number of clinical recurrences during the study was 0.11 in the famciclovir and 0.10 in the valacyclovir group (P = 0.39). Figure 1 illustrates the mean frequency of recurrent episodes over the course of the study in the efficacy-eligible population. The results did not vary substantially when the excluded patients with early recurrences were included or when analyses were restricted to those who complied with all protocol-specified procedures (the efficacy evaluable population; data not shown). Covariate analyses showed that women developed clinically confirmed lesional episodes at an earlier time than men, HR = 1.9 (95% CI, 1.2–3.0) for time to first recurrence for women compared with men.
Seventy persons (50 women, 20 men) were enrolled into the study. Thirty-four were randomized to famciclovir and 36 were randomized to valacyclovir. Four patients did not complete the study; 3 withdrew consent or were lost to follow-up, and 1 was withdrawn for an adverse event. Thus, 97% of the famciclovir- and 92% of the valacyclovir-treated patients completed the entire protocol. Baseline demographic and clinical characteristics by study are shown in Table 1, demonstrating that treatment assignment was well randomized.
The mean number of days with swabs of genital secretions collected for analysis of viral shedding was 66.4 (65.5 days in the famciclovir and 63.8 days in the valacyclovir group). At least 1 day of genital HSV shedding was detected in 18 (53%) famciclovir recipients and 18 (50%) valacyclovir recipients, P = 0.82. Overall, HSV was detected on 3.2% days among famciclovir recipients compared with 1.3% days among valacyclovir recipients (Table 3). The RR of HSV shedding was 2.33 (95% CI, 1.18–4.89) for patients treated with famciclovir compared with valacyclovir. Subclinical shedding was noted on 2.4% of days of famciclovir versus 1.1% of days of valacyclovir administration, RR = 2.05 (95% CI, 1.07–4.11). Specifically, 6 (17.6%) famciclovir recipients versus none of the valacyclovir recipients experienced >6% of days of shedding (Figure 2).
Among the 36 persons who had HSV detected in genital tract (18 in each arm), the amount of HSV found was compared between the 2 treatment groups. Overall, the mean copy number on days with detectable HSV was log10 3.6 copies/ml among famciclovir recipients versus log103.4 copies/ml among valacyclovir recipients (P = 0.27).
Adverse Events and Adherence
Adverse events were mild and consistent with previously reported safety profile of these medications. In study 1, headaches were the most common side effect, reported by 12.6% of famciclovir and 12.4% of valacyclovir recipients. During drug administration, 2 participants (both on valacyclovir) experienced serious adverse events: one, a hiatal hernia requiring elective surgery; and the other, an episode of chest pain. These were judged unrelated to the study medication. Five participants (2 in famciclovir and 3 in valacyclovir) withdrew secondary to adverse events that occurred during dosing study drug administration. These included palpitations and exacerbation of headaches in patients receiving famciclovir and elevated liver enzymes, headache exacerbation, and worsening of a personality disorder in patients receiving valacyclovir. In study 2, headaches occurred in 14.7% of famciclovir and 13.9% of valacyclovir recipients. One woman receiving valacyclovir was hospitalized for a ruptured appendix, and 1 woman receiving valacyclovir developed a rash after 5 weeks of valacyclovir therapy. As the investigator thought that the rash was possibly related to the study drug, treatment was permanently discontinued.
Adherence to the study medication was high in both protocols. In study 1, median adherence was 100% for valacyclovir arm and 98% for famciclovir arm; in study 2, median adherence was 97% for valacyclovir and 98% for famciclovir arm.
These 2 randomized clinical trials directly compared the efficacy of 2 approved, frequently used, antiviral therapies for genital herpes. The first study examined the efficacy of the medications for the prevention of genital herpes recurrences with daily administration of the study drug at the standard recommended doses. Although the results for the primary endpoint, proportion of persons with a recurrence at 16 weeks, did not demonstrate a statistically significant difference between the 2 antivirals, analyses of the secondary endpoint, virologically documented recurrence, showed a small but significant benefit for persons randomized to valacyclovir. The second study compared the effect of famciclovir and valacyclovir on abrogation of viral shedding in the genital tract. The rate of viral shedding as detected by HSV DNA PCR, albeit low in both groups, was twice as high in the recipients of famciclovir as valacyclovir. Both of these results were unexpected as the trials were designed to show an 18% reduction in the proportion of participants with a recurrence among those treated with famciclovir for study 1 and a 43% reduction in the frequency of viral shedding among famciclovir recipients in study 2.
Few direct comparisons of antiviral medications have been done, and we are not aware of any other studies comparing famciclovir to valacyclovir in the treatment of genital herpes. A previous study comparing famciclovir to valacyclovir for the treatment of first-episode genital herpes examined the time to first recurrence following therapy. Although data remain unpublished, to our knowledge, the outcome was similar for both groups. Studies of therapy for first-episode genital herpes used famciclovir twice a day in comparison with acyclovir dosed 5 times a day, and both medications appeared to have a similarly beneficial effect.7 Valacyclovir, the prodrug of acyclovir, has been directly compared to acyclovir in studies for first-episode genital herpes, suppressive therapy, and viral shedding.8–10 Both in terms of clinical as well as virological outcomes, acyclovir and valacyclovir appeared to have a similar effect, despite the higher level of acyclovir achieved by oral valacyclovir administration. In dose-ranging studies of suppressive valacyclovir, some dose response was seen. Patients with more severe genital herpes had better suppression with the higher dose (1 g qd) or more frequent dosing (250 mg bid).9 Similarly, dosing interval appears important for patients with HIV as the studies comparing dose regimens showed that valacyclovir 1 g once daily is inferior to 500 mg bid for suppression of genital herpes in this population.11 Dose response was also seen for suppression of genital herpes with famciclovir, with once-daily dosing, or 125 mg bid, achieving inadequate suppression.12 Thus, although the previous comparative studies have shown the importance of dose and dosing interval, this is the first study that suggests that the antiviral potency of famciclovir and valacyclovir is not equal at the dose that is usually used. One of the intriguing suggestions from our trials is that there is a subset of persons who have HSV-2 who do not attain what we could term significant virological suppression from standard doses of suppressive famciclovir and continue to shed >6% of days on 250-mg twice-daily dosage.
Famciclovir is a lipophilic prodrug of penciclovir, a agent that has negligible oral absorption.13 Valacyclovir is a valine ester of acyclovir, which has an oral absorption of only 10% to 20%.14 Thus, both are prodrugs that have been developed to deliver orally a higher dose of an antiviral, and both have an oral bioavailability of >50%. As both drugs have similar molecular weights (361 for valacyclovir and 321 for famciclovir), the dose regimen used in these studies should have resulted in similar amounts of antiviral compounds available for viral inhibition.
In vitro data have shown that acyclovir and penciclovir have comparable ability to inhibit HSV-1 and HSV-2 replication.15 Both are nucleoside analogues that require initial phosphorylation by viral thymidine kinase. This selective activity accounts for the remarkable safety profile of these medications as only virally infected cells are able to initiate the conversion of the drug to the triphosphorylated form that interferes with DNA synthesis.16 Acyclovir has increased affinity for HSV DNA polymerase, and penciclovir has a longer intracellular half-life in HSV-infected cells. The relevance of these pharmacodynamic properties to clinical or virologic outcomes is not clear. In animal models, some studies found famciclovir results in lower levels of latent virus and subsequent reactivation when administered around the time of infection.17 The relevance of these findings to human therapy, which is not administered before exposure, is unclear.
What are the implications of these studies regarding the care of patients with genital herpes? For study 1, although the differences in the antiviral efficacy were statistically significant, they are, in our opinion, not of major clinical significance. As shown in previous studies and confirmed in this study, both drugs markedly reduced clinical HSV-2 reactivation. Thus, for patient management we do not feel the distinctions are large enough to alter current guidelines for therapy, which recommend use of either one of these medications. Recent studies have shown that daily valacyclovir can reduce the transmission of HSV-2 in discordant, heterosexual couples by about 50%.18 The relationship between subclinical viral reactivation and transmission is not well defined, and it is clear that subclinical shedding and its suppression is not a perfect surrogate marker of HSV-2 transmission.19 Thus, whether the difference we noted between the 2 compounds would alter differences in the relative reduction in transmission is unclear. However, at present, we feel that we should use daily famciclovir with caution if indicated for reducing HSV-2 transmission between couples.
Recent publications have discussed the issues surrounding lack of publication of trials that yield negative results or results that are unfavorable to the sponsor.20 We acknowledge that the process of analyzing data for publication beyond a study report and preparing a manuscript is labor intensive, and companies are understandably wary of devoting resources to a report that is not in favor of their product. We appreciate that Novartis Corporation made these data available after their own in-house review. Although we received data tables and listings for this study, we were not able to obtain data tapes to verify the analyses and to conduct what we consider the most clinically relevant analyses for these types of data, such as the monthly frequency of recurrent episodes or the frequency of days with lesions during the observation period. The publication of these data shows the lack of equivalence between these antivirals in virological suppression is of importance for the further development of antivirals. The differences in subclinical reactivation during the administration of the 2 compounds warrant further study.
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13. Hodge RA, Cheng YC. The mode of action of penciclovir. Antiviral Chem Chemother 1993; 4:13–24.
14. Brigden D, Whitman P. The clinical pharmacology of acyclovir and its prodrug. Scand J Infect Dis Suppl 1985; 47:33.
15. Weinberg A, Bate B, Masters H, et al. In vitro activities of penciclovir and acyclovir against herpes simplex virus types 1 and 1. Antimicrob Agents Chemother 1992; 36:2037–2038.
16. Elion G, Furman P, Fyfe J, et al. The selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl) guanine. Proc Natl Acad Sci USA 1977; 74:5716–5720.
17. Thackray AM, Field HJ. Differential effects of famciclovir and valacyclovir on the pathogenesis of herpes simplex virus in a murine infection model including reactivation from latency. J Infect Dis 1996; 173:291–299.
18. Corey L, Wald A, Patel R, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med 2004; 350:11–20.
19. Sacks SL, Griffiths PD, Corey L, et al. Introduction: is viral shedding a surrogate marker for transmission of genital herpes? Antiviral Res 2004; 63(suppl 1):S3–9.
20. Steinbrook R. Gag clauses in clinical-trial agreements. N Engl J Med 2005; 352:2160–2162.
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