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Are the Antiherpes Nucleosides Really All the Same?

Fife, Kenneth H. MD, PhD

doi: 10.1097/01.olq.0000223245.66260.84

From the Departments of Medicine, Microbiology & Immunology, and Pathology, Indiana University School of Medicine, Indianapolis, Indiana

The author receives research funding from GlaxoSmithKline and Novartis and has served as a consultant for GlaxoSmithKline.

Correspondence: Kenneth H. Fife, MD, PhD, 545 Barnhill Dr., Room 435, Indianapolis, IN 46202-5124. E-mail:

ACYCLOVIR WAS FIRST APPROVED FOR the treatment of genital herpes in the early 1980s. Numerous placebo-controlled trials established its efficacy for the treatment of first-episode genital herpes1,2 and the episodic and suppressive treatment of recurrent genital herpes.3–5 Although treatment results with the oral capsule formulation of acyclovir were impressive, its low bioavailability (10–20%)6 suggested that its efficacy could be improved by designing a similar compound with better systemic absorption. This led to the development of famciclovir, which has excellent bioavailability and is rapidly metabolized to penciclovir,7 and to valacyclovir, the l-valine ester of acyclovir, which is readily absorbed and rapidly converted to acyclovir.8 Penciclovir is structurally very similar to acyclovir and has been shown to have comparable in vitro activity against herpes simplex virus (HSV) and varicella zoster virus.

During the clinical development phase of both famciclovir and valacyclovir, numerous randomized, controlled clinical trials were conducted that compared the new drug with either acyclovir or placebo depending on the condition studied and the trial design.9–17 These studies established the efficacy of both drugs in the treatment of genital herpes. The postmarketing phase for both drugs was similar, consisting of studies comparing each drug with either acyclovir or placebo. To broadly summarize those studies, famciclovir and valacyclovir (at the approved and marketed doses) were significantly better than placebo and similar to acyclovir in efficacy. The manufacturers of famciclovir and valacyclovir have cited differential in vitro effects of their respective drugs in promotional material to suggest that their product may have an advantage over the other product, but neither company has presented clinical data to validate these theoretical benefits. One product (famciclovir) has a longer intracellular half-life, whereas the other (valacyclovir) causes irreversible termination of replicating viral DNA chains. These observations permit the generation of hypotheses about possible clinical benefits, but these hypotheses have not been tested in the setting of a clinical trial. Most of the clinical studies that used acyclovir as a control were designed as noninferiority trials and not equivalence trials. Although no study published to date directly compared famciclovir with valacyclovir for the treatment of genital herpes, the magnitude of the treatment effect in similarly designed studies compared with placebo or acyclovir led most experts in the field to conclude that famciclovir and valacyclovir likely had comparable efficacy for most indications.

In this issue, Wald and colleagues18 report the results of 2 studies conducted in 1997 and 1998 that directly compared the efficacy of famciclovir and valacyclovir for the suppression of recurrent genital herpes and for suppression of HSV-2 shedding. The authors found a significant difference between the 2 drugs with respect to the time to the first virologically confirmed recurrence in the suppression study and in the percentage of days shedding virus in the viral shedding study. Both of these comparisons favored valacyclovir as the more effective drug. Do these studies provide an answer to the question of which drug is better? Perhaps they do, but there are some limitations that must be considered.

In the suppression study, although there was a difference in the time to the first culture confirmed recurrence, there was no difference between the 2 treatment arms in the time to the first clinically evident recurrence, suggesting that the 2 treatments are very similar in terms of clinical disease manifestations. If a nucleic acid amplification test, which is more sensitive than culture,19 had been used for virologic confirmation, the difference might have been even smaller. Are virologically confirmed recurrences more important than clinical recurrences with negative viral cultures? This question has not been answered. In many cases, patients with recurrent genital herpes are placed on suppressive therapy to reduce symptoms. From the patient's perspective, the important parameter is the presence of clinical disease and not the viral culture.

The results in the viral shedding study were more notable with subjects shedding on 3.2% of days while receiving daily famciclovir and on 1.3% of days while receiving daily valacyclovir. Viral shedding in this study was measured by polymerase chain reaction. Although the differential virologic effect of the 2 drugs seems clear, the clinical implications are less so. Viral shedding of HSV is associated with transmission to a susceptible partner, and it is tempting to speculate that valacyclovir might have a greater impact than famciclovir on sexual transmission of HSV. However, as the suppression study illustrates, virologic effects do not always translate into clinically meaningful results.

These studies took over 7 years to publish and some of the analyses are limited. The role of the study sponsor in this report should be considered. The studies were originally funded by SmithKline Beecham when it owned the rights to famciclovir. A condition imposed by U.S. regulatory agencies permitting the merger of SmithKline Beecham and Glaxo Wellcome that created GlaxoSmithKline was that famciclovir (including these study data) be sold. Novartis was the eventual buyer of famciclovir. As stated by the authors, Novartis provided the authors with the study report and the data listings, but not the primary data itself. Was the delay in the release and publication of the study data a result of the corporate shuffling and movement of responsibility for the study data created by the sale of famciclovir? Alternatively, was it an effort to suppress potentially unfavorable data? Should the full dataset have been provided so that the authors could confirm the analysis and perform additional analyses? Is Novartis to be criticized for delaying and limiting the release of the study report? Alternatively, should Novartis be praised for permitting potentially unfavorable results to be published? The answers to these questions may depend on one's view of the pharmaceutical industry.

Regardless of the clinical implications, Wald and colleagues have demonstrated that there are differences between the antiherpes nucleosides. The clinical importance of these differences will require further study and further studies should be done. In addition, these findings suggest that there may be room for further improvement in antiherpes drugs, despite the presence of existing drugs that are safe and effective.

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1. Corey L, Fife KH, Benedetti JK, et al. Intravenous acyclovir for the treatment of primary genital herpes. Ann Intern Med 1983; 98:914–921.
2. Mertz GJ, Critchlow CW, Benedetti J, et al. Double-blind placebo-controlled trial of oral acyclovir in first-episode genital herpes simplex virus infection. JAMA 1984; 252:1147–1151.
3. Douglas JM, Critchlow C, Benedetti J, et al. A double-blind study of oral acyclovir for suppression of recurrences of genital herpes simplex virus infection. N Engl J Med 1984; 310:1551–1556.
4. Fife KH, Crumpacker CS, Mertz GJ, Hill EL, Boone GS. Recurrence and resistance patterns of herpes simplex virus following cessation of ≥6 years of chronic acyclovir suppression. J Infect Dis 1994; 169:1338–1341.
5. Mertz GJ, Jones CC, Mills J, et al. Long-term acyclovir suppression of frequently recurring genital herpes simplex infection. JAMA 1988; 260:201–206.
6. de Miranda P, Blum MR. Pharmacokinetics of acyclovir after intravenous and oral administration. J Antimicrob Chemother 1983; 12(suppl B):29–37.
7. Perry CM, Wagstaff AJ. Famciclovir—A review of its pharmacological properties and therapeutic efficacy in herpesvirus infections. Drugs 1995; 50:396–415.
8. Perry CM, Faulds D. Valaciclovir. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in herpesvirus infections. Drugs 1996; 52:754–772.
9. Bodsworth NJ, Crooks RJ, Borelli S, et al. Valaciclovir versus aciclovir in patient initiated treatment of recurrent genital herpes: A randomised, double blind clinical trial. Genitourin Med 1997; 73:110–116.
10. Chosidow O, Drouault Y, Leconte-Veyriac F, et al. Famciclovir vs aciclovir in immunocompetent patients with recurrent genital herpes infections: A parallel-groups, randomized, double-blind clinical trial. Br J Dermatol 2001; 144:818–824.
11. Fife KH, Barbarash RA, Rudolph T, Degregorio B, Roth R. Valaciclovir versus acyclovir in the treatment of first-episode genital herpes infection. Results of an international, multicenter, double-blind, randomized clinical trial. The Valaciclovir International Herpes Simplex Virus Study Group. Sex Transm Dis 1997; 24:481–486.
12. Mertz GJ, Loveless MO, Levin MJ, et al. Oral famciclovir for suppression of recurrent genital herpes simplex virus infection in women: A multicenter, double-blind, placebo-controlled trial. Arch Intern Med 1997; 157:343–349.
13. Patel R, Bodsworth NJ, Woolley P, et al. Valaciclovir for the suppression of recurrent genital HSV infection: A placebo controlled study of once daily therapy. Genitourin Med 1997; 73:105–109.
14. Reitano M, Tyring S, Lang W, et al. Valaciclovir for the suppression of recurrent genital herpes simplex virus infection: A large-scale dose range-finding study. J Infect Dis 1998; 178: 603–610.
15. Sacks SL, Aoki FY, Diaz-Mitoma F, Sellors J, Shafran SD. Patient-initiated, twice-daily oral famciclovir for early recurrent genital herpes: A randomized, double-blind multicenter trial. JAMA 1996; 276:44–49.
16. Spruance SL, Tyring SK, DeGregorio B, Miller C, Beutner K. A large-scale, placebo-controlled, dose-ranging trial of peroral valaciclovir for episodic treatment of recurrent herpes genitalis. Arch Intern Med 1996; 156:1729–1735.
17. Tyring SK, Douglas JM, Corey L, Spruance SL, Esmann J. A randomized, placebo-controlled comparison of oral valacyclovir and acyclovir in immunocompetent patients with recurrent genital herpes infections. Arch Dermatol 1998; 134:185–191.
18. Wald A, Selke S, Warren T, et al. Comparative efficacy of famciclovir and valacyclovir for suppression of recurrent genital herpes and viral shedding. Sex Transm Dis 2006; 33:xxx–xxx.
19. Wald A, Corey L, Cone R, Hobson A, Davis G, Zeh J. Frequent genital herpes simplex virus 2 shedding in immunocompetent women—Effect of acyclovir treatment. J Clin Invest 1997; 99:1092–1097.
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