- Email: [email protected]
A meta-analysis to assess the efficacy of oral antiviral treatment to prevent genital herpes outbreaks
A meta-analysis to assess the efficacy of oral antiviral treatment to prevent genital herpes outbreaks Be´ne´dicte Lebrun-Vignes, MD,a Anissa Bouzamondo, PhD,a Alain Dupuy, MD,b Jean-Claude Guillaume, MD,c Philippe Lechat, MD, PhD,d and Olivier Chosidow, MD, PhDe Paris and Colmar, France Background: Efficacy of oral antiviral therapies, ie, acyclovir, valacyclovir (VACV), and famciclovir, for suppression of recurrent genital herpes was studied at different doses and regimens. Objective: We sought to compare the clinical efficacies of the different oral antiviral drugs prescribed prophylactically to suppress recurrent genital herpes. Methods: MEDLINE and EMBASE databases were searched for articles on genital herpes and selected antiviral drugs. The selected trials were: parallel randomized clinical trials testing prophylactic oral antiviral treatment of genital herpes versus placebo in immunocompetent and nonpregnant patients. Results: Fourteen randomized clinical trials were selected, including a total of 6158 patients. The global relative risk of developing at least one recurrence during the study was reduced by 47% (95% confidence interval 45%-49%) in antiviral drug groups compared with the placebo. The best evaluated regimens, with comparable efficacies, were given twice daily, ie, acyclovir (400 mg twice daily), VACV (250 mg twice daily), and famciclovir (250 mg twice daily), or once daily (VACV 500 mg). Limitations: The only end point available for all the studies was the number of patients presenting at least one recurrence of genital herpes during the observation period. Conclusion: The results of this first meta-analysis confirmed the high clinical efficacy of oral acyclovir, VACV, or famciclovir for prophylaxis against recurrent genital herpes. ( J Am Acad Dermatol 2007;57: 238-46.)
enital herpes is the most frequent cause of genital ulcer disease1 and it is sexually transmitted. Genital herpes is caused by herpes simplex virus (HSV)-2 in 60% to 80% of the cases, but HSV-1-related genital herpes is on the rise.1,2 Serologic studies have found HSV-2 prevalence in the general populations of developed countries to be 15% to 25%.3 Epidemiologic surveys have indicated an increase of HSV-2 seroprevalence of about 20% to 30% in these countries during the past 20 years.2,3 Symptomatic recurrent flares occur
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in 20% to 50% of patients who have anti-HSV antibodies.4 Patients have a median of 4 recurrences during the first year after a symptomatic first episode of genital herpes caused by HSV-2.5 Because recurrent genital herpes is associated with major medical and psychosocial morbidities,1 suppressive therapy is required, especially in patients with episodes that are frequent, severe, or both. Moreover, suppression of genital herpes is also important because genital lesions favor HIV transmission and other sexually transmitted diseases.6 Finally, the risk of fetal
From the Department of Pharmacology, Hoˆpital Pitie´eSalpeˆtrie`re,a and Department of Dermatology, Hoˆpital Saint-Louis,b Assistance PubliqueeHoˆpitaux de Paris; Department of Dermatology, Hoˆpital Pasteur, Colmarc; and Department of Pharmacology, Hoˆpital Pitie´eSalpeˆtrie`re, Assistance PubliqueeHoˆpitaux de Paris,d and Department of Dermatology and Allergology, Hoˆpital Tenon, Assistance PubliqueeHoˆpitaux de Paris,e Universite´ Pierre-et-Marie-Curie Paris VI. Funding sources: None. Disclosure: Olivier Chosidow is a consultant for GSK. Drs LebrunVignes, Bouzamondo, Dupuy, Guillaume, and Lechat have no conflicts of interest to declare.
Accepted for publication February 18, 2007. Reprint requests: Be´ne´dicte Lebrun-Vignes, Department of Pharmacology, Hoˆpital Pitie´eSalpeˆtrie`re, 47e83, boulevard de l’Hoˆpital, 75651 Paris Cedex 13, France. E-mail: benedicte. [email protected]. Published online April 13, 2007. 0190-9622/$32.00 ª 2007 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2007.02.008
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Abbreviations used: ACV: CI: FCV: HSV: RCT: RR: VACV:
acyclovir confidence interval famciclovir herpes simplex virus randomized controlled trial relative risk valacyclovir
contamination during childbirth leading to neonatal herpes is high.1 Since the early 1980 s, oral antiviral agents have been used successfully to suppress recurrent genital herpes. Acyclovir (ACV) was the first molecule to have a meaningful therapeutic effect in that setting with significant efficacy (reduction of relative risk [RR] of recurrence varying in clinical trials from 41% to 86% vs placebo). More recently, valacyclovir (VACV), a prodrug of ACV with higher bioavailability after oral administration, and famciclovir (FCV), a prodrug of penciclovir, were evaluated for this indication.1 These 3 molecules have been used at different doses and regimens in several randomized controlled trials (RCTs), but data on comparisons of the different regimens are lacking. To date, no metaanalysis has been published on this topic. The aims of this meta-analysis were to compare the clinical efficacies of 3 oral antiviral drugs and identify the best regimens.
METHODS Trial search strategy MEDLINE and EMBASE databases and the Cochrane Controlled Trials Register were searched for articles on genital herpes and selected antiviral drugs. The MEDLINE search included: (herpes genitalis[mh] OR (herp* AND genit*) OR (herpes simplex[mh: noexp] AND genit*)) AND (aciclovir OR acyclovir OR valaciclovir OR valacyclovir OR famciclovir OR famcyclovir). The search was then cross-checked with RCTs (using Cochrane’s highly sensitive search for randomized trials) and in English; it was conducted online on the National Library of Medicine PUBMED World Wide Web site and was updated in January 2004. The database searches were completed with a hand search of references, cited in the articles identified, but we did not look for unpublished studies in conference proceedings. Study selection We selected the studies meeting our inclusion criteria by hand screening the titles and abstracts (Fig 1): ie, RCTs testing prophylactic oral antiviral treatment of genital herpes versus placebo in immunocompetent and nonpregnant patients, and
providing exploitable information on recurrences (see ‘‘Outcome definition’’). Recurrent genital herpes at inclusion of patients was accepted as it was defined in each trial. We chose not to retain the studies including pregnant women or nonimmunocompetent patients to limit sources of heterogeneity. Crossover trials could not be included because of methodologic reasons: the intermediate data after each period were not available, making an independent analysis of the results difficult, if not impossible. For logistic reasons, we selected only English-language studies. Outcome definition The selected end point was the number of patients developing at least one genital herpes recurrence during the trial. For each trial, the given clinical diagnosis of recurrence of the investigator was accepted. Data extraction Data from published reports were extracted independently by two investigators (A. D. and B. L-V.) onto a standardized form. The following items were extracted from each RCT: number and characteristics (sex, mean age) of patients included, frequency of recurrences chosen for inclusion, treatment duration, antiviral drug used, evaluated total daily doses and regimens, and the number of recurrence-free patients. We chose this end point because it was the only one available in all the trials, unlike the number of recurrences. When necessary, we calculated the number of patients who developed at least one recurrence during an RCT from the percentage or the number of recurrence-free patients reported. Selected studies were assessed for quality using the 5-point Jadad scale.7 Statistical methods The pooled estimate of the global RR of recurrence during the trials was calculated using, for each study, the inversed variance-weighted RR, in a fixed model, yielding bilateral 95% confidence interval (CI) for trials and for the meta-analysis. As usual in metaanalyses, a chi-square test for association of the pooled estimate of global RR and a chi-square test for RR homogeneity among trials and among subgroups were performed. P = .05 for the chi-square test was considered significant for association and homogeneity. When the RCT investigated more than one antiviral drug and/or dose compared with placebo, each intervention group in these trials was independently analyzed versus the same placebo group. Data used were always those based on an intention-to-treat analysis.
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Fig 1. Description of procedure used for study identification and selection.
The meta-analysis was conducted with software (EasyMA, Lyons, France).
RESULTS Fig 1 describes the procedure followed to select RCTs for this analysis, giving the precise numbers of initial articles identified included and excluded and the reasons for their exclusion. Finally we retained 14 RCTs, including 10 with ACV, 2 with FCV, and 3 with VACV (one trial included ACV and VACV).8-21 In all, 6158 patients (4037 and 2121 in the treatment and placebo groups, respectively) were included with a sex ratio varying from 0 to 1.8. All the RCTs were parallel-group, doubleblind studies. The 14 RCTs included are summarized in Table I.
Clinical efficacy Global analysis (Fig 2) showed a significant benefit of oral antiviral drugs compared with placebo, with RR ranging from 0.16 to 0.73. The global RR of developing at least one recurrence during the trial was reduced by 47% (95% CI 45%-49%). The number of patients needed to treat was 2.15 (95% CI 2.062.25). This analysis showed significant heterogeneity among RCTs (P \.001). Subgroup analyses The analysis according to the drug (Fig 3) showed the efficacy of each antiviral agent tested (all doses and regimens pooled), with RR reductions of 53% (95% CI 51%-57%) for ACV, 43% (95% CI 41%-47%) for VACV, and 42% (95% CI 35%-50%) for FCV. The
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Table I. Description of the 14 randomized controlled trials included in the meta-analysis Trials*
Strauss 19848 Douglas 19849 Mindel 198410 Mostow 198811 Sacks 198812 Mattison 198813 Baker 198914 Kaplowitz 199115 Kinghorn 199216 Mertz 199717
No. of patients included
Frequency of recurrences at inclusion
35 153 56 46 50 156 261 1146 78 375
$ 12/y $ 6/y $ 4/y $ 4/y $ 6/6 mo $ 6/y $ 6/y $ 6/y $ 6/y $ 6/y
Duration of study, mo
4 4 3 12 6 12 12 12 6 4
Antiviral agent, daily dose (mg)
ACV ACV ACV ACV ACV ACV ACV ACV ACV ACV FCV FCV
(600) (1000) (400) (800) (800) (600) (800) (800) (800) (800) (125) (250)
FCV (500) Patel 199718 Reitano 199819
Diaz-Mitoma 199820
Corey 200421 Total
382 1479
$ 8/y $ 6/y
4 12
457
$ 6/y
12
1484 6158
\10/y
8
VACV ACV VACV VACV
(500) (800) (250) (500)
VACV FCV FCV FCV VACV
(1000) (375) (500) (750) (500)
Regimen
200 3 3 200 3 5 200 3 2 200 3 4 800 3 1 200 3 3 400 3 2 400 3 2 400 3 2 400 3 2 125 3 1 125 3 2 or 250 3 1 250 3 2 or 500 3 1 500 3 1 400 3 2 250 3 1 250 3 2 or 500 3 1 1000 3 1 125 3 3 250 3 2 250 3 3 500 3 1
Jadad score
4 5 2 5 4 3 2 5 5 3
2 3
5
3
ACV, Acyclovir; FCV, famciclovir; VACV, valacyclovir. *All trials were parallel group, and double-blinded.
heterogeneity among the subgroups was significant (P \.001). Analysis according to the total daily dose of each drug showed that all the studied ACV doses were effective (Fig 4). The best evaluated daily dose was 800 mg. It was not possible to evaluate a dose-effect response, because of the scarcity of data at the other doses. For VACV (Fig 4), all the doses studied were also effective with the best evaluated daily dose being 500 mg. The results of this analysis suggested a dose-dependent response with 250 mg/d being less effective than 500 mg/d, and a maximum efficacy above 500 mg/d. Considering FCV (Fig 4), 125 mg/d was not effective, but higher doses achieved significant efficacy, with a clear dose-effect response between 250 and 750 mg/d. Analysis according to the regimen for each drug could only be undertaken for the best doses evaluated, owing to the small number of studies and patients. For ACV, 800 mg/d (Fig 5), all regimens (once, twice, or 4 times daily), had significant efficacy, with the best evaluated regimen being the twice-daily (400 mg) schedule (total 800 mg). The analysis revealed schedule-dependent efficacy, with
the 4-times-daily schedule being more effective than the other regimens with significant subgroup heterogeneity. In contrast, no difference in efficacy was found between the two (once or twice daily) regimens for VACV at 500 mg/d (Fig 5). Lastly, only the FCV (250 mg) twice-daily schedule (total 500 mg/d) (Fig 5) was effective, with the once-daily administration failing to reach significance.
DISCUSSION We report results of the first meta-analysis to be conducted on the efficacy of prophylactic oral antiviral treatments (ACV, VACV, FCV) to prevent genital herpes recurrences. The results confirmed the high efficacy of these agents compared with a placebo. Indeed, oral ACV, VACV, or FCV reduced the RR of developing a recurrence by about half. We are aware of potential methodologic weaknesses of this study. We decided to include only studies published in English. This decision excluded only one trial (n = 55) comparing ACV at 400 mg twice daily versus placebo, with high ACV efficacy.22 Because the results of that study were similar to those of the selected trials, it is unlikely that including it
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Fig 2. Global meta-analysis of relative risk (RR) of genital herpes recurrence under oral antiviral therapy. Results are given as number of recurrences/patients. Cochrane Q heterogeneity: P \ .001.
Fig 3. Subgroup meta-analysis of relative risk (RR) of genital herpes recurrence according to oral antiviral agent (any dose or regimen). ACV, Acyclovir; FCV, famciclovir; VACV, valacyclovir. Subgroup heterogeneity: P \ .001.
would have changed the global and subgroup results of our meta-analysis. In addition, when the RCT investigated more than one dose or more than one antiviral drug, we chose to analyze each intervention group versus the placebo, considering each
comparison as independent in accordance with the meta-analysis routine. However, doing so increased the alpha risk of observing a false treatment effect. Nevertheless, it appeared to be the best way not to lose information from those well-designed trials.
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In addition, the observed P values in each of these trials excluded false-positive results with high confidence. Heterogeneity between the trials was highly significant. We analyzed the possible components of such heterogeneity, which can originate from different treatment modalities or patient characteristics. Only analysis of treatment modalities could be evaluated because we could did not perform subgroup analyses according to patient characteristics without individual data. In addition, demographics were quite similar for all trials. However, treatment modalities clearly provided sources of heterogeneity, especially according to dose and the number of drug intakes per day. Heterogeneity according to dose was significant for ACV and VACV but without a clear dose-effect relationship. For FCV, a trend toward a dose effect was observed, but without significant heterogeneity because of the lack of power of this test. Heterogeneity was also significant according to number of ACV intakes per day. The greatest efficacy (RR reduction = 86%) was observed in a small study, with ACV (200 mg 4 times daily). However, that regimen is not very convenient and, thus, not highly conducive to long-term compliance. A similar trend was observed for FCV, but not for VACV. According to our meta-analysis, the best evaluated prophylactic doses were twice-daily regimens, ie, ACV (400 mg twice daily), VACV (250 mg twice daily), and FCV (250 mg twice daily), or once-daily VACV (500 mg), all of which had similar efficacies. That finding was never elucidated in RCTs because, as a general rule, they each compared a single antiviral drug, often at different doses and/or regimens, with a placebo. Only one study in our metaanalysis compared the prophylactic efficacy of VACV and ACV,19 with no difference between the two drugs. Few comparative studies between oral antiviral drugs have been performed: in a double-blind, crossover trial including 69 participants with recurrent genital herpes, oral VACV (500 mg twice daily) and ACV (400 mg twice daily) demonstrated high efficacies in suppressing the frequency and quantity of genital HSV shedding compared with placebo. Despite the better oral absorption of VACV than ACV, the frequency and quantity of polymerase chain reactionedetected HSV did not differ between VACV and ACV groups.23 In another report on the results of two randomized, double-blind, placebo-controlled studies comparing FCV (250 mg twice daily) with VACV (500 mg once daily), VACV appeared to be somewhat better than FCV for suppression of genital herpes and associated shedding.24
Fig 4. Subgroup meta-analysis of relative risk (RR) of genital herpes recurrence according to total daily dose of antiviral agent independently of regimen. ACV, Acyclovir; FCV, famciclovir; VACV, valacyclovir. Subgroup heterogeneity: P = .0097 (ACV), P \.001 (VACV), and P = .51 (FCV).
Independently of the drug, the once-daily dose should theoretically be the most convenient regimen, thereby favoring compliance. Nevertheless, to our knowledge, it has never been shown that a oncedaily dose improves compliance compared with twice-daily intake, especially in real life. Surveys of patients given suppressive therapy in several countries indicated that those using a once-daily regimen claimed to be more satisfied than those on a twicedaily regimen.25 If we consider the agents that could be used once daily, only VACV had clearly demonstrated efficacy. We did not find any additional benefit associated with a twice-daily regimen (250 mg twice daily) for VACV (500 mg), which is at variance with the manufacturer’s recommendations and the results of one study.19 ACV (800 mg once daily) was found to be effective in only one very small trial, and better evaluation of its efficacy is warranted.11 FCV (500 mg once daily) was not effective. The observation periods of all the RCTs were relatively short in light of the chronic nature of the disease. One RCT included in this meta-analysis was prolonged as an open study for 5 years after
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Fig 5. Subgroup meta-analysis of relative risk (RR) of genital herpes recurrence according to antiviral drug regimen for best evaluated daily dose. ACV, Acyclovir; FCV, famciclovir; VACV, valacyclovir. Subgroup heterogeneity: P = .014 (ACV), P = .93 (VACV), and P = .11 (FCV).
the controlled phase.13 The long-term follow-up showed persistent efficacy of the prophylaxis.26,27 Adverse events were recorded in the RCTs, with the most frequent being headache, nausea, diarrhea, or viral infections. The frequencies and types of
adverse events were similar for patients treated with antiviral and placebo, and were described as minor and transient. Despite the lack of information with regard to their frequencies during routine clinical practice, oral ACV-, VACV-, and FCV-attributed
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serious side effects seem to be very rare. Nephrotoxicity and neurotoxicity attributed to high ACV doses usually occurred with parenteral administration28; data on very long-term suppressive therapy has shown good tolerance.26,27 Patients with recurrent genital herpes had significantly diminished quality of life, which was independently associated with shorter intervals between recurrences and more severe pain or discomfort during flares.25 Improving the quality of life of patients on suppressive therapy is a very meaningful criterion, but it was evaluated in only one study included in our meta-analysis.19,29 In that trial, genital herpes suppression with ACV or VACV significantly improved health-related quality of life compared with the placebo. This effect was sustained throughout the study duration (12 months). In another study, prophylactic ACV reduced the psychosocial morbidity associated with recurrent herpes.30 The effect of suppressive therapy is probably positive at the community level. First, recurrent genital herpes has an economic impact with more physician consultations and less workplace productivity.31 The cost of prolonged prophylaxis may be balanced by the economic impact of its efficacy. Second, prophylaxis significantly reduced the frequency of subclinical (asymptomatic) viral shedding,6,23 and VACV effectively lowered the risk of HSV transmission to a seronegative partner.21 Although oral antiviral drugs seem to provide prolonged prophylaxis, HSV resistant to ACV, VACV, or FCV has been encountered on rare occasions, in immunocompromised individuals who had been prescribed too low a dose of the drug. However, despite these reassuring data, monitoring for the possible emergence of resistant isolates from immunocompetent persons is warranted in nonresponders treated with standard regimens. In conclusion, the results of our meta-analysis confirmed the high efficacies of ACV, VACV, and FCV prophylaxis against recurrent genital herpes, and are sufficiently robust to make individual drug efficacy obvious. Advantages at the community level, especially in terms of economic impact, are probable, but data on this topic are lacking. REFERENCES 1. Kimberlin DW, Rouse DJ. Clinical practice: genital herpes. N Engl J Med 2004;350:1970-7. 2. Ashley RL, Wald A. Genital herpes: review of the epidemic and potential use of type-specific serology. Clin Microbiol Rev 1999;12:1-8. 3. Whitley RJ, Roizman B. Herpes simplex virus infections. Lancet 2001;357:1513-8. 4. Diamond C, Selke S, Ashley R, Benedetti J, Corey L. Clinical course of patients with serologic evidence of recurrent genital
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herpes presenting with signs and symptoms of first episode disease. Sex Transm Dis 1999;26:221-5. Benedetti J, Corey L, Ashley R. Recurrence rates in genital herpes after symptomatic first-episode infection. Ann Intern Med 1994;121:847-54. Wald A, Link K. Risk of human immunodeficiency virus infection in herpes simplex virus type 2-seropositive persons: a meta-analysis. J Infect Dis 2002;185:45-52. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1-12. Strauss SE, Takiff HE, Seidlin M, Bachrach S, Lininger L, DiGiovanna JJ, et al. Suppression of frequently recurring genital herpes: a placebo-controlled double-blind trial of oral acyclovir. N Engl J Med 1984;310:1545-50. Douglas JM, Critchlow C, Benedetti J, Mertz GJ, Connor JD, Hintz MA, et al. A double-blind study of oral acyclovir for suppression of recurrences of genital herpes simplex virus infection. N Engl J Med 1984;310:1551-6. Mindel A, Weller IV, Faherty A, Sutherland S, Hindley D, Fiddian AP, et al. Prophylactic oral acyclovir in recurrent genital herpes. Lancet 1984;2:57-9. Mostow SR, Mayfield JL, Marr JJ, Drucker JL. Suppression of recurrent genital herpes by single daily dosages of acyclovir. Am J Med 1988;85:30-3. Sacks SL, Fox R, Levendusky P, Stiver HG, Roland S, NusinoffLehrman S, et al. Chronic suppression for six months compared with intermittent lesional therapy of recurrent genital herpes using oral acyclovir: effects on lesions and nonlesional prodromes. Sex Transm Dis 1988;15:58-62. Mattison HR, Reichman RC, Benedetti J, Bolgiano D, Davis LG, Bailey-Farchione A, et al. Double-blind, placebo-controlled trial comparing long-term suppressive with short-term oral acyclovir therapy for management of recurrent genital herpes. Am J Med 1988;85(Suppl):20-5. Baker DA, Blythe JG, Kaufman R, Hale R, Portnoy J. One-year suppression of frequent recurrences of genital herpes with oral acyclovir. Obstet Gynecol 1989;73:84-7. Kaplowitz LG, Baker D, Gelb L, Blythe J, Hale R, Frost P, et al. Prolonged continuous acyclovir treatment of normal adults with frequently recurring genital herpes simplex virus infection: the acyclovir study group. JAMA 1991;265:747-51. Kinghorn GR, Woolley PD, Thin RN, De Maubeuge J, Foidart JM, Engst R. Acyclovir vs isoprinosine (immunovir) for suppression of recurrent genital herpes simplex infection. Genitourin Med 1992;68:312-6. Mertz GJ, Loveless MO, Levin MJ, Kraus SJ, Fowler SL, Goade D, et al. Oral famciclovir for suppression of recurrent genital herpes simplex virus infection in women: a multicenter, doubleblind, placebo-controlled trial; collaborative famciclovir genital herpes research group. Arch Intern Med 1997;157:343-9. Patel R, Bodsworth NJ, Woolley P, Peters B, Vejlsgaard G, Saari S, et al. Valaciclovir for the suppression of recurrent genital HSV infection: a placebo controlled study of once daily therapy: international valaciclovir HSV study group. Genitourin Med 1997;73:105-9. Reitano M, Tyring S, Lang W, Thoming C, Worm AM, Borelli S, et al. Valaciclovir for the suppression of recurrent genital herpes simplex virus infection: a large-scale dose rangefinding study; international valaciclovir HSV study group. J Infect Dis 1998;178:603-10. Diaz-Mitoma F, Sibbald RG, Shafran SD, Boon R, Saltzman RL. Oral famciclovir for the suppression of recurrent genital herpes: a randomized controlled trial: collaborative famciclovir genital herpes research group. JAMA 1998;280:887-92.
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21. Corey L, Wald A, Patel R, Sacks SL, Tyring SK, Warren T, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med 2004;350:11-20. 22. Velasco M, Saavedra T, Sepulveda C, Suarez M. Tratamiento prolongado con acyclovir en herpes genital recurrente. Respuesta clinica, viraologica e inmunologica. Rev Med Chil 1991;119:876-80. 23. Gupta R, Wald A, Krantz E, Selke S, Warren T, Vargas-Cortes M, et al. Valacyclovir and acyclovir for suppression of shedding of herpes simplex virus in the genital tract. J Infect Dis 2004;190:1374-81. 24. Wald A, Selke S, Warren T, Aoki FY, Sacks S, Diaz-Mitoma F, et al. Comparative efficacy of famciclovir and valacyclovir for suppression of recurrent genital herpes and viral shedding. Sex Transm Dis 2006;33:529-33. 25. Alexander L, Naisbett B. Patient and physician partnerships in managing genital herpes. J Infect Dis 2002;186(Suppl):S57-65. 26. Goldberg LH, Kaufman R, Kurtz TO, Conant MA, Eron LJ, Batenhorst RL, et al. Long-term suppression of recurrent
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genital herpes with acyclovir: a 5-year benchmark; acyclovir study group. Arch Dermatol 1993;129:582-7. Baker DA, Safrin S, Deeter RG, Walker A, Barton G, and the Acyclovir Study Group. Nine-year effectiveness of continuous suppressive therapy with acyclovir in patients with recurrent genital herpes. J Eur Acad Dermatol 1995;5(Suppl):S169. Kucers A, editor. The use of antibiotics: a clinical review of antibacterial, antifungal and antiviral drugs. Oxford: Butterworth-Heinemann; 1997. Patel R, Tyring S, Strand A, Price MJ, Grant DM. Impact of suppressive antiviral therapy on the health related quality of life of patients with recurrent genital herpes infection. Sex Transm Infect 1999;75:398-402. Carney O, Ross E, Bunker C, Ikkos G, Mindel A. A prospective study of the psychological impact on patients with a first episode of genital herpes. Genitourin Med 1994;70:40-5. Patel R, Boselli F, Cairo I, Barnett G, Price M, Wulf HC. Patients’ perspectives on the burden of recurrent genital herpes. Int J STD AIDS 2001;12:640-5.
enital herpes is the most frequent cause of genital ulcer disease1 and it is sexually transmitted. Genital herpes is caused by herpes simplex virus (HSV)-2 in 60% to 80% of the cases, but HSV-1-related genital herpes is on the rise.1,2 Serologic studies have found HSV-2 prevalence in the general populations of developed countries to be 15% to 25%.3 Epidemiologic surveys have indicated an increase of HSV-2 seroprevalence of about 20% to 30% in these countries during the past 20 years.2,3 Symptomatic recurrent flares occur
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in 20% to 50% of patients who have anti-HSV antibodies.4 Patients have a median of 4 recurrences during the first year after a symptomatic first episode of genital herpes caused by HSV-2.5 Because recurrent genital herpes is associated with major medical and psychosocial morbidities,1 suppressive therapy is required, especially in patients with episodes that are frequent, severe, or both. Moreover, suppression of genital herpes is also important because genital lesions favor HIV transmission and other sexually transmitted diseases.6 Finally, the risk of fetal
From the Department of Pharmacology, Hoˆpital Pitie´eSalpeˆtrie`re,a and Department of Dermatology, Hoˆpital Saint-Louis,b Assistance PubliqueeHoˆpitaux de Paris; Department of Dermatology, Hoˆpital Pasteur, Colmarc; and Department of Pharmacology, Hoˆpital Pitie´eSalpeˆtrie`re, Assistance PubliqueeHoˆpitaux de Paris,d and Department of Dermatology and Allergology, Hoˆpital Tenon, Assistance PubliqueeHoˆpitaux de Paris,e Universite´ Pierre-et-Marie-Curie Paris VI. Funding sources: None. Disclosure: Olivier Chosidow is a consultant for GSK. Drs LebrunVignes, Bouzamondo, Dupuy, Guillaume, and Lechat have no conflicts of interest to declare.
Accepted for publication February 18, 2007. Reprint requests: Be´ne´dicte Lebrun-Vignes, Department of Pharmacology, Hoˆpital Pitie´eSalpeˆtrie`re, 47e83, boulevard de l’Hoˆpital, 75651 Paris Cedex 13, France. E-mail: benedicte. [email protected]. Published online April 13, 2007. 0190-9622/$32.00 ª 2007 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2007.02.008
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Abbreviations used: ACV: CI: FCV: HSV: RCT: RR: VACV:
acyclovir confidence interval famciclovir herpes simplex virus randomized controlled trial relative risk valacyclovir
contamination during childbirth leading to neonatal herpes is high.1 Since the early 1980 s, oral antiviral agents have been used successfully to suppress recurrent genital herpes. Acyclovir (ACV) was the first molecule to have a meaningful therapeutic effect in that setting with significant efficacy (reduction of relative risk [RR] of recurrence varying in clinical trials from 41% to 86% vs placebo). More recently, valacyclovir (VACV), a prodrug of ACV with higher bioavailability after oral administration, and famciclovir (FCV), a prodrug of penciclovir, were evaluated for this indication.1 These 3 molecules have been used at different doses and regimens in several randomized controlled trials (RCTs), but data on comparisons of the different regimens are lacking. To date, no metaanalysis has been published on this topic. The aims of this meta-analysis were to compare the clinical efficacies of 3 oral antiviral drugs and identify the best regimens.
METHODS Trial search strategy MEDLINE and EMBASE databases and the Cochrane Controlled Trials Register were searched for articles on genital herpes and selected antiviral drugs. The MEDLINE search included: (herpes genitalis[mh] OR (herp* AND genit*) OR (herpes simplex[mh: noexp] AND genit*)) AND (aciclovir OR acyclovir OR valaciclovir OR valacyclovir OR famciclovir OR famcyclovir). The search was then cross-checked with RCTs (using Cochrane’s highly sensitive search for randomized trials) and in English; it was conducted online on the National Library of Medicine PUBMED World Wide Web site and was updated in January 2004. The database searches were completed with a hand search of references, cited in the articles identified, but we did not look for unpublished studies in conference proceedings. Study selection We selected the studies meeting our inclusion criteria by hand screening the titles and abstracts (Fig 1): ie, RCTs testing prophylactic oral antiviral treatment of genital herpes versus placebo in immunocompetent and nonpregnant patients, and
providing exploitable information on recurrences (see ‘‘Outcome definition’’). Recurrent genital herpes at inclusion of patients was accepted as it was defined in each trial. We chose not to retain the studies including pregnant women or nonimmunocompetent patients to limit sources of heterogeneity. Crossover trials could not be included because of methodologic reasons: the intermediate data after each period were not available, making an independent analysis of the results difficult, if not impossible. For logistic reasons, we selected only English-language studies. Outcome definition The selected end point was the number of patients developing at least one genital herpes recurrence during the trial. For each trial, the given clinical diagnosis of recurrence of the investigator was accepted. Data extraction Data from published reports were extracted independently by two investigators (A. D. and B. L-V.) onto a standardized form. The following items were extracted from each RCT: number and characteristics (sex, mean age) of patients included, frequency of recurrences chosen for inclusion, treatment duration, antiviral drug used, evaluated total daily doses and regimens, and the number of recurrence-free patients. We chose this end point because it was the only one available in all the trials, unlike the number of recurrences. When necessary, we calculated the number of patients who developed at least one recurrence during an RCT from the percentage or the number of recurrence-free patients reported. Selected studies were assessed for quality using the 5-point Jadad scale.7 Statistical methods The pooled estimate of the global RR of recurrence during the trials was calculated using, for each study, the inversed variance-weighted RR, in a fixed model, yielding bilateral 95% confidence interval (CI) for trials and for the meta-analysis. As usual in metaanalyses, a chi-square test for association of the pooled estimate of global RR and a chi-square test for RR homogeneity among trials and among subgroups were performed. P = .05 for the chi-square test was considered significant for association and homogeneity. When the RCT investigated more than one antiviral drug and/or dose compared with placebo, each intervention group in these trials was independently analyzed versus the same placebo group. Data used were always those based on an intention-to-treat analysis.
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Fig 1. Description of procedure used for study identification and selection.
The meta-analysis was conducted with software (EasyMA, Lyons, France).
RESULTS Fig 1 describes the procedure followed to select RCTs for this analysis, giving the precise numbers of initial articles identified included and excluded and the reasons for their exclusion. Finally we retained 14 RCTs, including 10 with ACV, 2 with FCV, and 3 with VACV (one trial included ACV and VACV).8-21 In all, 6158 patients (4037 and 2121 in the treatment and placebo groups, respectively) were included with a sex ratio varying from 0 to 1.8. All the RCTs were parallel-group, doubleblind studies. The 14 RCTs included are summarized in Table I.
Clinical efficacy Global analysis (Fig 2) showed a significant benefit of oral antiviral drugs compared with placebo, with RR ranging from 0.16 to 0.73. The global RR of developing at least one recurrence during the trial was reduced by 47% (95% CI 45%-49%). The number of patients needed to treat was 2.15 (95% CI 2.062.25). This analysis showed significant heterogeneity among RCTs (P \.001). Subgroup analyses The analysis according to the drug (Fig 3) showed the efficacy of each antiviral agent tested (all doses and regimens pooled), with RR reductions of 53% (95% CI 51%-57%) for ACV, 43% (95% CI 41%-47%) for VACV, and 42% (95% CI 35%-50%) for FCV. The
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Table I. Description of the 14 randomized controlled trials included in the meta-analysis Trials*
Strauss 19848 Douglas 19849 Mindel 198410 Mostow 198811 Sacks 198812 Mattison 198813 Baker 198914 Kaplowitz 199115 Kinghorn 199216 Mertz 199717
No. of patients included
Frequency of recurrences at inclusion
35 153 56 46 50 156 261 1146 78 375
$ 12/y $ 6/y $ 4/y $ 4/y $ 6/6 mo $ 6/y $ 6/y $ 6/y $ 6/y $ 6/y
Duration of study, mo
4 4 3 12 6 12 12 12 6 4
Antiviral agent, daily dose (mg)
ACV ACV ACV ACV ACV ACV ACV ACV ACV ACV FCV FCV
(600) (1000) (400) (800) (800) (600) (800) (800) (800) (800) (125) (250)
FCV (500) Patel 199718 Reitano 199819
Diaz-Mitoma 199820
Corey 200421 Total
382 1479
$ 8/y $ 6/y
4 12
457
$ 6/y
12
1484 6158
\10/y
8
VACV ACV VACV VACV
(500) (800) (250) (500)
VACV FCV FCV FCV VACV
(1000) (375) (500) (750) (500)
Regimen
200 3 3 200 3 5 200 3 2 200 3 4 800 3 1 200 3 3 400 3 2 400 3 2 400 3 2 400 3 2 125 3 1 125 3 2 or 250 3 1 250 3 2 or 500 3 1 500 3 1 400 3 2 250 3 1 250 3 2 or 500 3 1 1000 3 1 125 3 3 250 3 2 250 3 3 500 3 1
Jadad score
4 5 2 5 4 3 2 5 5 3
2 3
5
3
ACV, Acyclovir; FCV, famciclovir; VACV, valacyclovir. *All trials were parallel group, and double-blinded.
heterogeneity among the subgroups was significant (P \.001). Analysis according to the total daily dose of each drug showed that all the studied ACV doses were effective (Fig 4). The best evaluated daily dose was 800 mg. It was not possible to evaluate a dose-effect response, because of the scarcity of data at the other doses. For VACV (Fig 4), all the doses studied were also effective with the best evaluated daily dose being 500 mg. The results of this analysis suggested a dose-dependent response with 250 mg/d being less effective than 500 mg/d, and a maximum efficacy above 500 mg/d. Considering FCV (Fig 4), 125 mg/d was not effective, but higher doses achieved significant efficacy, with a clear dose-effect response between 250 and 750 mg/d. Analysis according to the regimen for each drug could only be undertaken for the best doses evaluated, owing to the small number of studies and patients. For ACV, 800 mg/d (Fig 5), all regimens (once, twice, or 4 times daily), had significant efficacy, with the best evaluated regimen being the twice-daily (400 mg) schedule (total 800 mg). The analysis revealed schedule-dependent efficacy, with
the 4-times-daily schedule being more effective than the other regimens with significant subgroup heterogeneity. In contrast, no difference in efficacy was found between the two (once or twice daily) regimens for VACV at 500 mg/d (Fig 5). Lastly, only the FCV (250 mg) twice-daily schedule (total 500 mg/d) (Fig 5) was effective, with the once-daily administration failing to reach significance.
DISCUSSION We report results of the first meta-analysis to be conducted on the efficacy of prophylactic oral antiviral treatments (ACV, VACV, FCV) to prevent genital herpes recurrences. The results confirmed the high efficacy of these agents compared with a placebo. Indeed, oral ACV, VACV, or FCV reduced the RR of developing a recurrence by about half. We are aware of potential methodologic weaknesses of this study. We decided to include only studies published in English. This decision excluded only one trial (n = 55) comparing ACV at 400 mg twice daily versus placebo, with high ACV efficacy.22 Because the results of that study were similar to those of the selected trials, it is unlikely that including it
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Fig 2. Global meta-analysis of relative risk (RR) of genital herpes recurrence under oral antiviral therapy. Results are given as number of recurrences/patients. Cochrane Q heterogeneity: P \ .001.
Fig 3. Subgroup meta-analysis of relative risk (RR) of genital herpes recurrence according to oral antiviral agent (any dose or regimen). ACV, Acyclovir; FCV, famciclovir; VACV, valacyclovir. Subgroup heterogeneity: P \ .001.
would have changed the global and subgroup results of our meta-analysis. In addition, when the RCT investigated more than one dose or more than one antiviral drug, we chose to analyze each intervention group versus the placebo, considering each
comparison as independent in accordance with the meta-analysis routine. However, doing so increased the alpha risk of observing a false treatment effect. Nevertheless, it appeared to be the best way not to lose information from those well-designed trials.
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In addition, the observed P values in each of these trials excluded false-positive results with high confidence. Heterogeneity between the trials was highly significant. We analyzed the possible components of such heterogeneity, which can originate from different treatment modalities or patient characteristics. Only analysis of treatment modalities could be evaluated because we could did not perform subgroup analyses according to patient characteristics without individual data. In addition, demographics were quite similar for all trials. However, treatment modalities clearly provided sources of heterogeneity, especially according to dose and the number of drug intakes per day. Heterogeneity according to dose was significant for ACV and VACV but without a clear dose-effect relationship. For FCV, a trend toward a dose effect was observed, but without significant heterogeneity because of the lack of power of this test. Heterogeneity was also significant according to number of ACV intakes per day. The greatest efficacy (RR reduction = 86%) was observed in a small study, with ACV (200 mg 4 times daily). However, that regimen is not very convenient and, thus, not highly conducive to long-term compliance. A similar trend was observed for FCV, but not for VACV. According to our meta-analysis, the best evaluated prophylactic doses were twice-daily regimens, ie, ACV (400 mg twice daily), VACV (250 mg twice daily), and FCV (250 mg twice daily), or once-daily VACV (500 mg), all of which had similar efficacies. That finding was never elucidated in RCTs because, as a general rule, they each compared a single antiviral drug, often at different doses and/or regimens, with a placebo. Only one study in our metaanalysis compared the prophylactic efficacy of VACV and ACV,19 with no difference between the two drugs. Few comparative studies between oral antiviral drugs have been performed: in a double-blind, crossover trial including 69 participants with recurrent genital herpes, oral VACV (500 mg twice daily) and ACV (400 mg twice daily) demonstrated high efficacies in suppressing the frequency and quantity of genital HSV shedding compared with placebo. Despite the better oral absorption of VACV than ACV, the frequency and quantity of polymerase chain reactionedetected HSV did not differ between VACV and ACV groups.23 In another report on the results of two randomized, double-blind, placebo-controlled studies comparing FCV (250 mg twice daily) with VACV (500 mg once daily), VACV appeared to be somewhat better than FCV for suppression of genital herpes and associated shedding.24
Fig 4. Subgroup meta-analysis of relative risk (RR) of genital herpes recurrence according to total daily dose of antiviral agent independently of regimen. ACV, Acyclovir; FCV, famciclovir; VACV, valacyclovir. Subgroup heterogeneity: P = .0097 (ACV), P \.001 (VACV), and P = .51 (FCV).
Independently of the drug, the once-daily dose should theoretically be the most convenient regimen, thereby favoring compliance. Nevertheless, to our knowledge, it has never been shown that a oncedaily dose improves compliance compared with twice-daily intake, especially in real life. Surveys of patients given suppressive therapy in several countries indicated that those using a once-daily regimen claimed to be more satisfied than those on a twicedaily regimen.25 If we consider the agents that could be used once daily, only VACV had clearly demonstrated efficacy. We did not find any additional benefit associated with a twice-daily regimen (250 mg twice daily) for VACV (500 mg), which is at variance with the manufacturer’s recommendations and the results of one study.19 ACV (800 mg once daily) was found to be effective in only one very small trial, and better evaluation of its efficacy is warranted.11 FCV (500 mg once daily) was not effective. The observation periods of all the RCTs were relatively short in light of the chronic nature of the disease. One RCT included in this meta-analysis was prolonged as an open study for 5 years after
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Fig 5. Subgroup meta-analysis of relative risk (RR) of genital herpes recurrence according to antiviral drug regimen for best evaluated daily dose. ACV, Acyclovir; FCV, famciclovir; VACV, valacyclovir. Subgroup heterogeneity: P = .014 (ACV), P = .93 (VACV), and P = .11 (FCV).
the controlled phase.13 The long-term follow-up showed persistent efficacy of the prophylaxis.26,27 Adverse events were recorded in the RCTs, with the most frequent being headache, nausea, diarrhea, or viral infections. The frequencies and types of
adverse events were similar for patients treated with antiviral and placebo, and were described as minor and transient. Despite the lack of information with regard to their frequencies during routine clinical practice, oral ACV-, VACV-, and FCV-attributed
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serious side effects seem to be very rare. Nephrotoxicity and neurotoxicity attributed to high ACV doses usually occurred with parenteral administration28; data on very long-term suppressive therapy has shown good tolerance.26,27 Patients with recurrent genital herpes had significantly diminished quality of life, which was independently associated with shorter intervals between recurrences and more severe pain or discomfort during flares.25 Improving the quality of life of patients on suppressive therapy is a very meaningful criterion, but it was evaluated in only one study included in our meta-analysis.19,29 In that trial, genital herpes suppression with ACV or VACV significantly improved health-related quality of life compared with the placebo. This effect was sustained throughout the study duration (12 months). In another study, prophylactic ACV reduced the psychosocial morbidity associated with recurrent herpes.30 The effect of suppressive therapy is probably positive at the community level. First, recurrent genital herpes has an economic impact with more physician consultations and less workplace productivity.31 The cost of prolonged prophylaxis may be balanced by the economic impact of its efficacy. Second, prophylaxis significantly reduced the frequency of subclinical (asymptomatic) viral shedding,6,23 and VACV effectively lowered the risk of HSV transmission to a seronegative partner.21 Although oral antiviral drugs seem to provide prolonged prophylaxis, HSV resistant to ACV, VACV, or FCV has been encountered on rare occasions, in immunocompromised individuals who had been prescribed too low a dose of the drug. However, despite these reassuring data, monitoring for the possible emergence of resistant isolates from immunocompetent persons is warranted in nonresponders treated with standard regimens. In conclusion, the results of our meta-analysis confirmed the high efficacies of ACV, VACV, and FCV prophylaxis against recurrent genital herpes, and are sufficiently robust to make individual drug efficacy obvious. Advantages at the community level, especially in terms of economic impact, are probable, but data on this topic are lacking. REFERENCES 1. Kimberlin DW, Rouse DJ. Clinical practice: genital herpes. N Engl J Med 2004;350:1970-7. 2. Ashley RL, Wald A. Genital herpes: review of the epidemic and potential use of type-specific serology. Clin Microbiol Rev 1999;12:1-8. 3. Whitley RJ, Roizman B. Herpes simplex virus infections. Lancet 2001;357:1513-8. 4. Diamond C, Selke S, Ashley R, Benedetti J, Corey L. Clinical course of patients with serologic evidence of recurrent genital
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