Oral antiviral therapy for prevention of genital herpes outbreaks in immunocompetent and nonpregnant patients(review)

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1 Cochrane Database of Systematic Reviews Oral antiviral therapy for prevention of genital herpes outbreaks in immunocompetent and nonpregnant patients (Review) LeCleachL,TrinquartL,DoG,MaruaniA,Lebrun-VignesB,RavaudP,ChosidowO LeCleachL,TrinquartL,DoG,MaruaniA,Lebrun-VignesB,RavaudP,ChosidowO. Oral antiviral therapy for prevention of genital herpes outbreaks in immunocompetent and nonpregnant patients. Cochrane Database of Systematic Reviews 2014, Issue 8. Art. No.: CD DOI: / CD pub2. Oral antiviral therapy for prevention of genital herpes outbreaks in immunocompetent and nonpregnant patients(review) Copyright 2014 The Cochrane Collaboration. Published by John Wiley& Sons, Ltd.

2 T A B L E O F C O N T E N T S HEADER ABSTRACT PLAIN LANGUAGE SUMMARY BACKGROUND OBJECTIVES METHODS RESULTS Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure DISCUSSION AUTHORS CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES CHARACTERISTICS OF STUDIES DATA AND ANALYSES Analysis 1.1. Comparison 1 Acyclovir vs placebo, Outcome 1 Particpants with at least 1 clinical recurrence Analysis 1.2. Comparison 1 Acyclovir vs placebo, Outcome 2 Participants with at least 1 clinical recurrence (according to daily dose) Analysis 1.3. Comparison 1 Acyclovir vs placebo, Outcome 3 Participants with at least 1 clinical recurrence (complete cases) Analysis 1.4. Comparison 1 Acyclovir vs placebo, Outcome 4 Particpants with at least 1 virologically confirmed recurrence Analysis 2.1. Comparison 2 Valacyclovir vs placebo, Outcome 1 Participants with at least 1 clinical recurrence Analysis 2.2. Comparison 2 Valacyclovir vs placebo, Outcome 2 Participants with at least 1 clinical recurrence (according to daily dose) Analysis 2.3. Comparison 2 Valacyclovir vs placebo, Outcome 3 Participants with at least 1 clinical recurrence (complete cases) Analysis 3.1. Comparison 3 Valacyclovir vs No treatment, Outcome 1 Participants with at least 1 clinical recurrence. 95 i

3 Analysis 3.2. Comparison 3 Valacyclovir vs No treatment, Outcome 2 Participants with at least 1 clinical recurrence (complete cases) Analysis 4.1. Comparison 4 Famciclovir vs placebo, Outcome 1 Participants with at least 1 clinical recurrence Analysis 4.2. Comparison 4 Famciclovir vs placebo, Outcome 2 Particpants with at least 1 clinical recurrence (according to daily dose) Analysis 4.3. Comparison 4 Famciclovir vs placebo, Outcome 3 Participants with at least 1 clinical recurrence (complete cases) Analysis 4.4. Comparison 4 Famciclovir vs placebo, Outcome 4 Participants with at least 1 virologically confirmed recurrence Analysis 5.1. Comparison 5 Valacyclovir vs acyclovir, Outcome 1 Participants with at least 1 clinical recurrence Analysis 5.2. Comparison 5 Valacyclovir vs acyclovir, Outcome 2 Participants with at least 1 clinical recurrence (complete cases) Analysis 6.1. Comparison 6 Famciclovir vs valacyclovir, Outcome 1 Participants with at least 1 clinical recurrence Analysis 6.2. Comparison 6 Famciclovir vs valacyclovir, Outcome 2 Participants with at least 1 clinical recurrence (complete cases) Analysis 6.3. Comparison 6 Famciclovir vs valacyclovir, Outcome 3 Participants with at least 1 virologically confirmed recurrence ADDITIONAL TABLES APPENDICES CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST SOURCES OF SUPPORT DIFFERENCES BETWEEN PROTOCOL AND REVIEW INDEX TERMS ii

4 [Intervention Review] Oral antiviral therapy for prevention of genital herpes outbreaks in immunocompetent and nonpregnant patients Laurence Le Cleach 1, Ludovic Trinquart 2, Giao Do 1, Annabel Maruani 3, Benedicte Lebrun-Vignes 4, Philippe Ravaud 5, Olivier Chosidow 1 1 Department of Dermatology, Hôpital Henri Mondor, Créteil, France. 2 French Cochrane Center, Hôpital Hôtel-Dieu, Paris, France. 3 Department of Dermatology, Université François-Rabelais de Tours, Tours, France. 4 Department of pharmacology, Hôpital Pitiésalpétrière, Paris, France. 5 Centre d Epidémiologie Clinique, Hôpital Hôtel-Dieu; Université Paris Descartes; INSERM U738, Paris, France Contact address: Laurence Le Cleach, Department of Dermatology, Hôpital Henri Mondor, 51 avenue du Général de Lattre de Tassigny, Créteil, 94010, France. laurence.lecleach@free.fr. Editorial group: Cochrane STI Group. Publication status and date: New, published in Issue 8, Citation: Le Cleach L, Trinquart L, Do G, Maruani A, Lebrun-Vignes B, Ravaud P, Chosidow O. Oral antiviral therapy for prevention of genital herpes outbreaks in immunocompetent and nonpregnant patients. Cochrane Database of Systematic Reviews 2014, Issue 8. Art. No.: CD DOI: / CD pub2. Background A B S T R A C T Genital herpes is caused by herpes simplex virus 1 (HSV-1) or 2 (HSV-2). Some infected people experience outbreaks of genital herpes, typically, characterized by vesicular and erosive localized painful genital lesions. Objectives To compare the effectiveness and safety of three oral antiviral drugs (acyclovir, famciclovir and valacyclovir) prescribed to suppress genital herpes outbreaks in non-pregnant patients. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the search portal of the World Health Organization International Clinical Trials Registry Platform and pharmaceutical company databases up to February We also searched US Food and Drug Administration databases and proceedings of seven congresses to a maximum of 10 years. We contacted trial authors and pharmaceutical companies. Selection criteria We selected parallel-group and cross-over randomized controlled trials including patients with recurrent genital herpes caused by HSV, whatever the type (HSV-1, HSV-2, or undetermined), with at least four recurrences per year (trials concerning human immunodeficiency virus (HIV)-positive patients or pregnant women were not eligible) and comparing suppressive oral antiviral treatment with oral acyclovir, famciclovir, and valacyclovir versus placebo or another suppressive oral antiviral treatment. Data collection and analysis Two review authors independently selected eligible trials and extracted data. The Risk of bias tool was used to assess risk of bias. Treatment effect was measured by the risk ratio (RR) of having at least one genital herpes recurrence. Pooled RRs were derived by conventional pairwise meta-analyses. A network meta-analysis allowed for estimation of all possible two-by-two comparisons between antiviral drugs. 1

5 Main results A total of 26 trials (among which six had a cross-over design) were included. Among the 6950 randomly assigned participants, 54% (range 0 to100%) were female, mean age was 35 years (range 26 to 45.1), and the mean number of recurrences per year was 11 (range 6.3 to 17.8). Duration of treatment was two to 12 months. Risk of bias was considered high for half of the studies and unclear for the other half. A total of 14 trials compared acyclovir versus placebo, four trials compared valacyclovir versus placebo and 2 trials compared valacyclovir versus no treatment. Three trials compared famciclovir versus placebo. Two trials compared valacyclovir versus famciclovir and one trial compared acyclovir versus valacyclovir versus placebo. We analyzed data from 22 trials for the outcome: risk of having at least one clinical recurrence. We could not obtain the outcome data for four trials. In placebo-controlled trials, there was a low quality evidence that the risk of having at least one clinical recurrence was reduced with acyclovir (nine parallel-group trials, n = 2049; pooled RR 0.48, 95% confidence interval (CI) 0.39 to 0.58), valacyclovir (four trials, n = 1788; pooled RR 0.41, 95% CI 0.24 to 0.69), or famciclovir (two trials, n = 732; pooled RR 0.57, 95% CI 0.50 to 0.64). The six cross-over trials showed larger treatment effects on average than the parallel-group trials. We found evidence of a smallstudy effect for acyclovir placebo-controlled trials (adjusted pooled RR 0.61, 95% CI 0.49 to 0.75). In analyzing parallel-group trials by daily dose, no clear evidence was found of a dose-response relationship for any drug. In head-to-head trials, the risk of having at least one recurrence was increased with valacyclovir rather than acyclovir (one trial, n = 1345; RR 1.16, 95% CI 1.01 to 1.34) and was not significantly different from that seen with famciclovir as compared with valacyclovir (one trial, n = 320; RR 1.18, 95% CI 0.86 to 1.63). We included 16 parallel-arm trials in a network meta-analysis and we were unable to determine which of the drugs was most effective in reducing the risk of at least one clinical recurrence (after adjustment for small-study effects, pooled RR 0.83, 95% CI 0.61 to 1.11 for valacyclovir vs acyclovir; pooled RR 1.04, 95% CI, 0.71 to 1.49 for famciclovir vs acyclovir; and pooled RR 1.26, 95% CI 0.89 to 1.75 for famciclovir vs valacyclovir). Safety data were sought but were reported as total numbers of adverse events. Authors conclusions Owing to risk of bias and inconsistency, there is low quality evidence that suppressive antiviral therapy with acyclovir, valacyclovir or famciclovir in pacients experiencing at least four recurrences of genital herpes per year decreases the number of pacients with at least one recurrence as compared with placebo. Network meta-analysis of the few direct comparisons and the indirect comparisons did not show superiority of one drug over another. P L A I N L A N G U A G E S U M M A R Y (Oral antiviral treatment to prevent genital herpes outbreaks in immunocompetent and nonpregnant patients) Review question Are oral antiviral drugs (acyclovir, famciclovir, and valacyclovir) effective compared with placebo? And is one of these three drugs superior to the others in suppressing genital herpes outbreaks in patients experiencing four or more recurrences per year? Effectiveness in this review was evaluated by determining the risk of experiencing at least one recurrence during the treatment period in each group. Background Genital herpes is a sexually transmitted disease (STD) related to herpes simplex virus type 1 (HSV-1) or 2 (HSV-2). In some people infected with this virus, painful mucocutaneous vesicles develop in a small zone of the genital area and evolve into erosions and crusts. The repetition of this event is called recurrence. Each recurrence lasts five to 10 days.treatment options in patients experiencing recurrences of genital herpes include no treatment, symptomatic treatment, episodic antiviral treatment for a few days each time a recurrence occurs, and suppressive daily continuous treatment. Study characteristics A total of 26 trials including 6950 patients were included in this review. Fifty-four percent of these patients were female, mean age was 35 years, and mean number of recurrences per year before entry into the trials was 11. Duration of treatment in trials ranged from two to 12 months. A total of 14 trials compared acyclovir versus placebo. Four trials compared valacyclovir versus placebo and two trials compared valacyclovir versus no treatment. Three trials compared famciclovir versus placebo. Two trials compared valacyclovir versus famciclovir, and one trial compared acyclovir versus valacyclovir versus placebo. Among the 26 included trials, 22 declared pharmaceutical company funding. The last search for studies was carried out in February

6 Key results Suppressive antiviral therapy with acyclovir, valacyclovir, or famciclovir in patients experiencing at least four recurrences per year decreases the number of patients having at least one recurrence compared with placebo. There is no evidence that suggests that any of these drugs is superior to the others. Quality of evidence Althought the three antiviral drugs showed better results compared with placebo, we are uncertain as to how much a difference there are likely to make, because of issues with the conduct and reporting of studies, and inconsistency of their results. The quality of the evidence is low and we think that the size of the effects is likely to change with more research. Because few studies compared the three drugs against one other, we are moderately confident in the fact that there is no difference between the three drugs in terms of effectiveness. B A C K G R O U N D Description of the condition Genital herpes is the most frequent cause of genital ulcer disease (Celum 2004). Genital herpes is a sexually transmitted disease caused by herpes simplex virus type 2 (HSV-2) in 60% to 80% of cases, but HSV-1-related genital herpes is increasing and accounts for about half of new cases in developed countries (Gupta 2007; Kimberlin 2004). Serological studies have found a seroprevalence of HSV-2 of 15% to 25% in the general population of developed countries (Looker 2008; Whitley 2001). The HSV-2 seroprevalence in people 14 to 49 years of age in the United States was 16.2% in , and did not significantly differ from that reported in (MMWR 2010). Seroprevalence was highest among women (20.9%). Genital herpes favors transmission of human immunodeficiency virus (HIV) and other sexually transmitted diseases (Freeman 2006). Besides, transmission during childbirth can lead to neonatal herpes (Kimberlin 2013). Infection occurs during close contact with the mucous membrane, abraded skin lesions or mucosal secretions of a person who has genital lesions or is shedding HSV. Viral invasion of epithelial cells occurs at the site of the exposed infection then HSV ascends to the sensory nerve root ganglia and enters a latent state. The primary HSV genital infection can be asymptomatic or characterized by the appearance four to seven days after sexual contact of painful mucocutaneous vesicles on the genital area, which evolve into erosions and crusts. Systemic symptoms such as fever may be associated (Fife 2006). Recurrent episodes are caused by HSV reactivation. Viruses travel along sensory neurons to the corresponding mucocutaneous area (Gupta 2007). Reactivation of latent HSV leads to subclinical (asymptomatic shedding) or symptomatic genital mucocutaneous outbreaks. Recurrences are milder than primary infection, with more limited and less painful unilateral lesions and without systemic symptoms. Spontaneous healing occurs in five to 10 days (Sen 2007). Symptomatic recurrent flares occur in 20% to 50% of patients with anti-hsv antibodies. Following a symptomatic first episode of HSV-2 genital infection, the median recurrence rate is four recurrences during the first year (Sen 2007). The rate of recurrence usually decreases over time but increases in about one quarter of patients. Immunosuppressed patients have more severe and frequent recurrences (Benedetti 1994). Genital HSV- 1 infection leads to less frequent outbreaks (mean recurrence rate 1.3/y) than are seen with HSV-2 infection (Engelberg 2003). Shedding (viral detection at mucosal sites) occurs during symptomatic episodes of genital herpes but also in the absence of genital lesions, even in people without genital herpes recurrences. A prospective study observed 498 immunocompetent HSV-2- seropositive patients for a median of 57 days. HSV-2 viral shedding (measured by polymerase chain reaction (PCR)) was detected on 20% of days with swabs collected in people with symptomatic genital HSV-2 infection and on 10.2% of days in people with asymptomatic infection (Tronstein 2011). A meta-analysis found that people who reported always using condoms had a 30% decreased risk of HSV-2 infection as compared with people who reported no condom use (Martin 2009). The clinical diagnosis of genital herpes and virus typing should be confirmed by laboratory testing. Viral isolation in cell culture has low sensitivity and allows virus typing and antiviral sensitivity testing. PCR, a rapid and sensitive method of viral detection and virus typing, is now frequently used (Scoular 2002). In a study of detection of HSV by PCR or by isolation in Vero cell culture on genital swabs taken from 194 participants who presented with genital ulceration or symptoms suggestive of genital herpes infection, comparison of cell culture versus PCR showed a sensitivity of 93/115 (80.9%) and a specificity of 79/79 (100%) (Slomka 3

7 1998). HSV type-specific serology (enzyme-linked immunosorbent assay (ELISA) or Western-blot analysis) is indicated in the absence of or negative results of direct virus detection methods in patients with a history of recurrent or atypical genital lesions. HSV-2 antibodies suggest a diagnosis of genital herpes; the presence of HSV-1 antibodies does not allow differentiation between genital and oropharyngeal infection (European guidelines (IUSTI)). Description of the intervention Three oral antiviral drugs are available to treat genital herpes: acyclovir; valacyclovir, a prodrug of acyclovir with higher bioavailability after oral administration, and famciclovir (FCV). Famciclovir is the well-absorbed (77% bioavailable) oral form of penciclovir. Randomized controlled trials demonstrated that these three drugs reduce the severity and duration of the recurrence by one to two days when started early after the beginning of the first symptoms (prodromes) or clinical signs of recurrence. This intermittent regimen does not reduce the number of recurrences by year (Abudalu 2008; Aoki 2006; Bodsworth 2009; Goldberg 1986; Leone 2002; Reichman 1984;Romanowski 2000; Sacks 2005; Saiag 1999 Tyring 1998; Wald 2002; Warren 2004). Because none of these drugs can eradicate the latent virus, and because recurrent genital herpes is associated with medical and psychosocial morbidities, suppressive therapy is recommended in patients with frequent and/or severe episodes (Gupta 2007; Sen 2007). One trial demonstrated that valacyclovir as suppressive antiviral treatment decreased the risk of HSV-2 in serodiscordant couples (Corey 2004). Two randomised trials found that acyclovir suppressive therapy used to suppress HSV-2 failed to reduce the risk of HIV acquisition in HSV-2-infected but HIV-negative participants (Celum 2004; Watson-Jones 2008). How the intervention might work The action mechanism of these drugs consist of the following: viral thymidine kinase converts penciclovir or acyclovir to penciclovir or acyclovir monophosphate, which is converted by cellular enzymes to penciclovir or acyclovir triphosphate. Penciclovir or acyclovir triphosphate inhibits viral DNA polymerase, thereby halting DNA synthesis and viral replication (De Clercq 2006). The minimum inhibitory concentration of acyclovir is slightly higher for HSV-2 than for HSV-1 (Rosenberry 1982). The suppressive antiviral therapy consists of daily oral administration of acyclovir, famciclovir, or valacyclovir for six to 12 months. After completion of the treatment regimen, the number of recurrences without suppressive therapy is assessed. The aim of the suppressive antiviral therapy is to reduce the number of recurrences, viral shedding, and the risk of transmission during treatment. Acyclovir was the first molecule to have a meaningful therapeutic effect in this setting, with significant efficacy (reduction of recurrence varying in clinical trials from 41% to 86% vs placebo). More recently, valacyclovir and famciclovir have been evaluated for this indication. Why it is important to do this review Most trials assessing antiviral drugs for HSV (at different doses and regimens) used a placebo or no treatment arm. A previous metaanalysis showed that acyclovir, famciclovir, and valacyclovir were superior to placebo or no treatment for prophylaxis of recurrent genital herpes (Lebrun-Vignes 2007). However, direct comparisons between the different regimens are lacking, and no conclusive evidence on the optimal antiviral therapy has been provided. It is important to synthesize up-to-date evidence from randomized controlled trials (RCTs), by using a network meta-analysis, and to compare the different drugs against one another, thus allowing for comparisons not addressed in the individual primary trials. O B J E C T I V E S To compare the effectiveness and safety of three oral antiviral drugs (acyclovir, famciclovir, and valacyclovir) prescribed to suppress genital herpes outbreaks versus placebo or versus one another in nonpregnant patients. M E T H O D S Criteria for considering studies for this review Types of studies Eligible studies were parallel-group or cross-over RCTs. No restriction was placed on publication status or language. Types of participants We reviewed studies of participants with recurrent genital herpes (defined as four or more outbreaks per year) due to HSV, whatever the type (HSV-1, HSV-2, or undetermined). We identified a threshold that corresponded to an indication for suppressive therapy. See Overall completeness and applicability of evidence for discussion of the choice of four recurrences per year. Studies of HIV-positive participants or pregnant women were not eligible (Hollier 2008). 4

8 Types of interventions Suppressive oral antiviral treatment with oral acyclovir, famciclovir and valacyclovir for genital herpes compared against each one other or compared with placebo. A suppressive treatment is defined a continuous treatment for several months that aims to prevent herpes recurrence. In multi-arm trials, study groups assessing drugs other than acyclovir, famciclovir or valacyclovir and study groups assessing intermittent treatment only were not eligible. Types of outcome measures Primary outcomes Proportion of participants with at least one recurrent episode of genital herpes during the treatment period. Recurrence-free survival. Secondary outcomes Proportion of participants with at least one virologically confirmed recurrent episode of genital herpes during the treatment period. Rate of days with symptomatic or asymptomatic viral excretion (shedding) during the treatment period. Proportion of participants with adverse events. Search methods for identification of studies Electronic searches We searched a range of bibliographical databases, including the Cochrane Central Register of Controlled Trials (CENTRAL); the specialized registers of the Cochrane Infectious Diseases Group, the Cochrane Skin Group, and the Cochrane Sexually Transmitted Infections Group; MEDLINE, EMBASE and LILACS, with no restriction on language or date. The search was performed in collaboration with the Trials Search Co-ordinator of the Cochrane Sexually Transmitted Diseases Group and a healthcare librarian. MEDLINE and EMBASE were searched with both controlled vocabulary (namely, Medical Subject Headings (MeSH) in MED- LINE and EMTREE in EMBASE) and a wide range of freetext terms (Appendix 1, Appendix 2, Appendix 3). The search of MEDLINE involved use of the Cochrane Highly Sensitive Search Strategy, sensitivity-maximizing version. Another search equation included the filter used by the Cochrane HIV/acquired immunodeficiency syndrome (AIDS) group. The search of EMBASE involved use of the UK Cochrane Centre search filter to identify reports of randomized trials. The search last ran until February Searching other resources We screened the reference lists of all selected trials. We contacted the main authors in the field to identify any additional published or unpublished data. We searched the proceedings of the following conferences. European Congress International Union Against Sexually Transmitted Infections (IUSTI), 2004, 2006, 2007, 2008, 2010, 2012, 2013 European Congress of Clinical Microbiology and Infectious Diseases, Interscience Conference on Antimicrobial Agents and Chemotherapy, American Academy of Dermatology, Annual Society for Dermatological Research Meeting, World Congress of IUSTI, We contacted the pharmaceutical companies producing the antiviral agents of interest and searched the clinical trial results database of each company ( and to identify ongoing and unpublished trials. We searched reviews submitted to the Food Drug Administration (FDA) for drug registration ( scripts/cder/drugsatfda/). We also searched the search portal of the World Health Organization (WHO) International Clinical Trials Registry Platform to identify ongoing trials. Finally, we sent the listing of included trials to two main authors in the field (Prof. Corey and Prof. Wald), and we asked whether they were aware of any additional potentially relevant trials. The search of these sources was run until February 26, Data collection and analysis Selection of studies Two review authors (LLC and GD) independently examined each title and abstract to exclude irrelevant reports. The two review authors independently examined full-text articles to determine eligibility. Trial authors were contacted for clarification when required to assess eligibility. Disagreements were discussed to reach consensus. We linked together multiple reports of the same study and we specified which report was used as the primary data source. We listed excluded trials and documented the primary reason for exclusion. The trial selection process involved the use of Cochrane-resyweb.net, which handles the importation of references from multiple databases, as well as the semi-automatic deletion of duplicate 5

9 records of the same report, selection of trials by independent review authors, the use of consensus procedures in cases of disagreement, and the linkage of multiple reports of the same trial. Finally, the web service automatically produced a flow chart for reporting the search process. Measures of treatment effect For at least one recurrence of genital herpes, we measured treatment effects using risk ratios (RRs) and associated 95% confidence intervals (95% CIs). Data extraction and management The data from published and unpublished reports were extracted independently by two review authors (LLC, and AM). They use a standardized form which was piloted. Consensus was achieved by discussion with a statistician (LT). We abstracted information regarding trial design and setting (parallel-arm or cross-over design, single center or multicenter, country, period of inclusion), population (age, sex, number of recurrences the previous year), interventions (dosage, frequency, duration, co-intervention), and outcome data. These data were checked and entered into the Cochrane Review Manager (RevMan) computer software by one review author (AM). Assessment of risk of bias in included studies The Cochrane Collaboration Risk of bias tool was used to assess the risk of bias. Randomization was considered adequate if the allocation sequence was generated from a table of random numbers or by computer. It was considered inadequate if sequences could be related to prognosis. It was considered unclear if it was stated that the report noted that the trial was randomized, but the method was not described. Allocation concealment was deemed adequate if the report stated that it was undertaken by means of sequentially pre-numbered, sealed opaque envelopes or by a centralized system. The risk of bias associated with inadequate blinding was evaluated separately for personnel and participants on one hand, and for outcomes assessors on the other hand. A double-blind doubledummy process was considered at low risk of bias. Concerning the risk of bias associated with incomplete outcome data, we examined the presence of imbalance in numbers or reasons for missing data across intervention groups, and determined wether the analysis was performed according to the intention-to-treat principle. The use of strategies to handle missing data (last observation carried forward, multiple imputation, etc.) was assessed. For selective reporting of outcomes, we considered the risk of bias high when results for outcomes detailed in the methods section were not reported in the results section; otherwise, the risk of bias was considered as unclear in the absence of an available protocol. A risk of bias table was completed for each included trial. Moreover, for crossover trials, we took into account the following items according to Section of the Cochrane Handbook for Systemic Reviews of Interventions (Cochrane Handbook) : whether a carry-over effect was evident, whether only first period data were available, and whether the analysis performed was appropriate. Unit of analysis issues The primary unit of analysis was the participant. In parallel-group trials, participants are randomly assigned to one intervention. In cross-over trials, participants are randomly assigned to a sequence of interventions, and participants act as their own control. Crossover studies that ignore the pairing commit a unit-of-analysis error. We have reported such errors, but we could not reanalyze data appropriately (Curtin 2002). Dealing with missing data We checked whether each trial used the intention-to-treat principle for analysis (i.e., the number of analyzed participants equals the number of randomly assigned participants). For the main analysis, we assumed that any participants with missing outcome data experienced at least one recurrent episode, whatever the group. We also synthesised data as analyzed in each trial (complete cases). Assessment of heterogeneity To assess to what extent the results of trials were consistent, we examined variability in point estimates and overlap of confidence intervals across studies; we used Higgins and Thompson s I 2 statistic. We interpreted the I 2 value according to the following thresholds (Section of the Cochrane Handbook): 0% to 40% might not be important; 30% to 60% may represent moderate heterogeneity; 50% to 90% may represent substantial heterogeneity; and 75% to 100% represents considerable heterogeneity. We also computed the 95% CI for the I 2 (Ioannidis 2007). In all cases, we considered the results from both the fixed-effect model and random-effects models, and the choice between the two models was based on the number of studies, the distribution of effect sizes, measures of heterogeneity, and clinical and methodological diversity. Assessment of reporting biases To address reporting biases and related small-study effects, we drew funnel plots for each pairwise meta-analysis. Funnel-plot asymmetry tests were used when the validity conditions were met: no significant heterogeneity (I 2 statistic < 50%), 10 or more studies and at least one with significant results, and a ratio of maximal to minimal variance across studies > 4 (Ioannidis 2007a). In cases of evidence of small-trial effects, we performed sensitivity analyses according to a regression-based adjustment model (Moreno 2009; Rucker 2011). 6

10 Data synthesis First, we derived pooled RR estimates from pairwise meta-analyses for available direct comparisons. The Mantel-Haenszel method was used. We analyzed cross-over trials by a simple approach using all outcome data from the experimental intervention periods and all outcome data from the control intervention periods and analyzing these as if the trial were a parallel-group trial. This incorrect analysis is conservative. One trial reported data from the first period only, so we analyzed only these data. Cross-over trials were synthesized separately from parallel-group trials and in cases of differences between the two strata, we did not combine all trials together. In cases of multi-arm trials, we compared arms two at a time in separate comparisons. In cases of multi-dose trials, we grouped together all the different dose groups and compared them collectively with the control group. Second, we derived pooled estimates for all possible two-by-two comparisons between interventions from a network meta-analysis; a hierarchical model with a Bayesian approach was used (Lu 2004). This model handles multi-arm trials appropriately. We assessed the consistency of the network by using inconsistency factors on closed loops; we estimated the difference between direct and adjusted indirect estimates and associated 95% CIs and tested whether it was statistically significant. Estimates of three two-bytwo comparisons between each antiviral drug and the others were reported, along with 95% credibility intervals (95%CrIs). The rank-order of efficacy of the different drugs and the probability that each drug is the best among the three antiviral drugs were estimated (Salanti 2010). We also performed a sensitivity analysis to adjust for small-study effects based on a network meta-regression model, which assumed that biases were exchangeable across comparisons versus placebo across the network (Trinquart 2012). Pairwise meta-analyses involved use of RevMan software, adjustment models for small-study effects were fitted by the use of R software, and network meta-analyses involved the use of Win- BUGS software. Finally, we presented the findings into a Summary of findings table including a summary of the amount of evidence, estimates of relative effects of treatments and estimates of typical absolute risks for people receiving drugs or placebo. We also assessed the quality of the body of evidence according to the GRADE framework. Subgroup analysis and investigation of heterogeneity in order to assess the influence of doses, we performed subgroup analyses according to the total daily dose. Subgroup analyses initially planned to determine efficacy in men versus women, with HSV-1 versus HSV-2 genital herpes, were not possible because these data were not reported in the included trials. R E S U L T S Description of studies Results of the search Overall, we included 26 trials corresponding to 42 reports (Figure 1). The search of electronic databases (MEDLINE, EMBASE, LILACS, and CENTRAL) yielded 5563 citations. The search of other sources identified nine reports: we found eight reports through the clinical trial results databases of pharmaceutical companies (four were also published (Bartlett 2008; Fife 2006; Reitano 1998; Patel 1997), and one report was identified by screening conference proceedings (Sekhin 2004)). No report was identified by searching FDA reviews and the WHO International Clinical Trials Registry Platform nor by contacting the main authors in the field. The two main authors in the field whom we contacted were not aware of any other relevant trial. 7

11 Figure 1. Flow of information through the different phases of t he review After duplicate records were removed, we had 3785 citations. After reviewing the titles and abstracts, we discarded 3676 citations. We examined the full text of the remaining 109 citations: 61 did not meet the inclusion criteria (see Excluded studies), and six trials were classified as studies awaiting classification. Among these, information regarding risk of bias assessment and data analyses were lacking in four trials ( Douglas 1988; Frenkel 1989; Mastrolorenzo 1991; Tyring 2003). We contacted the study authors, but they did not provide information (Table 1). For two trials potentially eligible according to the abstract, we could not retrieve the fulltext article (Wu 2000, Zhang 2011). Among the 26 included trials, three trials (Fife 2006; Patel 1997; Reitano 1998) provided both published and unpublished results; when this occurred, we used the unpublished results because numerical data were available (for two trials (Fife 2006;Patel 1997) discrepancies were observed). Results of six trials were published in more than one journal article (Halsos 1985; Mattison 1988; Mertz 1988; Reitano 1998; Romanowski 2003; Straus 1984). For two trials, only unpublished results were available (HS ; PREV ). See Characteristics of included studies In all, 22 studies declared pharmaceutical company funding, and four studies did not report the source of funding (Blom 1986; Kroon 1989; Mindel 1984; Sekhin 2004). In 13 of the 22 studies, at least one of the trial authors was employed by the funding pharmaceutical company. Trial design A total of 20 trials used a parallel-group design, and six a crossover design (Blom 1986; Halsos 1985; Kinghorn 1985; Kroon 1989; Romanowski 2003; Thin 1985). Across the 26 trials, the median sample size was 95 (Table 2). For the parallel-group trials, the median sample size was 128, and for cross-over trials, 40. In all, 16 trials were multicenter trials (two to 76 centers) and eight were single-center trials (Douglas 1984; Kinghorn 1985; Kroon 1989; Mindel 1984; Mostow 1988; Sacks 1988; Sacks 1988; Velasco 1991); for two trials, single-center or multicenter status was not clear (Sekhin 2004; Straus 1984). Four multiarm trials assessed the same experimental drug at multiple dose levels (acyclovir in Douglas 1984; valacyclovir in Reitano 1998; famciclovir in Diaz- Mitoma 1998 and Mertz 1997). Moreover, Reitano 1998 assessed two experimental drugs (acyclovir and valacyclovir) versus placebo. 8

12 Characteristics of participants The characteristics of participants are summarized in Table 2. Across the 26 included trials, 1437 participants were randomly assigned to receive acyclovir, 2123 valacyclovir, and 1162 famciclovir (Table 2). Moreover, 1659 participantss were randomly assigned to receive placebo and 569 no treatment. Females represented 54% (min to max 0% to100%) of included participants, Halsos 1985 included only men, and Mertz 1997 and Sacks 2004 included only women. The overall mean age of participants was 35.0 (min to max 26.0 to 45.1) years. The overall mean number of recurrences was 11.0 (range 6.3 to 17.8) (information available for 15 trials). For 15 trials, confirmation of genital herpes by viral culture or PCR was required for inclusion, and in the other trials, a clinical diagnosis of genital herpes without laboratory confirmation was sufficient. In four trials, all participants had recurrent genital herpes due to HSV2 (Blom 1986; Douglas 1984; Fife 2006; Sacks 2004). The number of participants with HSV-1 or HSV-2 infection was reported in one study (Kinghorn 1985). For the others, this information was not provided. Comparisons A total of 14 trials compared acyclovir with placebo (Blom 1986; Douglas 1984; Halsos 1985; Kinghorn 1985; Kinghorn 1992; Kroon 1989; Mattison 1988; Mertz 1988; Mindel 1984; Mostow 1988; Sacks 1988; Straus 1984; Thin 1985; Velasco 1991). Four trials compared valacyclovir with placebo (Fife 2006; HS ; Patel 1997; Sekhin 2004) and two trials compared valacyclovir with no treatment (PREV ; Romanowski 2003). Three trials compared famciclovir with placebo (Diaz-Mitoma 1998; Mertz 1997; Sacks 2004). Two trials compared valacyclovir with famciclovir (Wald 2006 study 1; Wald 2006 study 2) and one trial compared acyclovir with valacyclovir with placebo (Reitano 1998). Characteristics of interventions The duration of suppressive treatment was two months in two trials (Fife 2006, HS ), 2.5 months in one (Wald 2006 study 2), three months in six (Blom 1986; Halsos 1985; Kinghorn 1985; Kroon 1989; Mindel 1984; Thin 1985), four months in seven (Douglas 1984; Patel 1997; Reitano 1998; Sacks 2004; Sekhin 2004; Straus 1984; Wald 2006 study 1), six months in five (Kinghorn 1992; PREV ; Romanowski 2003; Sacks 1988; Velasco 1991), and 12 months in five (Diaz-Mitoma 1998; Mattison 1988; Mertz 1988; Mertz 1997; Mostow 1988). For five studies, treatment was stopped after the first recurrence (Blom 1986; Kinghorn 1985; Patel 1997; Straus 1984; Thin 1985). The suppressive treatment duration for cross-over trials was three months, except for one of six months duration (Romanowski 2003). For cross-over trials, the wash-out period was never indicated; however, it was specified in three studies that second period treatment was started after a new recurrence occurred (Blom 1986; Kinghorn 1985; Thin 1985). In 12 trials, the daily dose received by participants randomised to receive acyclovir was 800 mg per day distributed as follows: 200mg 4 times a day in 5 trials ( Mindel 1984; Blom 1986; Halsos 1985; Kinghorn 1985; Thin 1985), 400 mg twice a day in 6 trials (Kroon 1989; Reitano 1998; Mertz 1988; Mattison 1988; Kinghorn 1992; Velasco 1991) and 800 mg once a day in 1 trial (Mostow 1988); it was 600 mg per day (200 mg 3 times a day) in 2 trials (Sacks 1988; Straus 1984). There was one multi-dose trial: 400 mg per day (200mg twice a day) versus 1000 mg per day (200mg five times a day) versus placebo (Douglas 1984). The daily dose received by participants randomly assigned to receive valacyclovir was 1000 mg per day (500 mg twice daily) in one trial (Fife 2006). In seven trials, it was 500 mg per day, distributed as follows: 500 mg once a day in six trials (HS ; Patel 1997; PREV for participants with < 10 recurrences per year; Romanowski 2003; Wald 2006 study 1; Wald 2006 study 2) and 250 mg twice a day in one trial (PREV for patients with > 10 recurrences per year). One multidose trial provided 1000 mg once a day versus 250 mg twice a day versus 500 mg once a day versus 250 mg once a day versus acyclovir versus placebo (Reitano 1998). The daily dose received by participants randomly assigned to receive famciclovir was 250 mg twice daily in two trials (Wald 2006 study 1; Wald 2006 study 2). Three mutidose trials provided 250 mg three times daily versus 250 twice a day versus 125 mg three times daily versus placebo (Diaz-Mitoma 1998); 500 mg once daily versus 250 mg twice daily versus 250 mg once daily versus 125 mg twice daily versus 125 mg once daily versus placebo (Mertz 1997); and 250 mg three times daily versus 125 mg twice daily versus placebo (Sacks 2004). In nine trials, participants received intermittent antiviral treatment for recurrence (Fife 2006; Halsos 1985; HS ; Mertz 1988; Mostow 1988; PREV ; Reitano 1998; Romanowski 2003; Sacks 1988). In two trials, participants received the intermittent treatment in one arm and suppressive treatment in the other arm (Bartlett 2008; Fife 2007). Excluded studies We classified six trials as studies awaiting classification, and we excluded 61 full-text reports. A total of 28 reports were not RCT reports, and in 11 trials, the experimental treatment consisted of intermittent treatment only. The reason for exclusion of the 22 other reports (corresponding to 19 trials) are detailed in Characteristics of excluded studies. The main reason for exclusion (10 reports corresponding to eight studies) was the absence of a minimum number of recurrences required for inclusion. For one trial (Corey 2004), we asked the study authors to provide the results for the subgroup of participants with at least four recurrences, but these data were not available and the study was excluded (Table 1). For two studies with three arms, one arm was not included: Kinghorn 1992 compared acyclovir versus placebo versus isoprinosine, and the isoprinosine arm was not included; Mattison 1988 compared acyclovir plus placebo intermittent treatment versus placebo acyclovir plus placebo intermittent treatment versus placebo acyclovir plus 9

13 intermittent treatment, and the last arm was not included. Finally, two trials identified from searches of clinical trial results databases of pharmaceutical companies were excluded because they were stopped after two and six inclusions, respectively, following a decision by the FDA (HS240018; HS240021). Risk of bias in included studies Risk of bias assessments are summarized in Figure 2 and Figure 3. Regarding the overall risk of bias, no trial had low risk of bias, 13 were at high risk of bias, and 13 were at unclear risk of bias. 10

14 Figure 2. Risk of bias summary: review authors judgements about each risk of bias item for each included trial. 11

15 Figure 3. Risk of bias graph: review authors judgements about each risk of bias item presented as percentages across all included studies. Allocation In all, 22 trials were reported as randomized, but as reports did not contain a description of the process of sequence generation, they were considered at unclear risk of bias for generation of sequence generation. For the four other trials, the process of sequence generation was reported and adequate, and these studies were considered at low risk of bias for sequence generation (Diaz-Mitoma 1998; Kinghorn 1992; Mostow 1988; Romanowski 2003). For allocation concealment, the risk of bias was considered unclear in 24 trials because of absence of reporting of the method used to guarantee concealment. The risk was considered low for two trials (Diaz-Mitoma 1998; Fife 2006). Blinding Two trials were open-label (PREV ; Romanowski 2003). Given that the outcome was subjective, we considered the risk of bias as high for these studies. A total of 24 trials were reported as double-blind. These studies were placebo-controlled or doubledummy. We thus considered these trials at low risk of bias, even if no additional information was available. Incomplete outcome data Seven trials were considered at high risk of bias because of the high numbers of withdrawn participants and/or because of an imbalance between groups in the numbers of withdrawn participants and/or an imbalance in reasons for missing outcomes (Diaz-Mitoma 1998; Mattison 1988; Mertz 1988; Mostow 1988; Patel 1997; PREV ; Romanowski 2003). Six trials were considered at unclear risk of bias because the numbers of participants and/or reasons and/or missing data methods were not reported. Selective reporting Five trials were considered at high risk of selective outcome reporting because results for outcomes detailed in the methods section were not reported in the results section. For HS duration of recurrences and duration of clinical shedding, and for Kinghorn 1985; Mattison 1988; Mostow 1988; and Thin 1985, number of recurrences, were confirmed by positive viral culture. For other studies, the risk of bias was considered unclear because we did not have access to any protocol. Other potential sources of bias In the cross-over design, no mention was made in any trial of the duration of the washout period and of the possibility of a carryover of treatment effect across periods; we considered that the carry-over effect was unlikely because of the natural course of the disease, and because the half-life of the drugs is short. However, all cross-over trials had unit of analysis errors. In one trial, results were reported for the first period only (Romanowski 2003), and the trial was considered at high risk of bias. In the other crossover trials, the analysis was incorrect: in two trials, results were 12

16 reported only from the experimental and control treatment periods combined together (Blom 1986; Halsos 1985). In other crossover trials, results were reported for the two treatment periods, but paired data were not reported, so adequate analysis was not possible (Curtin 2002). Effects of interventions At least one clinical recurrence (pairwise metaanalyses) We were not able to analyze this outcome for four included trials (HS ; Mattison 1988; Sacks 2004; Wald 2006 study 2). The outcome was not reported, and we were not able to obtain missing information from the trial authors (Table 1). For one trial (PREV ), information was provided after contact was made with the pharmaceutical company. For another trial (Sacks 2004), only virologically confirmed recurrences were reported. The findings are presented in the Summary of findings table (Table 3). Acyclovir versus placebo Fourteen trials (2549 randomly assigned participants) were analyzed (Figure 4). In the nine parallel-group trials (2049 randomly assigned participants), 1462 participants had at least one recurrence: 583 in the acyclovir arm and 879 in the placebo arm. The risk of at least one recurrence was reduced with acyclovir rather than placebo (pooled RR 0.48, 95% CI 0.39 to 0.58). Substantial heterogeneity was noted across trials (I² = 81%, 95% CI 64% to 90%). In the five cross-over trials (500 participants), reported analyses did not take into account the pairing. We analyzed them through a simple approach and found no evidence of statistical heterogeneity (I² = 0, 95% CI 0% to 79%); however, the pooled treatment effect estimate was significantly larger than in parallelgroup trials (pooled RR 0.35, 95% CI 0.29 to 0.42), so we did not combine cross-over trials with parallel-group trials. Figure 4. Forest plot of comparison: 1 Acyclovir vs placebo, outcome: 1.1 Participants with at least 1 clinical recurrence. The funnel plot showed strong asymmetry, with smaller trials showing larger treatment effect estimates than larger trials (Figure 5). 13

17 Figure 5. Funnel plot of comparison: 1 Acyclovir vs placebo, outcome: 1.1 Participants with at least 1 clinical recurrence. For the nine parallel-group trials, we performed a sensitivity analysis for small-study effects: when we used the regression-based approach of Moreno et al, the pooled treatment effect adjusted for small-study effects still showed a significant benefit with acyclovir but was smaller than with the unadjusted analysis (pooled RR 0.61, 95% CI 0.49 to 0.75). When the limited meta-analysis of Rucker et al was used, findings were similar (pooled RR, 0.63, 95% CI 0.54 to 0.73). When we analyzed the nine parallel-group trials by daily dose, we found no evidence of a clear dose-response relationship (test for subgroup differences P value 0.38); (Figure 6). The comparison between acyclovir 800 mg/d and placebo involved the largest number of participants (pooled RR 0.52, 95% CI 0.43 to 0.64). The other daily doses involved one randomly assigned comparison only (400 and 1000 mg/d) and three randomly assigned comparisons (totaling 140 participants) regarding acyclovir 600 mg/ d; in the latter case, heterogeneity was substantial and the pooled estimate may not be relevant. 14

18 Figure 6. Forest plot of comparison: 1 Acyclovir vs placebo, outcome: 1.2 Participants with at least one clinical recurrence (according to daily dose). Results from the analysis of data without imputation of missing outcomes (complete cases as analyzed in trials) were similar to results from our main analysis, although treatment effect estimates were slightly larger (Figure 7). 15

19 Figure 7. Forest plot of comparison: 1 Acyclovir vs Placebo, outcome: 1.3 Participants with at least 1 clinical recurrence (complete cases). Valacyclovir versus placebo or no treatment Four parallel-group trials (1788 randomly assigned participants) compared valacyclovir versus placebo (Figure 8). The risk of at least one recurrence was reduced with valacyclovir rather than placebo (pooled RR 0.41, 95% CI 0.24 to 0.69). Substantial heterogeneity was noted across trials (I² = 94%, 95% CI 87% to 97%). Because of the small number of trials, the funnel plot did not allow for assessment of small-study effects. When we analyzed the four parallel-group trials by daily dose, we found moderate evidence of a dose-response relationship (Figure 9). However, heterogeneity across trials was noted. The comparison between valacyclovir 500 mg/d and placebo involved the largest numbers of participants. Note that for valacyclovir 1000 mg/d, heterogeneity was particularly substantial, and the pooled estimate may not be relevant. 16

20 Figure 8. Forest plot of comparison: 3 Valacyclovir vs placebo, outcome: 3.1 Participants with at least 1 clinical recurrence. Figure 9. Forest plot of comparison: 2 Valacyclovir vs placebo, outcome: 2.2 Participants with at least 1 clinical recurrence (according to daily dose). Two trials compared valacyclovir versus no treatment (Figure 10). One parallel-group trial (237 participants) showed the superiority of valacyclovir (RR 0.46, 95% CI 0.37 to 0.56) with consistent results as compared with trials versus placebo. One cross-over trial (450 participants) reported outcome data from the first period only (RR 0.57, 95% CI 0.50 to 0.66). We did not combine the findings of the cross-over trial with those of the parallel-group trial. 17

21 Figure 10. Forest plot of comparison: 3 Valacyclovir vs No treatment, outcome: 3.1 Participants with at least 1 clinical recurrence. Finally, results from the analysis of data without imputation of missing outcomes (complete cases as analyzed in trials) were similar to results from our main analysis, although treatment effect estimates were slightly larger (Figure 11; Figure 12). Figure 11. Forest plot of comparison: 2 Valacyclovir vs placebo, outcome: 2.3 Participants with at least 1 clinical recurrence (complete cases). 18

22 Figure 12. Forest plot of comparison: 3 Valacyclovir vs No treatment, outcome: 3.2 Participants with at least 1 clinical recurrence (complete cases). Famciclovir versus placebo Two parallel-group trials (732 randomly assigned participants) compared famciclovir versus placebo (Figure 13). The risk of at least one recurrence was reduced with famciclovir rather than placebo (pooled RR 0.57, 95% CI 0.50 to 0.64). We found no evidence of statistical heterogeneity (I²= 0%). Because of the small number of trials, the funnel plot did not allow for assessment of small-study effects. Figure 13. Forest plot of comparison: 2 Famciclovir vs control, outcome: 2.1 Participants with at least 1 clinical recurrence. When we analyzed the two parallel-group trials by daily dose, we found a tendency toward a dose-response relationship, but the test for subgroup differences revealed no significance (P value = 0.21 (Figure 14). Finally, results from the analysis of data without imputing missing outcomes (complete cases as analyzed in trials) were similar to results from our main analysis although treatment effect estimates were slightly larger (Figure 15). 19

23 Figure 14. Forest plot of comparison: 4 Famciclovir vs placebo, outcome: 4.2 Participants with at least 1 clinical recurrence (according to daily dose). Figure 15. Forest plot of comparison: 4 Famciclovir vs placebo, outcome: 4.3 Participants with at least 1 clinical recurrence (complete cases). 20

24 Valacyclovir versus acyclovir One parallel-group trial (1345 randomly assigned participants) compared valacyclovir versus acyclovir (Figure 16). The risk of at least one recurrence was increased with valacyclovir rather than acyclovir (RR 1.16, 95% CI 1.01 to 1.34). Because only one trial was found, the funnel plot did not allow for assessment of smallstudy effects. Figure 16. Forest plot of comparison: 4 Valacyclovir vs. Acyclovir, outcome: 4.1 participants with at least one clinical recurrence. Finally, because the analysis in this trial was performed according to intention-to-treat principles, results from analysis of data without imputation of missing outcomes (complete cases as analyzed in trials) were similar to results from our main analysis (Figure 17). Figure 17. Forest plot of comparison: 5 Valacyclovir vs acyclovir, outcome: 5.2 Participants with at least 1 clinical recurrence (complete cases). 21

25 Famciclovir versus valacyclovir One parallel-group trial (320 randomly assigned participants) compared famciclovir with valacyclovir (Figure 18). The risk of at least one recurrence was not significantly different with famciclovir rather than valacyclovir (RR 1.18, 95% CI 0.86 to 1.63). Because only one trial was identified, the funnel plot did not allow for assessment of small-study effects. Figure 18. Forest plot of comparison: 5 Famciclovir vs valacyclovir, outcome: 5.1 Participants with at least 1 clinical recurrence. Finally, results from the analysis of data without imputation of missing outcomes (complete cases as analyzed in trials) were similar to results from our main analysis, although treatment effect estimates were slightly larger (Figure 19). Figure 19. Forest plot of comparison: 6 Famciclovir vs valacyclovir, outcome: 6.2 Participants with at least 1 clinical recurrence (complete cases). At least one recurrence (network meta-analyses) We included 16 parallel-arm trials in a network meta-analysis: eight trials compared acyclovir versus placebo (Douglas 1984; Kinghorn 1992; Mertz 1988; Mindel 1984; Mostow 1988; Sacks 1988; Straus 1986; Velasco 1991), four trials compared valacyclovir versus placebo/no treatment (which were lumped together) (Fife 2006; Patel 1997; PREV ; Sekhin 2004), two trials compared famciclovir versus placebo (Diaz-Mitoma 1998, Mertz 1997), one trial compared famciclovir versus valacyclovir (Wald 22

26 2006 study 1), and one trial compared acyclovir versus valacyclovir versus placebo (Reitano 1998) (Figure 20). Of the three possible pairwise comparisons between the three treatments, two were addressed directly, each by one trial. Figure 20. Network of randomly assigned comparisons from parallel-arm trials for the network metaanalysis of efficacy (at least 1 recurrence). Convergence of the network meta-analysis model was reached. The three drugs were significantly superior to placebo in reducing the risk of at least one recurrence (pooled RR 0.46, 95% CI 0.34 to 0.57 for acyclovir, pooled RR 0.42, 95% CI 0.31 to 0.56 for valacyclovir; and pooled RR 0.57, 95% CI 0.37 to 0.84 for famciclovir). However, results were not statistically significantly different when drugs were compared against each other (pooled RR 0.94, 95% CI 0.65 to 1.38 for valacyclovir vs acyclovir; pooled RR 1.27, 95% CI 0.78 to 2.06 for famciclovir vs acyclovir; and pooled RR 1.37, 95% CI 0.86 to 2.11 for famciclovir vs valacyclovir). The probability of being the best antiviral drug was 29% for acyclovir, 65% for valacyclovir, and 6% for famciclovir (Figure 21), but we found substantial uncertainty in rank-order efficacy. In fact the ranks and associated 95% CrIs were second (first to third) for acyclovir, first (first to third) for valacyclovir, and third (first to third) for famciclovir. Of note, we found no evidence of loop inconsistency, although direct evidence suggested that valacyclovir was inferior to acyclovir, whereas indirect evidence indicated the contrary (inconsistency factors on the the log odds ratio scale: φ 23