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. 2014 Aug 3;2014(8):CD009036.
doi: 10.1002/14651858.CD009036.pub2.

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

Laurence Le Cleach  1 , Ludovic Trinquart, Giao Do, Annabel Maruani, Benedicte Lebrun-Vignes, Philippe Ravaud, Olivier Chosidow
Affiliations

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

Laurence Le Cleach et al. Cochrane Database Syst Rev. .

Abstract

Background: 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 2014. 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.

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 to 100%) 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 small-study 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.

PubMed Disclaimer

Conflict of interest statement

L Le Cleach, L. Trinquart, Giao Do, B Lebrun‐Vignes and Philippe Ravaud have no conflicts of interest to declare

O Chosidow was a consultant for GSK.

Figures

1
1
Flow of information through the different phases of t he review
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included trial.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
4
4
Forest plot of comparison: 1 Acyclovir vs placebo, outcome: 1.1 Participants with at least 1 clinical recurrence.
5
5
Funnel plot of comparison: 1 Acyclovir vs placebo, outcome: 1.1 Participants with at least 1 clinical recurrence.
6
6
Forest plot of comparison: 1 Acyclovir vs placebo, outcome: 1.2 Participants with at least one clinical recurrence (according to daily dose).
7
7
Forest plot of comparison: 1 Acyclovir vs Placebo, outcome: 1.3 Participants with at least 1 clinical recurrence (complete cases).
8
8
Forest plot of comparison: 3 Valacyclovir vs placebo, outcome: 3.1 Participants with at least 1 clinical recurrence.
9
9
Forest plot of comparison: 2 Valacyclovir vs placebo, outcome: 2.2 Participants with at least 1 clinical recurrence (according to daily dose).
10
10
Forest plot of comparison: 3 Valacyclovir vs No treatment, outcome: 3.1 Participants with at least 1 clinical recurrence.
11
11
Forest plot of comparison: 2 Valacyclovir vs placebo, outcome: 2.3 Participants with at least 1 clinical recurrence (complete cases).
12
12
Forest plot of comparison: 3 Valacyclovir vs No treatment, outcome: 3.2 Participants with at least 1 clinical recurrence (complete cases).
13
13
Forest plot of comparison: 2 Famciclovir vs control, outcome: 2.1 Participants with at least 1 clinical recurrence.
14
14
Forest plot of comparison: 4 Famciclovir vs placebo, outcome: 4.2 Participants with at least 1 clinical recurrence (according to daily dose).
15
15
Forest plot of comparison: 4 Famciclovir vs placebo, outcome: 4.3 Participants with at least 1 clinical recurrence (complete cases).
16
16
Forest plot of comparison: 4 Valacyclovir vs. Acyclovir, outcome: 4.1 participants with at least one clinical recurrence.
17
17
Forest plot of comparison: 5 Valacyclovir vs acyclovir, outcome: 5.2 Participants with at least 1 clinical recurrence (complete cases).
18
18
Forest plot of comparison: 5 Famciclovir vs valacyclovir, outcome: 5.1 Participants with at least 1 clinical recurrence.
19
19
Forest plot of comparison: 6 Famciclovir vs valacyclovir, outcome: 6.2 Participants with at least 1 clinical recurrence (complete cases).
20
20
Network of randomly assigned comparisons from parallel‐arm trials for the network meta‐analysis of efficacy (at least 1 recurrence).
21
21
Ranking for efficacy (at least 1 recurrence): probability to be the best treatment, the second, the third, or the fourth among acyclovir, valacyclovir, famciclovir, placebo/no treatment. Estimates from the unadjusted analysis are in red; estimates from the adjusted analysis on small‐study effects are in black.
22
22
Forest plot of comparison: 1 Acyclovir vs placebo, outcome: 1.4 Particpants with at least 1 virologically confirmed recurrence.
23
23
Forest plot of comparison: 4 Famciclovir vs placebo, outcome: 4.4 Participants with at least 1 virologically confirmed recurrence.
24
24
Forest plot of comparison: 6 Famciclovir vs valacyclovir, outcome: 6.3 Participants with at least one virologically confirmed recurrence.
1.1
1.1. Analysis
Comparison 1 Acyclovir vs placebo, Outcome 1 Particpants with at least 1 clinical recurrence.
1.2
1.2. Analysis
Comparison 1 Acyclovir vs placebo, Outcome 2 Participants with at least 1 clinical recurrence (according to daily dose).
1.3
1.3. Analysis
Comparison 1 Acyclovir vs placebo, Outcome 3 Participants with at least 1 clinical recurrence (complete cases).
1.4
1.4. Analysis
Comparison 1 Acyclovir vs placebo, Outcome 4 Particpants with at least 1 virologically confirmed recurrence.
2.1
2.1. Analysis
Comparison 2 Valacyclovir vs placebo, Outcome 1 Participants with at least 1 clinical recurrence.
2.2
2.2. Analysis
Comparison 2 Valacyclovir vs placebo, Outcome 2 Participants with at least 1 clinical recurrence (according to daily dose).
2.3
2.3. Analysis
Comparison 2 Valacyclovir vs placebo, Outcome 3 Participants with at least 1 clinical recurrence (complete cases).
3.1
3.1. Analysis
Comparison 3 Valacyclovir vs No treatment, Outcome 1 Participants with at least 1 clinical recurrence.
3.2
3.2. Analysis
Comparison 3 Valacyclovir vs No treatment, Outcome 2 Participants with at least 1 clinical recurrence (complete cases).
4.1
4.1. Analysis
Comparison 4 Famciclovir vs placebo, Outcome 1 Participants with at least 1 clinical recurrence.
4.2
4.2. Analysis
Comparison 4 Famciclovir vs placebo, Outcome 2 Particpants with at least 1 clinical recurrence (according to daily dose).
4.3
4.3. Analysis
Comparison 4 Famciclovir vs placebo, Outcome 3 Participants with at least 1 clinical recurrence (complete cases).
4.4
4.4. Analysis
Comparison 4 Famciclovir vs placebo, Outcome 4 Participants with at least 1 virologically confirmed recurrence.
5.1
5.1. Analysis
Comparison 5 Valacyclovir vs acyclovir, Outcome 1 Participants with at least 1 clinical recurrence.
5.2
5.2. Analysis
Comparison 5 Valacyclovir vs acyclovir, Outcome 2 Participants with at least 1 clinical recurrence (complete cases).
6.1
6.1. Analysis
Comparison 6 Famciclovir vs valacyclovir, Outcome 1 Participants with at least 1 clinical recurrence.
6.2
6.2. Analysis
Comparison 6 Famciclovir vs valacyclovir, Outcome 2 Participants with at least 1 clinical recurrence (complete cases).
6.3
6.3. Analysis
Comparison 6 Famciclovir vs valacyclovir, Outcome 3 Participants with at least 1 virologically confirmed recurrence.
See this image and copyright information in PMC

Comment in

References

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Bartlett 2008 {published and unpublished data}
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Douglas 1988 {published data only (unpublished sought but not used)}
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Tyring 2003 {published data only}
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Wu 2000 {published data only}
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Zhang 2011 {published data only}
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References to ongoing studies

NCT01658826 {unpublished data only}
    1. Safety and efficacy comparator trial of a new drug against genital herpes. Ongoing study October 2012.

Additional references

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