Oral antiviral therapy for prevention of genital herpes outbreaks in immunocompetent and nonpregnant patients: Cochrane systematic review
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.
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.
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.
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.
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 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.
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.
Le Cleach Laurence, Trinquart Ludovic, Do Giao, Maruani Annabel, Lebrun-Vignes Benedicte, Ravaud Philippe, Chosidow Olivier
(Oral antiviral treatment to prevent genital herpes outbreaks in immunocompetent and nonpregnant patients)
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.
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.
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 2014.
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.
Implications for practice
Owing to risk of bias and inconsistency, there is a low quality evidence that suppressive antiviral therapy with acyclovir, valacyclovir or famciclovir for participants experiencing at least 4 recurrences per year of genital herpes decreases the number of participants with at least one recurrence as compared with placebo. Network meta-analysis could not reveal a superiority of one drug over another. The dose used in the included and analyzed studies was from 400 to 800 mg per day for acyclovir, 250 to 1000 mg per day for valacyclovir and 125 to 750 mg per day for famciclovir. There was no clear evidence of a dose-effect relationship for any drug. The duration of suppressive treatment was from 2 to 12 months.
Implications for research
Inclusion criteria in future trials should be decided according to current practice based on the impact of genital herpes recurrences on quality of life rather than on the minimum number of recurrences. Comparative trials between acyclovir or valacyclovir or famciclovir versus placebo are no longer suitable because the efficacy of these treatments has been demonstrated. A large pragmatic trial of a direct comparison between these drugs or between new antiviral drugs and these drugs is needed. The main outcome should be a patient-reported outcome including burden of treatment and impact on quality of life, notably sexual life. Secondary outcomes should include safety, time to first recurrence, number of recurrences, and severity (number of days, severity of pain) of recurrences. The duration of treatment could also be an outcome according to patient wishes.