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Episodic therapy for recurrent genital herpes in non‐immunocompromized adults

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effectiveness and safety of episodic therapy for the treatment of recurrent genital herpes in non‐immunocompromized adults.

Background

This is the protocol for a review and there is no abstract.

The objective is to assess the effectiveness and safety of episodic therapy for the treatment of recurrent genital herpes in non‐immunocompromized adults.

Description of the condition

Genital herpes simplex virus (HSV) is a recurrent disease that can occur throughout life and has no known cure (Beauman 2005). The virus consists of a viral DNA core, capsid, tegument, and an envelope (Whitley 1998). The two types of HSV (HSV‐1 and HSV‐2) have antigenic differences in their envelope proteins (Beauman 2005). HSV‐1 is normally associated with orolabial infections while HSV‐2 with genital disease, but cutaneous infections at other body sites may occur (Beauman 2005). Genital herpes is a prevalent condition in United States adults, with a trend towards an increase in diagnosed cases in the last decades (Xu 2002). The number of lifetime sexual partners, for both men and women, and a history of a different sexually transmitted disease are important associations with genital HSV‐2 infection (Wald 1997).

Herpes is a very common infectious disease and its genital form is globally recognized as a major sexually transmitted disease. Genital herpes affects millions of people worldwide and its estimated prevalence is increasing, similar to the AIDS epidemic. The seroprevalence of HSV‐2 in the world is as low as 10% in Asian countries to as high as 80%, in some sub‐Saharan African countries (WHO 2007). The infection affects adolescents and adults after initiation of sexual intercourse, with a global peak incidence of HSV‐2 during middle and late adolescence (15 to 19 years of age) of 6.9 million per year in 2003 (Looker 2008).

In the United States, the average age of sexual debut is 16.5 years (Shafii 2009). The majority of cases of genital herpes are caused by HSV‐2, however, HSV‐1 is becoming increasingly prevalent in young adults and women (Ross 1993; Samra 2003; Tran 2004). Genital herpes negatively affects the quality of life and work productivity of patients (Patel 2001), and in the United States is a major public health problem with high direct medical costs caused by diagnostic testing, drug treatments, and outpatient and hospital care (Chesson 2000).

Almost all patients experiencing an outbreak of HSV‐2 subsequently suffer at least one recurrence, about 38% experience more than six recurrences per year (Azwa 2009). The median number of recurrences are four episodes per year (Benedetti 1994). Although recurrences of genital herpes tend to be less severe and shorter compared to the primary outbreak, they can be very painful and emotionally distressing (Swanson 1999). Besides clinical symptoms, persons who suffer from genital herpes worry about the social implications of a recurrent disease, the possibility of transmission to their partner, and fear of disclosing the truth about their health status to a new sexual partner (Brentjens 2003).

Pregnant women and any immunocompromized population are also adversely affected by the infection and have different clinical outcomes. About 22% of pregnant women are seropositive to one of the herpes simplex viruses and 2% are diagnosed with a new infection during pregnancy (Brown 2005). Vertical transmission occurs mainly after a primary episode of genital HSV in the third trimester, through virus contact with active HSV lesions at time of delivery, with a high morbidity and mortality in neonates, if not treated (Brown 2005).

Immunocompromized patients have more severe and atypical progression of the disease (Fatahzadeh 2007). HSV‐2 increases the risk of HIV infection (Wald 2002), enhances both HIV susceptibility and infectiousness, promoting a susceptible environment in genital mucosa with an increase in HIV target cell population (Rebbapragada 2007). Enhanced transmission occurs due to more frequent clinical and subclinical shedding in HIV infected women, and subclinical shedding in HIV positive men (Røttingen 2001).

Acute infection starts as HSV enters the body through the skin or mucosa by direct sexual contact with secretions or mucosal surfaces of an infected person (Whitley 1998). Replication of HSV occurs at epidermic tissue, causing cellular damage. Subsequent inflammation of the dermis, passage to peripheral nerves, and retrograde transport to the nervous system (where the virus remains in a latent state) finishes the first stage of natural history (Gupta 2007). Clinical manifestations present four to seven days after sexual contact and vary in presentation. Classical signs and symptoms can be both local and systemic, although subclinical presentation is common (Kimberlin 2004). Patients complain of redness and bumps that advance to fluid‐filled blisters and ulcers over the next one to two weeks. These lesions crust and then heal with no visible scarring. Pain in adjacent areas to the lesion and tenderness in regional swollen glands are the main local symptoms. Fever, headache, muscle pain, and urinary symptoms are regular complaints (Corey 1993). Patients with primary infection (no pre‐existing antibodies to the other serotype of HSV, usually HSV‐1) have harsher symptoms (Beauman 2005; Schiffer 2009).

During the latent stage, patients are asymptomatic but HSV transmission is possible through viral shedding (Schiffer 2009). Although risk is greater when ulcers are present, subclinical viral shedding is considered the most common means of transmission. Reactivations occur when the latent virus in peripheral nerve cells migrate to the skin and mucous membranes, causing clinical recurrences (Whitley 1998). In this stage, symptoms tend to be of milder severity and shorter duration than in acute infections. Fewer days of viral shedding with lower concentration of the virus are typical (Corey 1993). Prodromal symptoms may precede the advent of lesions. Altered sensation or pain around buttocks, thighs, hips, or the perineum, are characteristic 30 minutes to 48 hours before new lesions appear (Kimberlin 2004). Persisting stressors or high levels of anxiety may be required to increased risk of recurrences (Cohen 1999). Compared with HSV‐1, HSV‐2 infected patients present six times more frequently with outbreaks and more severe symptoms (Beauman 2005).

There are three available methods for the diagnosis of genital herpes. Viral culture can be used and is useful when distinguishing between serotypes (Patel 2011). However, it has less sensitivity in recurrences (lower viral load) and in the healing stages of the outbreak (Workowski 2010); in addition culture is slow (7 to 10 days for a negative result) (Patel 2011). Polymerase chain reaction testing is a faster option than viral culture and has greater sensitivity, particularly during ulceration and crusting of the acute episode (Kimberlin 2004; Patel 2011). Type specific serologic testing (TSST) targets IgG of glycoprotein G of HSV‐1 or HSV‐2. TSST have acceptable accuracy (Wald 1997), but false‐negatives could be common in the first stages of the disease (Workowski 2010). TSST might be useful in recurrent genital symptoms or atypical symptoms with negative HSV cultures (Workowski 2010).

Description of the intervention

Therapy for recurrent genital herpes includes nucleoside analogues: aciclovir, valaciclovir, and famciclovir. These drugs compete with nucleosides in infected cells. Their main antiviral action mechanisms are the incorporation of the phosphorylated molecule to the viral DNA chain and the inhibition of viral polymerase, blocking viral genome replication without affecting non‐infected human cells (Nath 2009). Valaciclovir and famciclovir are prodrugs and, as such, their antiviral activity depends on metabolism before targeting virus infected cells. Once targeted, activation is completed (De Clercq 2006; Simpson 2006).

Aciclovir is highly active against HSV‐1 and less against HSV‐2. Aciclovir is activated intracellularly by the viral enzyme thymidine kinase (Nath 2009). The extent to which Aciclovir is available to the body after oral administration (oral bioavailability) is poor (10% to 20%) and the length of time half of the molecule is metabolized and excreted (half‐life) is short (Nath 2009; Martín 2009). To achieve effective concentrations in plasma, oral administration should be more frequent in comparison to other nucleoside analogues (Wagstaff 2004). Half‐life and total systemic drug clearance is dependent on renal function. In patients with normal renal function, plasma half‐life is approximately three hours (Wagstaff 2004).

Aciclovir is the only nucleoside analogue approved for parenteral administration, specifically for episodic treatment and suppression of HSV disease in immunocompromized patients and in the management of severe genital herpes in immunocompetent patients (Workowski 2010). The Sexually Transmitted Diseases Treatment Guidelines (2010) discourage the use of topical treatment of genital herpes with aciclovir because it offers minimal clinical benefit (Workowski 2010).

Valaciclovir is an oral prodrug. Following absorption, it is rapidly converted to aciclovir by intestinal and hepatic metabolism (Wagstaff 2004). It has up to five times more oral bioavailability than aciclovir and thus, requires less frequency of administration (MacDougall 2004; Wagstaff 2004). The absolute bioavailability is about 54.2% (Soul‐Lawton 1995), and the maximum plasma concentrations are reached within the first two hours after administration (MacDougall 2004). Plasma half‐life after oral administration is close to three hours (Beutner 1995).

Famciclovir is a prodrug of analogue penciclovir (De Clercq 2001) with a higher bioavailability (77%) because of its affinity to lipids (Gudmundsson 2007). Oral famciclovir is characterized by high stability in the lumen of the small intestine, which favours constant absorption (Simpson 2006). Penciclovir, the active compound, has a greater affinity for thymidine kinase compared to aciclovir, which helps to achieve higher intracellular concentrations (Simpson 2006). Peak plasma concentrations are reached within 15 to 30 minutes after oral administration (Wagstaff 2004). In vitro intracellular half‐life of penciclovir triphosphate is 10 hours for HSV‐1 and 20 hours for HSV‐2 (Crumpacker 1996).

Excretion of the nucleoside analogues is primarily renal. Caution is recommended when used in patients with underlying renal dysfunction (Wagstaff 2004). Nausea, vomiting, headache, and diarrhea are known nucleoside analogues' side effects (Beauman 2005; Wagstaff 2004). Serious adverse events are rare (Simpson 2006). Nucleoside analogues’ resistance is caused mostly by mutations in the enzymes genes involved in drug activation, and less frequently with the DNA polymerase gene. Resistance is more common in immunocompromized patients (3.5% to 10% ) (Piret 2011).

Other available complementary therapies, such as dietary modifications and natural remedies, have limited clinical evidence (Gaby 2006). Phase 2, randomized trials with local immune therapies (imiquimod and resiquimod) present controversial results (Mark 2007; Schacker 2002). Research on vaccination to prevent or treat genital herpes recurrences is underway, however an effective vaccine has yet to be achieved (Awasthi 2014).

How the intervention might work

Recurrent genital herpes (four or more episodes per year) can be approached with two different treatment strategies: episodic or suppressive therapies (Workowski 2010). In the former, an antiviral drug is prescribed for a cycle of two to five days, which corresponds with the usual duration of symptoms. In the latter, the prescription of a daily dose of the antiviral drug can last for several months.

Episodic therapy is a short cycle antiviral regimen strategy aimed to reduce symptoms and viral replication during recurrences. It is indicated in those patients who develop mild and infrequent outbreaks (Workowski 2010). This treatment strategy works best if initiated during the prodromal phase, before the onset of lesions. Patients are taught by their physicians to recognize the prodromal phase and start therapy with antivirals as soon as they identify the symptoms (Nath 2009). As mentioned previously, primary treatment are nucleoside analogues.

Why it is important to do this review

Evidence of the effectiveness of antiviral agents on clinical outcomes of recurrent genital herpes is not conclusive. A non‐Cochrane meta‐analysis that compared suppressive therapy with placebo for recurrent genital herpes, found a significant reduction in the number of patients developing at least one outbreak for the duration of the trial (risk ratio (RR) 0.53, 95% confidence interval (CI) 0.16 to 0.73) (Lebrun‐Vinges 2013). However, in a recent Cochrane systematic review (Le Cleach 2014), there was low quality evidence supporting that suppressive therapy with nucleoside analogues decreases the proportion of patients with recurrent genital herpes that experienced at least one new outbreak, compared to placebo. In a similar context, another non‐Cochrane systematic review that included patients with herpes labialis treated with prophylactic antiviral agents (topical and systemic) had a 30% relative risk reduction of recurrent lesions with the antiviral treatment (RR 0.70, 95% CI 0.55 to 0.89) compared with placebo (Rahimi 2012).

Clinical treatment guidelines of sexually transmitted diseases (Steben 2008; Patel 2011; Workowski 2010), recommend various treatment strategies for patients with recurrent genital herpes, however, there is no supporting evidence from a systematic review that shows effectiveness. Furthermore, episodic therapy implies short‐course treatment, with patient control over their own treatment strategy (they can start medication as soon as symptoms begin ‐ contrary to suppressive therapy, which is a long‐term treatment strategy). This could lead to less adverse effects, and possibly lower costs of episodic therapy compared to suppressive therapy. To the best of our knowledge there is no systematic review that addresses episodic therapy in recurrent genital herpes.

Objectives

To assess the effectiveness and safety of episodic therapy for the treatment of recurrent genital herpes in non‐immunocompromized adults.

Methods

Criteria for considering studies for this review

Types of studies

We will include all published and unpublished randomized clinical trials (RCTs), where the participants used episodic therapy compared with placebo, no intervention, any other episodic therapy, suppressive therapy, or any other therapy for the treatment of recurrent genital herpes in non‐immunocompromized adults.

We will include cross‐over trials because of the nature of the condition (stable and chronic) (Higgins 2011).

We will not include quasi‐RCTs or controlled clinical trials because effect estimates may indicate more extreme benefits when compared to randomized clinical trials (Higgins 2011).

Types of participants

  • Adults (16 years or more).

  • Recurring genital herpes (four or more episodes per year).

  • Patients with clinical diagnosis of genital herpes (type I or II).

We will not include immunocompromized individuals and pregnant women.

Types of interventions

  • Antiviral episodic therapy (any route, dose, frequency, and duration of treatment) versus placebo.

  • Antiviral episodic therapy (any route, dose, frequency, and duration of treatment) versus no intervention.

  • Antiviral episodic therapy (any route, dose, frequency, and duration of treatment) versus antiviral suppressive therapy (any route, dose, frequency, and duration of treatment).

  • Antiviral episodic therapy (any route, dose, frequency, and duration of treatment) versus any other intervention (any route, dose, frequency, and duration of treatment).

  • Antiviral episodic therapy (any route, dose, frequency, and duration of treatment) versus any other episodic therapy (any route, dose, frequency, and duration of treatment).

Types of outcome measures

Primary outcomes

  • Time to healing (days from initiation of therapy to complete loss of all crusts and re‐epithelialization of lesions).

  • Time to resolution of pain (number of days from treatment initiation to complete resolution of pain, as reported by the patient).

  • Recurrences during follow‐up (proportion of participants that experience recurrence during the observation period; 0 to 6 and 6 to 12 months).

  • Adverse events (proportion of participants with untoward medical occurrences, as defined by the International Conference on Harmonisation (ICH) Harmonised Tripartite Guideline) (ICH 1996).

Secondary outcomes

  • Time to clinical resolution (number of days from treatment initiation to complete resolution of all signs and symptoms).

  • Time to clinical recurrence (number of days from initiation of therapy until the first onset of lesions).

  • Viral shedding rate (the number of days in which HSV was isolated from more than one site by viral culture or HSV DNA polymerase chain reaction, divided by the total number of days on which samples were obtained, expressed as a percentage).

  • Aborted lesions (proportion of patients with lesions that did not progress beyond papule stage).

  • Aborted outbreak (proportion of patients in whom prodromal symptoms were present, but lesions never developed).

  • Partner’s seroconversion (proportion of sexual partners that change their serological status during follow‐up).

  • Patient’s satisfaction with treatment.

  • Cost‐effectiveness.

Search methods for identification of studies

Electronic searches

We will contact the Trials Search Co‐ordinator (TSC) of the Cochrane Sexually Transmitted Infections Group in order to implement a comprehensive search strategy to identify as many relevant RCTs as possible in electronic databases. We will use a combination of controlled vocabulary (MeSH, Emtree, DeCS, including exploded terms) and free‐text terms (considering spelling variants, synonyms, acronyms and truncation) for "genital herpes" and "episodic therapy", with field labels, proximity operators and boolean operators. We have listed our search strategies in Appendix 1, Appendix 2, Appendix 3, Appendix 4, Appendix 5, Appendix 6, and Appendix 7.

We will search the following electronic databases.

  • Cochrane Sexually Transmitted Infections Group Specialized Register: inception to present.

  • Cochrane Central Register of Controlled Trials (CENTRAL), Ovid platform: inception to present.

  • MEDLINE, Ovid platform: inception to present.

  • MEDLINE In‐Process & Other Non‐Indexed Citations, Ovid platform: inception to present.

  • MEDLINE Daily Update, Ovid platform: inception to present.

  • EMBASE: inception to present.

  • LILACS, IAHx interface: inception to present.

For MEDLINE, we will use the Cochrane highly sensitive search strategy for identifying RCTs: sensitivity and precision‐maximizing version (2008 revision), Ovid format (Higgins 2011). We will combine the LILACS search strategy with a RCT filter of IAHx interface.

Furthermore, we will search for evidence in electronic open‐access repositories such as Zenodo (https://zenodo.org/) and Figshare (http://figshare.com/) with the following search terms: "genital herpes" and "episodic therapy".

Searching other resources

We will search trial registers, handsearch conference proceedings and reviews, and contact trial authors and pharmaceutical companies for additional trials, as detailed below.

  1. Trial registers

  2. Web of Science®: inception to present.

  3. We will contact the trial authors of all RCTs identified by other methods.

  4. We will handsearch conference proceeding abstracts of the following events.

  5. We will handsearch within previous systematic reviews, within other relevant publications on the same topic and the reference lists of all RCTs identified by other methods.

  6. We will contact pharmaceutical companies that produce antiviral agents for genital herpes for additional studies.

  7. We will search drug registration reviews on the Food and Drugs Administration (FDA) database (http://www.accessdata.fda.gov/scripts/cder/drugsatfda/).

Data collection and analysis

Selection of studies

Two review authors (MC, MM) will independently assess for inclusion all the potential studies we identify as a result of the search strategy. We will resolve any disagreement through discussion or, if required, through consultation with a third review author (CFGA).

Data extraction and management

We will design a form to extract data. For eligible studies, two review authors (CFGA, LC) will extract the data using the agreed form. We will resolve discrepancies through discussion or, if required, we will consult a third review author (MC). We will enter data into Review Manager software (RevMan 2014) and check for accuracy. When information regarding any of the above is unclear, we will attempt to contact authors of the original reports to provide further details.

Assessment of risk of bias in included studies

Two review authors (MC, MI) will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreement by discussion or involving a third review author (CFGA). For each included study, the review authors will make a decision by assigning a judgement of 'low risk' of bias, 'high risk' of bias, or 'unclear risk' of bias for the following domains.

(1) Random sequence generation (checking for possible selection bias)

We will describe for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

We will assess the method as:

  • low risk of bias (any truly random process, e.g. random number table; computer random number generator);

  • high risk of bias (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number); or

  • unclear risk of bias.

(2) Allocation concealment (checking for possible selection bias)

We will describe for each included study the method used to conceal allocation to interventions prior to assignment and we will assess whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We will assess the methods as:

  • low risk of bias (e.g. telephone or central randomization; consecutively numbered sealed opaque envelopes);

  • high risk of bias (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth); or

  • unclear risk of bias.

(3.1) Blinding of participants and personnel (checking for possible performance bias)

We will describe for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We will consider that studies are at low risk of bias if they were blinded, or if we judge that the lack of blinding would be unlikely to affect results. We will assess blinding separately for different outcomes or classes of outcomes.

We will assess the methods as:

  • low, high or unclear risk of bias for participants; and

  • low, high or unclear risk of bias for personnel.

(3.2) Blinding of outcome assessment (checking for possible detection bias)

We will describe for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We will assess blinding separately for different outcomes or classes of outcomes.

We will assess methods used to blind outcome assessment as:

  • low, high or unclear risk of bias.

(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

We will describe for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We will state whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomized participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information is reported, or can be supplied by the trial authors, we will re‐include missing data in the analyzes which we undertake.

We will assess methods as:

  • low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);

  • high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomization); or

  • unclear risk of bias.

We will use a cut‐off point of 20% to consider that a study is at low or high risk of bias according to the level of missing data.

(5) Selective reporting (checking for reporting bias)

We will describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We will assess the methods as:

  • low risk of bias (where it is clear that all of the study’s prespecified outcomes and all expected outcomes of interest to the review have been reported);

  • high risk of bias (where not all the study’s prespecified outcomes have been reported; one or more reported primary outcomes were not prespecified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported); or

  • unclear risk of bias.

(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)

We will describe for each included study any important concerns we have about other possible sources of bias (e.g. related to the specific study design, stopped early due to some data‐dependent process, extreme baseline imbalance, the study been claimed to be fraudulent). We will assess whether each study was free of other problems that could put it at risk of bias.

We will assess the methods as:

  • low risk of other bias;

  • high risk of other bias; or

  • unclear whether there is risk of other bias.

(7) Overall risk of bias

We will make explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). With reference to (1) to (6) above, we will assess the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings. We will explore the impact of the level of bias through undertaking sensitivity analyzes ‐ seeSensitivity analysis.

Risk of bias in cross‐over trials

For cross‐over trials, in addition we will to take into account the following items according to Section 16.4.3 of the Cochrane Handbook for Systemic Reviews of Interventions (Higgins 2011).

  • Was use of a cross‐over design appropriate?

  • Is it clear that the order of receiving treatments was randomized?

  • Can it be assumed that the trial was not biased from carry‐over effects?

  • Are unbiased data available?

We will assess as low risk of bias for carry‐over effect, if the included studies report a wash out period of at least seven days between the interventions (based on the antiviral half‐time). In presence of carry‐over, we will analyze only the first period.

Measures of treatment effect

Time‐to‐event data

For time‐to‐event outcomes, we will present treatment effects as overall hazard ratios (HRs) with 95% confidence intervals (CIs). Ideally, overall HRs will be calculated as the individual log hazard ratio (ln(HR)) with proportional inverse weights to the variance of each trials' ln(HR) (Parmar 1998). If we cannot extract these statistics, we will calculate ln(HR) and its variance through the coefficient of treatment comparison of a Cox proportional hazards model, reported CI or P value from a Mantel‐Haenzel (log rank) test, the coefficient of treatment comparison of a Cox proportional hazards model, or published Kaplan‐Meier curves (Parmar 1998; Tierney 2007).

Dichotomous data

For dichotomous outcomes, we will present results as summary risk ratios (RRs) with 95% CI. The RR as a relative effect measure has consistency, works well with a low or high rate of events, and is easy to interpret and use in clinical practice.

Continuous data

For continuous outcomes, we will use the mean difference (MD) if outcomes are measured in the same way between trials. We will use the standardized mean difference (SMD) to combine trials that measure the same outcome with different methods.

Unit of analysis issues

Parallel trials

If we identify a clinical trial that randomized participants to several intervention groups, we will determine which of them are relevant. To avoid confusion for the reader, we will include all intervention groups of the study in the “Characteristics of Included Studies” table, in the notes cell, providing a detailed description only of the intervention groups relevant to the review, and only these groups will be used in the analyzes.

In order to overcome a unit of analysis error for studies that could contribute multiple, correlated comparisons, we will use two approaches: we will combine all relevant experimental intervention groups of the studies into a single group, and also combine all relevant control intervention groups into a single control group, in order to create a single pair‐wise comparison (Higgins 2011) when the objective is the comparison of the experimental branch with any other control group (e.g. episodic therapy versus placebo). However, when the target is to detect differences between treatment groups (e.g. between different episodic therapies) we will split the sample of the control group in order to attain the respective comparison (Higgins 2011).

Cross‐over trials

We will pool cross‐over with parallel‐group trials if there is no evidence of carry‐over effect. In case of this type of bias, we would include cross‐over trials with data from the first period, as a parallel‐group RCT. We will perform pooling if the following data are available, as recommended in the Cochrane Handbook for Systemic Reviews of Interventions (Higgins 2011): individual patient data provided by the original authors; mean and standard deviation (or standard error of the mean) of within‐person differences between experimental and control groups; the MD and a paired t‐test statistic, a P value or a CI from a paired t‐test; graphs from which individual data values of experimental and control groups can be extracted.

We will perform analyses for quantitative variables with SMD and extract the correlation coefficients from data in those studies or imputed from similar studies. We will analyze qualitative variables with Mantel‐Haenzel odds ratio (OR) for paired data with 95% CIs.

Dealing with missing data

For all outcomes, we will carry out analyzes, as far as possible, on an intention‐to‐treat basis, i.e. we will attempt to include all participants randomized to each group in the analyzes, and all participants will be analyzed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial will be the number randomized minus any participants whose outcomes are known to be missing. We will contact the study investigators in order to obtain the missing data.

Assessment of heterogeneity

We will assess statistical heterogeneity in each meta‐analysis using the T², I² and Chi² statistics. We will regard heterogeneity as substantial if I² is greater than 40% and either T² is greater than zero, or there is a low P value (less than 0.10) in the Chi² test for heterogeneity.

Assessment of reporting biases

If there are 10 or more studies in the meta‐analysis we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually, and use formal tests for funnel plot asymmetry. For continuous outcomes we will use the test proposed by Egger 1997, and for dichotomous outcomes we will use the test proposed by Harbord 2006. If we detect asymmetry in any of these tests or it is suggested by a visual assessment, we will perform exploratory analyzes to investigate it.

Data synthesis

We will carry out statistical analysis using the Review Manager software (RevMan 2014). We will use a fixed‐effect meta‐analysis for combining data where it is reasonable to assume that studies are estimating the same underlying treatment effect, i.e. where trials are examining the same intervention, and the trials’ populations and methods are judged sufficiently similar. If there is clinical heterogeneity sufficient to expect that the underlying treatment effects differ between trials, or if substantial statistical heterogeneity is detected, we will use a random‐effects meta‐analysis to produce an overall summary if an average treatment effect across trials is considered clinically meaningful. The random‐effects summary will be treated as the average range of possible treatment effects and we will discuss the clinical implications of treatment effects differing between trials. If the average treatment effect is not clinically meaningful we will not combine trials.

We will summarize time‐to‐event outcomes using the generic inverse variance method with a fixed‐effect model. If we use random‐effects analyzes, we will present the results as the average treatment effect with 95% CIs, and the estimates of T² and I².

'Summary of findings’ table

We will use the GRADE approach (Guyatt 2011) in order to produce a 'Summary of findings' table (Higgins 2011) for the outcomes: time to healing, time to resolution of pain, viral shedding rate, and adverse events. We will downgrade the quality of evidence depending on the presence of the following factors.

  1. Study limitations.

  2. Inconsistency of results.

  3. Indirectness of evidence.

  4. Imprecision.

  5. Publication bias.

Subgroup analysis and investigation of heterogeneity

We will explore heterogeneity sources through subgroup analysis for the following.

  1. Antiviral therapy types.

  2. Antiviral administration routes.

  3. Antiviral therapy doses (500 mg or less per dose versus more than 500 mg per dose).

  4. Antiviral therapy frequency (twice a day, or less, versus three times a day, or more).

  5. Antiviral duration of treatment (single doses, three days or less, and more than three days).

  6. Phase at the moment of the initiation of therapy (prodromal phase versus clinical phase).

  7. HSV types (Type I and Type II).

  8. Gender.

We will restrict subgroup analyzes to the primary outcomes: time to healing, time to resolution of pain, recurrences during follow‐up, and adverse events.

For fixed‐effect inverse variance meta‐analyzes we will assess differences between subgroups by interaction tests. For random‐effects and fixed‐effect meta‐analyzes using methods other than inverse variance, we will assess differences between subgroups by inspection of the subgroups’ CIs; non‐overlapping CIs indicate a statistically significant difference in treatment effect between the subgroups.

Sensitivity analysis

We will perform a sensitivity analysis for aspects of the review that might affect the results. For example, where there is risk of bias associated with the quality of the included trials based on overall risk of bias assessment ('low' versus 'unclear' and 'high' risk of bias), definition of recurrent genital herpes used (four episodes per year; more than four episodes per year), and design of included studies (cross‐over and parallel trials).