Intervention Protocol

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Interventions for men and women with their first episode of genital herpes

  1. Rachel Heslop1,*,
  2. Vanessa Jordan1,
  3. Marialena Trivella2,
  4. Vasileios Papastamopoulos3,
  5. Helen Roberts1

Editorial Group: Cochrane Sexually Transmitted Infections Group

Published Online: 31 JUL 2013

DOI: 10.1002/14651858.CD010684

How to Cite

Heslop R, Jordan V, Trivella M, Papastamopoulos V, Roberts H. Interventions for men and women with their first episode of genital herpes (Protocol). Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.: CD010684. DOI: 10.1002/14651858.CD010684.

Author Information

  1. 1

    University of Auckland, Department of Obstetrics & Gynaecology, Auckland, New Zealand

  2. 2

    University of Oxford, Centre for Statistics in Medicine, Oxford, UK

  3. 3

    Evaggelismos General Hospital, 5th Department of Internal Medicine and Infectious Diseases Unit, Athens, Greece

*Rachel Heslop, Department of Obstetrics & Gynaecology, University of Auckland, Private Bag 92019, Auckland, 1023, New Zealand.

Publication History

  1. Publication Status: New
  2. Published Online: 31 JUL 2013




  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

Description of the condition

Genital herpes is a sexually transmitted infection caused by herpes simplex virus (HSV) type 1 and 2. Type 2 infections usually cause more recurrent and severe symptoms and primary infections are generally more severe than recurrences. HSV-2 infection is more common in women, possibly because the rate of male-to-female transmission is at least twice that of female-to-male transmission. The prevalence of genital HSV infection increases with age and numbers of sexual partners, with higher rates in specific ethnic and lower socioeconomic groups. The strongest predictor for genital HSV infection is a person's number of lifetime partners. HSV infection results in lifelong infection, which can be asymptomatic or present with recurrent lesions. It is estimated that up to 70% of all genital HSV-2 is transmitted during asymptomatic shedding from an index partner with HSV-2 (Azwa 2009). The virus enters the body by direct contact of the infected person's secretions or mucus membranes with the skin or mucus membrane of another. The herpes virus multiplies in the basal epithelial layer and then becomes latent in the dorsal root ganglion where it can reactivate spontaneously and travel back to the epithelium. This is known as viral shedding (Whitley 1998).

The initial infection may or may not cause symptoms and is followed by seroconversion with type-specific antibodies four to six weeks after infection. There are two types of first-episode infections. Nonprimary infections are those that occur in a person already infected with HSV, while true primary infection is HSV acquisition for the first time in an HSV-seronegative person. Nonprimary infections are associated with fewer systemic symptoms, a shorter duration of disease, a shorter duration of viral shedding and fewer lesions than primary infections (Azwa 2009). A primary episode can last up to two weeks if untreated (Cernik 2008). As symptomatic primary first-episode herpes is usually more severe than non-primary it is important to ascertain that interventions are effective for these symptoms.

After an incubation period of one to 26 days, classical primary genital herpes begins with prodromal symptoms characterized by localized pain or tingling lasting up to 24 hours. Clinical manifestations of herpes are diverse (Corey 1983). However, 'classic' prodromal symptoms are followed by the appearance of randomly distributed vesicles clustered on a red base. Tiny papules develop into vesicles, which subsequently ulcerate and crust. Constitutional symptoms such as fever, chills, fatigue, and muscle aches accompany the disease and last 10 to 14 days. Enlarged inguinal or femoral glands may accompany constitutional symptoms, and dysuria is common in women.

For women, the classic clinical picture is that of painful vaginal and vulva lesions; however, infection of the cervix, often subclinical, is common. Men typically develop lesions on the glans, prepuce, or shaft of the penis.

Male circumcision significantly reduces the incidence of HSV-2 infection (Tobian 2009), and appears to reduce the number of recurrences and evidently prolongs the disease-free period in between two recurrences (Jerath 2009). Male circumcision does not affect HSV-2 acquisition among female partners (Tobian 2012).

Extragenital complications occur in a minority of peoples who present with primary HSV infection, such as:

  • central nervous system disease, such as aseptic meningitis, encephalitis, or transverse myelitis;
  • end-organ disease including hepatitis or pneumonitis;
  • disseminated HSV.


Description of the intervention

There is no cure for genital herpes. The aim of treatment is to improve symptoms and speed recovery. All the antiviral agents have been shown to reduce the duration and severity of symptoms, and reduce healing times and duration of viral shedding in primary genital herpes. For treatment to be effective, it needs to be initiated as early as possible once a clinical diagnosis has been made and before laboratory confirmation. Treatment of primary infection does not alter the natural history of the disease and has no effect on the rates of recurrences of genital herpes. Topical agents are less effective than oral agents and combined oral and topical treatment is of no additional benefit (Azwa 2009).

Currently, there are three classes of drugs licensed for the treatment of HSV infection, all of which target viral deoxyribonucleic acid (DNA) replication.

Guanosine analogs, including acyclovir, valacyclovir, famciclovir, and ganciclovir, are the drugs of choice for the management of primary HSV. The acyclic nucleotide analog, cidofovir, and the pyrophosphate analog, foscarnet, are reserved for use in resistant viruses. Acyclovir, a thymidine nucleoside analog, was the first drug introduced to treat HSV infection. It has poor bioavailability and a short half-life and, as a result, requires frequent dosing. Valacyclovir is a prodrug of acyclovir and famciclovir is a prodrug of the guanosine nucleoside analog, penciclovir.

Acyclovir can be administered topically, orally, or intravenously. When commenced within 72 hours of the formation of the lesions acyclovir shortens the course of the primary attack, prevents new lesion formation, and helps decrease any accompanying constitutional symptoms (Azwa 2009).

Imidazoquinolines such as imiquimod and resiquimod has been found in preclinical studies to be immune response modifiers by inducing cytokines (Stanley 2002). Imiquimod is currently used as a topical treatment for external genital and perianal warts in adults (approved by the US Food and Drug Administration (FDA) in 1997). Application is topical, which appears to have minimal systemic absorption. Adverse reactions are mainly related to the application site with some people reporting systemic symptoms (Gupta 2002).

Interferons (IFNs) are known well for their antiviral effects, and are also potent cell growth regulators and have immunomodulation properties (Katze 2002). Some randomized double-blind placebo-controlled trials (RCTs) have reported positive results with the use of IFN topically. The treatment was also reported to be well tolerated and only minor local reactions were noted (Chiu 2011).

Natural products include plant extracts, antioxidants, and vitamins. Many small molecules, including phenols, polyphenols, terpenes, flavonoids, and sugar-containing compounds, have potential anti-HSV activity (Zhong 2013). Some of the products that have been trialed include Clinacanthus nutans (Kongkaew 2011), lysine, vitamin C, zinc, vitamin E, and adenosine monophosphate (Gaby 2006). However, most of the studies were for recurrent genital herpes so treatment of first episodes needs to be studied further.


How the intervention might work

Acyclovir, valacyclovir, and famciclovir are competitive inhibitors of viral DNA polymerase, resulting in inhibition of viral DNA synthesis. The drugs have an excellent margin of safety because they are converted by viral thymidine kinase to the active drug only inside virally infected cells (Cernik 2008). Adverse effects are rare and include nausea, vomiting, headache, and diarrhea (Azwa 2009). Ganciclovir (myelosuppressive), foscarnet (nephrotoxic), and cidofovir (nephrotoxic) are very toxic drugs and are not used as a first-line treatment (Vajpayee 2000).

Imiquimod and its potent analog (100 times more), resiquimod, are from the family of imidazoquinolines. Both have mechanisms of action that modify the immune response. This is mediated through the induction of various cytokines including tumor necrosis factor alpha (TNF-α), IFN-alpha (IFN-α), and interleukins (IL) such as IL-1, IL-6, and IL-12 (Brown 2002). It is thought that it may stimulate or enhance the innate and adaptive immune system (Gupta 2002).

IFN works by stimulating the host immune system by increasing activation of natural killer cells, macrophages, and cytotoxic T cells, therefore interfering with the lifecycle of the virus (Chiu 2011).

Natural products contain a wide variety of compounds that have been found to have anti-HSV properties. The majority have a mechanism of action that inhibits attachment and entry of the virus into the host cell. However, the specific mechanisms and targets of most of the active natural products are unknown and still require investigation (Zhong 2013).


Why it is important to do this review

HSV is a major global health problem, and is the leading cause of encephalitis and genital ulcerative disease, and a major cofactor for HIV infection. The virus can establish latency, reactivate frequently, and be horizontally and vertically transmitted during periods of unrecognized or asymptomatic shedding. Seroprevalence varies widely between different geographical and population groups and is particularly high in HIV-infected individuals, reaching levels over 90% in countries where HIV is endemic (Malkin 2004; Weiss 2004).

Genital herpes is a significant risk factor for acquiring HIV for both men and women, which is of serious concern. Many mechanisms have been suggested as to how this takes place. It is thought to be due to the presence of broken skin giving transmission enhancement, or that HSV interacts with HIV leading to increased success of the infection (Huang 2012). One systematic review found an approximately three-fold increase in risk of HIV acquisition in men and women infected with HSV-2 (Freeman 2006).

There is significant concern surrounding maternal herpes infection due to the risk of neonatal infection, which has been shown to lead to significant morbidity and mortality (Brown 2005).The most critical determinant of neonatal infection is primary genital HSV infection near delivery. This clinical observation may be related to the absence of maternal anti-HSV antibodies and to greater viral exposure during primary infection. Other predictors of neonatal infection include viral shedding during labor, invasive fetal monitoring, and premature delivery (Brown 2003). Although cesarean section does not completely eliminate the risk for HSV transmission to the infant, women with genital herpetic lesions at the onset of labor should deliver by cesarean section to prevent neonatal HSV infection (Workowski 2010).

At present there is no therapy or vaccine to prevent HSV, though the use of condoms offers moderate protection from acquisition (Martin 2009).

Treatment of the disease in the most effective and beneficial way is imperative. If HSV-2 is a cofactor for HIV infection then HSV-2 treatment may have a role as an HIV prevention strategy. Confusion often arises because various dosing regimens are recommended for treatment. This review will help clarify the situation for health practitioners regarding the extent of improvement of health outcomes for particular treatments, along with their adverse events.



  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

To determine the effectiveness and safety of the treatment of first episode of genital herpes on the duration and severity of symptoms and time to recurrence.



  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

Criteria for considering studies for this review


Types of studies

Published and unpublished RCTs and cluster randomised trials will be included with the exception of those that are quasi-randomized.


  • drug dosing trials;
  • suppressive therapy regimens (long-term therapy) for first episodes.


  • studies of vaccinations;
  • studies for which the objective was to look at the treatment for complications of HSV, for example, herpes simplex encephalitis or herpes proctitis.


Types of participants

Men and women with their first episode of genital herpes including:

  • immunocompetent individuals;
  • immunodeficient individuals.


Types of interventions

We will be looking at antivirals (both topical and systemic), interferon (IFN) (both topical and systemic), imiquimod (topical or analogue e.g. resiquimod) and natural products which are all to be compared with no treatment, placebo, other medication or differing drug dosages. The timing of the treatments will be in relation to the onset of symptoms. The interventions are:


  • antiviral (such as acyclovir: topical and systemic) versus placebo.
  • antiviral (topical and systemic) versus no treatment.
  • antiviral (topical and systemic) versus other medication.


  • IFN (topical and systemic) versus placebo.
  • IFN (topical and systemic) versus no treatment.
  • IFN (topical and systemic) versus other medication.


  • imiquimod (topical or analog) versus placebo.
  • imiquimod (topical or analog) versus no treatment.
  • imiquimod (topical or analog) versus other medication.

Natural product

  • natural product versus placebo.
  • natural product versus no treatment.
  • natural product versus other medication.

Antiviral + natural product

  • antiviral + natural product versus placebo.
  • antiviral + natural product versus no treatment.
  • antiviral + natural product versus other medication.

Dosage studies:

  • antiviral versus antiviral (both topical and systemic).
  • IFN versus IFN (both topical and systemic).
  • imiquimod versus imiquimod (both topical and analog).
  • natural product versus natural product.


Types of outcome measures


Primary outcomes

1. Duration of symptoms from onset of treatment: symptoms will be defined by the authors of the original papers. When several symptoms are reported, we will include the longest duration, but will make a note of the type and numbers of symptoms reported, as part of the exploration of heterogeneity.

2. Time to first recurrence.

3. Adverse events.


Secondary outcomes

4. Duration of lesions from onset of treatment: we will define this as time to complete lesion healing.

5. Neonatal effects: as defined by the authors of the original papers.

6. Cesarean section delivery.


Search methods for identification of studies

RH and VJ will identify as many relevant RCTs as possible of 'antiviral agents, interferon, imiquimod, and biological agents' for 'genital herpes', irrespective of their language of publication, publication date and publication status (published, unpublished, in press, and in progress). We will use both electronic searches of bibliographic databases and handsearching, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).


Electronic searches

We will contact the Trials Search Co-ordinator (TSC) of the Sexually Transmitted Infections Cochrane Review Group in order to implement a comprehensive search strategy to capture as many relevant RCTs as possible in electronic databases. For this purpose, 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 'antiviral agents, IFN, imiquimod, and biological agents', with field labels, proximity operators, and boolean operators. Appendix 1 shows the search strategies.

Specifically, we will search in the following electronic databases:

  • MEDLINE®, Ovid platform (1946 to present);
  • MEDLINE® In-Process & Other Non-Indexed Citations, Ovid platform (1946 to present);
  • MEDLINE® Daily Update, Ovid platform (1946 to present);
  • (1947 to present);
  • The Cochrane Central Register of Controlled Trials (CENTRAL), Ovid platform (1991 to present);
  • LILACS, IAHx interface (1982 to present);
  • PsycINFO, Ovid platform (1806 to present);
  • Cumulative Index to Nursing and Allied Health (CINAHL) (inception to present);
  • Allied and Complementary Medicine Database (AMED), Ovid platform (inception to present).

We will use for MEDLINE, Cochrane Highly Sensitive Search Strategy for Identifying RCTs: Sensitivity and Precision Maximizing Version (2008 revision), Ovid format (Higgins 2011). The LILACS search strategy will be combined with the RCT filter of the IAHx interface.

These searches will be updated within six months before publication of the review.


Searching other resources

We will attempt to identify additional relevant RCTs by using of the following methods:

  • searching in the Sexually Transmitted Infections Cochrane Review Group's Specialized Register (using the term 'herpes' in title, abstract, and keywords), that includes RCTs and controlled clinical trials, from 1944 to present, located through electronic searching (MEDLINE, EMBASE, and CENTRAL) and handsearching;
  • searching in Complementary and Alternative Medicines (CAM) Specialised Register ProCite Database (using the terms 'herpes' OR 'herpe*') (inception to present);
  • searching in trials registers:
  • searching in Web of Knowledge (inception to present) using key words Topic=(herpes) AND Topic=(genital) AND Topic=("first episode"). Refined by: Document Types=( CLINICAL TRIAL ). Timespan=All Years;
  • searching in Proquest Dissertations and Theses ( (inception to present);
  • searching for gray literature in System for Information on Grey Literature in Europe 'OpenGrey' ( 1990, 1992, 1995, 1996, and 1997.
  • searching by contact with authors of all RCTs identified by others methods;
  • searching by contact with pharmaceutical companies producing 'antiviral agents, interferon, imiquimod, and biological agents' for 'genital herpes';
  • handsearching in the following journals not indexed in MEDLINE and EMBASE: Anatolian Journal of Obstetrics & Gynecology, Current Medical Literature Gynecology & Obstetrics, Current Obstetrics and Gynecology Reports, ISRN Obstetrics and Gynecology, Journal of South Asian Federation of Obstetrics & Gynecology, Obstetrics and Gynecology International, Obstetrics Gynaecology and Reproductive Medicine, and Sexual Science: the newsletter of the Society for the Scientific Study of Sexuality and Sexualities;

  • handsearching of conference abstracts in the following events:
    • The International Society for Sexually Transmitted Diseases Research (ISSTDR) ( 2007, 2009, and 2011;
    • The British Association for Sexual Health and HIV (BASHH) ( 2004, 2006, 2007, and 2009;
    • International Congress on Infectious Diseases (ICID) ( 2010 and 2012;
    • The International Union against Sexually Transmitted Infections (IUSTI) ( 2011 and 2012;
    • International Society for Infectious Diseases (ISID) ( 2011;
    • International Meeting on Emerging Diseases and Surveillance (IMED) ( 2007, 2009, and 2011;
    • Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) ( 2011 and 2012;
    • The International Federation of Gynecology and Obstetrics (FIGO) ( 2012;
    • Australasian Society for HIV Medicine (ASHM) (2009 to present);
  • handsearching within previous systematic reviews and other relevant publications on the same topic;
  • handsearching within reference lists of all RCTs identified by others methods.


Data collection and analysis


Selection of studies

After all searches have been conducted, we will check for duplicates using EndNote. RH and VJ will independently assess trials for inclusion by scanning the titles and abstracts based on the established inclusion criteria. They will then compare what trials they have identified. We will obtain full-text articles and identify the final studies for possible inclusion in the review. We will resolve any disagreements regarding studies for inclusion by discussion with a third review author, HR. Further information will be sought from authors if there is insufficient information to make a decision about eligibility. We will include details of studies that are excluded at this stage in the 'Characteristics of excluded studies' table.


Data extraction and management

Two review authors will extract the data from eligible studies independently (RH and DF), using a data extraction form that has been developed by the review authors (Appendix 2). We will resolve any differences by discussion or by consultation (or both) with a third review author to reach consensus. Extracted data will include study characteristics and outcome data (see data extraction form, Appendix 2). Where there are multiple publications of one study, the main trial report will be used as the reference and any additional details will be sourced from secondary papers. We will contact study authors if further data are required, such as methods or results so as to confirm the suitability of the study for meta-analysis. We will routinely seek information on whether data was recorded that was not reported in the published paper from the corresponding authors for all included trials.


Assessment of risk of bias in included studies

Two of three review authors (RH, VJ or DF) will independently assess the quality of the selected studies using of the Cochrane 'Risk of bias' assessment tool ( We will classify studies as 'low risk of bias', 'high risk of bias', or 'unclear risk of bias'. Any disagreements regarding bias will be resolved by consensus or discussion with a third review author.

The review authors will search for within-trial selective reporting, such as reporting of outcomes in insufficient detail or trials failing to report obvious outcomes. We will seek protocols and then compare the outcomes of the protocol with the outcomes in the final study.

The Cochrane 'Risk of bias' tool recommends explicit reporting of the following seven domains (Higgins 2011).

Random sequence generation (selection bias)

  • Adequate: use of random number table, random number computer generation, coin toss, dice, shuffling of serial numbered opaque envelopes.
  • Inadequate: using a nonrandom element in the randomisation process (i.e. sequence generated by odd or even date of birth).
  • Unclear: insufficient information about the process of sequence generation.

Allocation concealment (selection bias)

  • Adequate: central randomisation, serially numbered drug containers of identical appearance, serially number opaque sealed envelopes.
  • Inadequate: use of open random allocation (e.g. unsealed envelopes, readily accessed randomisation).
  • Unclear: insufficient information about the process of allocation concealment.

Blinding of participants and personnel (performance bias)

  • Adequate: Blinding of participants and personnel, or no blinding/partial blinding but review authors conclude that outcome is unlikely to be influenced.
  • Inadequate: No blinding/partial blinding of participants and personnel which is likely to have affected the outcome.
  • Unclear: Insufficient information about the process of blinding the participants and personnel.

Blinding of outcome assessment (detection bias)

  • Adequate: blinding of outcome assessors or no blinding/partial blinding but review authors conclude that outcome measurement is unlikely to be influenced.
  • Inadequate: no blinding/partial blinding of outcome assessors that is likely to have affected the outcome measurement.
  • Unclear: insufficient information about the process of blinding the outcome assessors.

Incomplete outcome data (attrition bias)

  • Adequate: there are no data missing or any missing data has clear reasoning why.
  • Inadequate: data are missing or there is no reasons why data are missing.
  • Unclear: insufficient information about the attrition's/exclusions.

Selective outcome reporting (reporting bias)

  • Adequate: all prespecified outcomes as reported in the protocol have been addressed in the published article.
  • Inadequate: not all prespecified outcomes reported in the published article or outcomes have been published without good reasoning that were not prespecified.
  • Unclear: insufficient information about the process of outcome reporting.

Other potential sources of bias

  • Adequate: it appears there are no sources of other bias.
  • Inadequate: there is at least one important potential bias.
  • Unclear: insufficient information about the other sources of bias.

The conclusion of all judgments will be presented in the 'Risk of bias' table, which by means of sensitivity analysis, will be incorporated into the interpretation of review findings.


Measures of treatment effect

Dichotomous data, such as cesarean section delivery, will be expressed as a risk ratio (RR) and 95% confidence intervals. Continuous data, such as duration of symptoms, will be expressed as a mean difference (MD) between treatment groups. We anticipate that some data will be presented as medians as duration data maybe be skewed; if this is the case median data will be presented in an additional table and will be discussed but not summarized. If similar outcomes are reported on different scales then the standardized mean difference (SMD) will be calculated. Where data required to calculate RRs or MDs is unavailable, we will utilize the most detailed numerical data available that will give a similar way to analyze the included studies (e.g. P values, test statistics). The magnitude and direction of effect that is reported by the studies will be compared with how these effects present in the review, taking into account legitimate differences between the two. Hazard ratios (HRs) will be used to express time to recurrence.


Unit of analysis issues

In the case of cross-over trials, we will only include the first phase data. In order to avoid a unit of analysis error, caesarean section data will be considered per woman, not per cesarean section. In the case of cluster randomised data, the interclass correlation coefficient (ICC) as discussed in the Cochrane Handbook (Higgins 2011) will be employed. If the ICC is not available then a suitable factor will borrowed from other trials as an estimate of relative variability.


Dealing with missing data

If there are missing data, we will contact the authors for further information. We will note characteristics of any participants that have left the study to determine if the groups remain balanced. We will look at the method used to impute the missing data if intention-to-treat (ITT) analyses are supplied by the primary authors. If imputed data is included we will do a sensitivity analysis to remove these studies temporarily to determine the effect on the summary statistic.

If there is sufficient detail reported to calculate the MDs but no information on the corresponding standard deviation (SD) is given, we will assume the outcome to have a standard SD that is equal to the highest SD, after it has been approximately matched for sample size with the study from where the SD is borrowed.The robustness of this decision will be explored separately by sensitivity analysis.


Assessment of heterogeneity

We will assess the characteristics of the included studies to judge whether there are sufficient similarities for meta-analysis to be considered clinically meaningful. If studies are sufficiently homogeneous in terms of their clinical and methodological characteristics, we will carry out meta-analysis. In addition to visual inspection of the forest plots we will use the I2 statistic (Higgins 2011) to quantify any heterogeneity in the meta-analysis. For levels of I2 up to 50%, we will not consider heterogeneity to be important. Our increased tolerance is due to the fact that we are expecting a degree of heterogeneity in the included studies. For I2 levels between 50% and 80%, we will consider heterogeneity to be moderate and, where possible, random effects models will be employed to allow for the present heterogeneity. If I2 values exceed 80%, we will consider heterogeneity to be substantial and hence we will not present pooled results. Instead we will report any observations as a narrative (Higgins 2011).


Assessment of reporting biases

We will minimize the impact of a reporting bias by undertaking a comprehensive search. We will do this by searching multiple electronic databases and additional resources for both unpublished and published articles, being alert for duplication of data, and there being no language restriction. Publication bias will be assessed if there are 10 or more studies in an analysis by using a funnel plot to inspect for asymmetry visually (Higgins 2011). If there is large asymmetry, there is the possibility of small study effects being present (a tendency for estimates of the intervention effect to be more beneficial in smaller studies).


Data synthesis

Statistical analysis will be carried out using RevMan (RevMan 2011). Data from primary studies will be combined using a fixed-effect model. If moderate heterogeneity is detected by the use of the methods listed in the 'Assessment of heterogeneity section', a random-effects model will be used (Higgins 2011) to allow for the heterogeneity.

Dichotomous data (RR) will be meta-analysed using the Mantel-Heanszel method, whereas for continuous data the polled mean difference (MD), or standardised mean difference (SMD) as appropriate, will be used. Time to recurrence data (HRs) will be meta-analysed using the Generic inverse variance method.

If the obtained data includes rare events (as might be the case for adverse events), then the Peto's odds method will be used as appropriate.


Subgroup analysis and investigation of heterogeneity

We will conduct subgroup analyses where data are available to determine the separate evidence within the following subgroups:

  • gender;
  • the recommended length of treatment is five days with no evidence of benefit for longer periods of time (Azwa 2009), and where the information is available we will subgroup by length of treatment (five days or less, more than five days);
  • oral/topical/intravenous administration;
  • type of drug within a class;
  • high and low dose as defined by the included studies;
  • for treatment to be effective it needs to be initiated as early as possible once a clinical diagnosis has been made (Azwa 2009). Where the information is provided we will subgroup by initiation of treatment five days or less since appearance of lesions and more than five days;
  • immunodeficiency.

We will take any statistical heterogeneity into account in the interpretation of the results, especially if there is variation in the direction of the effect.


Sensitivity analysis

If we detect substantial heterogeneity, we will employ the use of sensitivity analyses to determine the influence of the random effects model.

In the case of cluster randomised trials, for analysis to be undertaken with other randomised trials, the generic inverse method should be employed.

The following analyses will be also carried out to determine the robustness of the pooled results:

  • studies if judged to have a low risk of bias will be grouped separately from other studies to assess the effects on the overall meta-analysis.
  • if a study shows outliers in the forest plot, it will be temporarily excluded from the meta-analysis to assess the overall effect.



  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

We would like to thank the Sexually Transmitted Infections Group (STIG) and the Cochrane Menstrual Disorders and Subfertility Group (MDSG). In particular Miguel Ortega, Trials Search Co-ordinator (TSC) of STIG and Marian Showell, TSC of MDSG, for writing the searches, and Cindy Farquhar (MDSG Coordinating Editor) for support throughout.



  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

Appendix 1. Electronic search strategies

MEDLINE and CENTRAL (Ovid platform)

1 exp Herpes Genitalis/
2 herpe$.tw.
3 exp Herpes Simplex/
4 exp Simplexvirus/
5 simplexviru$.tw.
6 herpesvirus$.tw.
7 marmoset virus$.tw.
8 or/2-7
9 genital$.tw.
19 vulva$.tw.
21 or/9-20
22 8 and 21
23 exp Herpesvirus 2, Human/
24 herpesvirus 2
25 hhv
27 hsv
29 or/1,22-28
30 exp Antiviral Agents/
31 antiviral$.tw.
32 exp Acyclovir/
33 ac?
34 valac?
36 exp Ganciclovir/
37 ganc?
39 exp Foscarnet/
41 exp Interferons/
42 interferon$.tw.
45 exp Biological Agents/
46 (biological adj5 agent$).tw.
47 (biologic$ adj5 product$).tw.
48 (natural adj5 product$).tw.
49 Clinacanthus
50 exp Lysine/
52 exp Ascorbic Acid/
53 (ascorbic adj5 acid).tw.
54 vitamin
55 (sodium adj5 ascorbate).tw.
56 magnesium
57 (ferrous adj5 ascorbate).tw.
58 exp Vitamin E/
59 vitamin
60 exp Zinc/
62 exp Lithium/
64 exp Adenosine Monophosphate/
65 adenosine
66 (adenosine adj5 phosphate).tw.
68 adenylic
69 or/30-68
70 randomized controlled
71 controlled clinical
72 randomized.ab.
73 placebo.ab.
74 clinical trials as
75 randomly.ab.
76 trial.ti.
77 or/70-76
78 exp animals/ not
79 77 not 78
80 29 and 69 and 79

Note: the CENTRAL search strategy does not include the terms 70-80.

#1.1 'genital herpes'/exp
#1.2 (herpes NEAR/5 progenitalis):ab,ti
#1.3 'herpes simplex'/exp
#1.4 herpes:ab,ti
#1.5 'simplexvirus'/exp
#1.6 simplexvirus*:ab,ti
#1.7 'herpes virus'/exp
#1.8 herpesvir*:ab,ti
#1.9 herpetovirus:ab,ti
#1.10 (marmoset NEAR/5 virus*):ab,ti
#1.11 'herpes simplex virus'/exp
#1.12 hsv:ab,ti
#1.13 hhv:ab,ti
#1.14 #1.3 OR #1.4 OR #1.5 OR #1.6 OR #1.7 OR #1.8 OR #1.9 OR #1.10 OR #1.11 OR #1.12 OR #1.13
#1.15 genital*:ab,ti
#1.16 venereal:ab,ti
#1.17 anogenital:ab,ti
#1.18 rectal:ab,ti
#1.19 anal:ab,ti
#1.20 anorectal:ab,ti
#1.21 perianal:ab,ti
#1.22 penile:ab,ti
#1.23 penis:ab,ti
#1.24 vaginal:ab,ti
#1.25 vulva*:ab,ti
#1.26 vulvovaginal:ab,ti
#1.27 #1.15 OR #1.16 OR #1.17 OR #1.18 OR #1.19 OR #1.20 OR #1.21 OR #1.22 OR #1.23 OR #1.24 OR #1.25 OR #1.26
#1.28 #1.14 AND #1.27
#1.29 'herpes simplex virus 2'/exp
#1.30 (herpes NEAR/5 (2 OR ii OR ii)):ab,ti
#1.31 'herpesvirus 2':ab,ti
#1.32 'hsv 2':ab,ti
#1.33 hsv2:ab,ti
#1.34 'hhv 2':ab,ti
#1.35 hhv2:ab,ti
#1.36 #1.1 OR #1.2 OR #1.28 OR #1.29 OR #1.30 OR #1.31 OR #1.32 OR #1.33 OR #1.34 OR #1.35
#1.37 'antivirus agent'/exp
#1.38 antivirus:ab,ti
#1.39 'viral inhibitor':ab,ti
#1.40 vir?static:ab,ti
#1.41 virucid*:ab,ti
#1.42 'virus repressor':ab,ti
#1.43 'antiviral therapy'/exp
#1.44 antiviral*:ab,ti
#1.45 'anti viral':ab,ti
#1.46 'aciclovir'/exp
#1.47 ac?clovir:ab,ti
#1.48 'valaciclovir'/exp
#1.49 valac?clovir:ab,ti
#1.50 'famciclovir'/exp
#1.51 famciclovir:ab,ti
#1.52 'interferon'/exp
#1.53 interferon*:ab,ti
#1.54 interferron:ab,ti
#1.55 ifn:ab,ti
#1.56 'imiquimod'/exp
#1.57 imiquimod:ab,ti
#1.58 'biological product'/exp
#1.59 (biologic* NEAR/5 product*):ab,ti
#1.60 (biological NEAR/5 agent*):ab,ti
#1.61 'natural product'/exp
#1.62 (natural NEAR/5 product*):ab,ti
#1.63 'natural compound':ab,ti
#1.64 #1.37 OR #1.38 OR #1.39 OR #1.40 OR #1.41 OR #1.42 OR #1.43 OR #1.44 OR #1.45 OR #1.46 OR #1.47 OR #1.48 OR #1.49 OR #1.50 OR #1.51 OR #1.52 OR #1.53 OR #1.54 OR #1.55 OR #1.56 OR #1.57 OR #1.58 OR #1.59 OR #1.60 OR #1.61 OR #1.62 OR #1.63
#1.65 'randomized controlled trial'/exp
#1.66 'single blind procedure'/exp
#1.67 'double blind procedure'/exp
#1.68 'crossover procedure'/exp
#1.69 #1.65 OR #1.66 OR #1.67 OR #1.68
#1.70 random*:ab,ti
#1.71 placebo*:ab,ti
#1.72 allocat*:ab,ti
#1.73 crossover*:ab,ti
#1.74 'cross over':ab,ti
#1.75 trial:ti
#1.76 (doubl* NEXT/1 blind*):ab,ti
#1.77 #1.70 OR #1.71 OR #1.72 OR #1.73 OR #1.74 OR #1.75 OR #1.76
#1.78 #1.69 OR #1.77
#1.79 'animal'/de
#1.80 'animal experiment'/de
#1.81 'nonhuman'/de
#1.82 #1.79 OR #1.80 OR #1.81
#1.83 'human'/de
#1.84 #1.82 AND #1.83
#1.85 #1.82 NOT #1.84
#1.86 #1.78 NOT #1.85
#1.87 #1.36 AND #1.64 AND #1.86 AND [embase]/lim


1 exp Herpes Genitalis/
3 exp Herpes Simplex/
4 simplexviru$.tw.
5 simplex viru$.tw.
6 marmoset virus$.tw.
7 or/2-6
8 genital$.tw.
18 vulva$.tw.
20 or/8-19
21 7 and 20
22 herpesvirus 2
23 hhv
25 hsv
27 or/1,21-26
28 exp Antiviral Drugs/
29 antivir$.tw.
30 ac?
31 valac?
33 exp Interferons/
34 interferon$.tw.
36 (biological adj5 agent$).tw.
37 (biologic$ adj5 product$).tw.
38 (natural adj5 product$).tw.
39 or/28-38
40 27 and 39
44 clinical trials/
45 placebo/
46 exp Treatment/
47 or/41-46
48 40 and 47


((mh:"Herpes Genital" OR tw:"herpes genital" OR tw:"herpes simple genital") OR ((mh:"Herpes Simple" OR tw:herpes OR mh:"Simplexvirus" OR tw:simplexvirus OR tw:"virus herpes simplex" OR tw:herpesvirus OR tw:"virus marmoset") AND (tw:genital OR tw:venérea OR tw:anogenital OR tw:rectal OR tw:anal OR tw:anorectal OR tw:perianal OR tw:peneana OR tw:vaginal OR tw:vulvar OR tw:vulvovaginal)) OR (mh:"Herpesvirus Humano 2" OR tw:"herpesvirus humano 2" OR tw:"virus 2 del herpes simple" OR tw:"herpesvirus humano tipo 2" OR tw:hsv-2 OR tw:"hsv 2" OR tw:hsv2) AND (mh:"Antivirales" OR tw:antiviral$ OR tw:antivíricos OR mh:"Aciclovir" OR tw:aciclovir OR tw:valaciclovir OR tw:famciclovir OR mh:"Interferones" OR tw:interferon$ OR tw:imiquimod OR mh:"Agentes Biológicos" OR tw:"agentes biológicos" OR tw:"productos biológicos" OR tw:"productos naturales" OR tw:"sustancias biológicas"))

RCTs filter:

((PT:"ensayo clinico controlado aleatorio" OR PT:"ensayo clinico controlado" OR PT:"estudio multicéntrico" OR MH:"ensayos clinicos controlados aleatorios como asunto" OR MH:"ensayos clinicos controlados como asunto" OR MH:"estudios multicéntricos como asunto" OR MH:"distribución aleatoria" OR MH:"método doble ciego" OR MH:"metodo simple-ciego") OR ((ensaio$ OR ensayo$ OR trial$) AND (azar OR acaso OR placebo OR control$ OR aleat$ OR random$ OR enmascarado$ OR simpleciego OR ((simple$ OR single OR duplo$ OR doble$ OR double$) AND (cego OR ciego OR blind OR mask))) AND clinic$)) AND NOT (MH:animales OR MH:conejos OR MH:ratones OR MH:ratas OR MH:primates OR MH:perros OR MH:gatos OR MH:porcinos OR PT:"in vitro")


  1. S29 S19 AND S28
  2. S28 S20 OR S21 OR S22 OR S23 OR S24 OR S25 OR S26 OR S27
  3. S27 TX primary presentation
  4. S26 TX index
  5. S25 TX primary occurrence*
  6. S24 TX primary episode*
  7. S23 TX first occurrence*
  8. S22 TX first episode*
  9. S21 TX initial
  10. S20 TX first time
  11. S19 S5 AND S18
  12. S18 S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15
  13. S17 TX virucid
  14. S16 TX virucid
  15. S15 TX anti viral
  16. S14 TX ac?clovir
  17. S13 TX valaciclovir
  18. S12 TX famciclovir
  19. S11 TX interferon
  20. S10 TX interferron
  21. S9 TX imiquimod
  22. S8 (MH "Antiviral Agents+") OR (MH "Antiretroviral Therapy, Highly Active") OR (MH "Acyclovir")
  23. S7 antiviral
  24. S6 Antiviral agent
  25. S5 S1 OR S2 OR S3 OR S4
  26. S4 TX herpes
  27. S3 TX herpesvirus
  28. S2 TX Herpes Genital*
  29. S1 (MH "Herpes Genitalis")


Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

RH wrote the protocol. All review authors commented on the protocol and assisted in the drafting of it.


Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

GlaxoWellcome produced Zovirax® (acyclovir) and Valtrex® (valacyclovir). Vasileios Papastamopoulos was an employee (medical advisor) for GlaxoWellcome Greece in 1995 to 1998 but did not participate in any clinical trials.


Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

Internal sources

  • University of Auckland, New Zealand.


External sources

  • No sources of support supplied


Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Acknowledgements
  7. Appendices
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support
  11. Additional references
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