Intervenciones para pacientes masculinos y femeninos con un primer episodio de herpes genital
Resumen
Antecedentes
El herpes genital es incurable, y está causado por el virus del herpes simple (VHS). El primer episodio de herpes genital es el primer cuadro clínico de herpes que presenta el paciente. El tratamiento actual se basa en la supresión viral para reducir la duración y la gravedad del episodio.
Objetivos
Determinar la efectividad y la seguridad de los diferentes tratamientos existentes para el primer episodio de herpes genital en cuanto a la duración de los síntomas y el tiempo hasta la recurrencia.
Métodos de búsqueda
Se hicieron búsquedas en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) (CENTRAL) (desde su inicio hasta abril 2016), MEDLINE (desde su inicio hasta abril 2016), en el registro especializado del Grupo de Revisión Cochrane de Infecciones de Transmisión Sexual (Specialised Register of the Cochrane Sexually Transmitted Infections Review Group) (desde su inicio hasta abril 2016), EMBASE (desde su inicio hasta abril 2016), PsycINFO (desde su inicio hasta abril 2016), CINAHL (desde su inicio hasta abril 2016), LILACS (desde su inicio hasta abril 2016), AMED (desde su inicio hasta abril 2016), y en el Alternative Medicines Specialised Register (desde su inicio hasta abril 2016). Se hicieron búsquedas manuales en varias revistas relevantes, se buscó en las listas de referencias de todos los estudios incluidos, en las bases de datos de ensayos en curso y en otras bases de datos de Internet.
Criterios de selección
Se incluyeron ensayos controlados aleatorios (ECA) con pacientes con un primer episodio de herpes genital. Se excluyeron los ensayos de la vacunación, y los ensayos en los cuales el objetivo primario evaluó una complicación de la infección por VHS.
Obtención y análisis de los datos
Todos los estudios escritos en inglés fueron evaluados de forma independiente por al menos dos revisores en cuanto a la inclusión, el riesgo de sesgo para cada ensayo, y para extraer los datos. Los estudios que requerían traducción se evaluaron en cuanto a la inclusión, la calidad del ensayo y la extracción de datos por parte de traductores externos.
Resultados principales
Se incluyeron 26 ensayos con 2084 participantes analizados. La mayoría de los estudios se realizaron en el Reino Unido y los Estados Unidos (EE.UU.), e incluyeron a pacientes masculinos y femeninos que presentaban su primer episodio de herpes genital, con la excepción de tres estudios que incluyeron sólo a pacientes mujeres. La mayoría de estos estudios se consideró en riesgo incierto de sesgo; en gran parte debido a la ausencia de información presentada en las publicaciones, y debido a la antigüedad de los ensayos. Esta revisión halló pruebas de muy baja calidad de dos estudios de que el aciclovir oral, en comparación con placebo, redujo la duración de los síntomas en los individuos que presentaron su primer episodio de herpes genital (diferencia de medias [DM] ‐3,22; intervalo de confianza [IC] del 95%: ‐5,91 a ‐0,54; I2 = 52%). En dos estudios (112 participantes), el aciclovir intravenoso disminuyó la mediana del número de días en que los pacientes con un primer episodio de herpes presentaron síntomas. El valaciclovir oral (convertido a aciclovir) también mostró una duración similar de los síntomas en comparación con el aciclovir en dos estudios.
Actualmente, no hay pruebas de que el aciclovir tópico reduzca los síntomas (DM ‐0,61 días, IC del 95%: ‐2,16 a 0,95; 3 ECA, 195 participantes, estadística I2 = 56%). Tampoco hay pruebas actuales de que los tratamientos tópicos con crema de cicloxolona, crema de carbenoxolona sodio, arabinósido de adenosina, idoxuridina en dimetil sulfóxido, en comparación con placebo redujeran la duración de los síntomas en pacientes que presentan su primer episodio de herpes.
Dos estudios no informaron pruebas de una reducción en el número de días medianos hasta la recurrencia luego del tratamiento con aciclovir oral versus placebo. Los eventos adversos se informaron por lo general de manera deficiente en todos los estudios incluidos, y no fue posible analizar este resultado de forma cuantitativa. Para los que recibieron aciclovir no hubo ningún evento adverso grave; los eventos adversos más frecuentes informados para el aciclovir oral fueron coriza, mareos, cansancio, diarrea y cólicos renales. Para el aciclovir intravenoso los mismos fueron flebitis, náuseas y pruebas anormales de la función hepática y para el aciclovir tópico hubo dolor con la aplicación tópica. Los que recibieron tratamiento con interferón tuvieron significativamente más eventos adversos en comparación con los que recibieron placebo.
Conclusiones de los autores
Hay pruebas de muy baja calidad a partir de esta revisión de que el aciclovir oral redujo la duración de los síntomas para el herpes genital. Sin embargo, hay pruebas de muy baja calidad que no indicaron que los antivirales tópicos redujeran la duración de los síntomas para los pacientes que presentaban el primer episodio de herpes genital. Esta revisión fue limitada por la inclusión de datos asimétricos, lo cual dio lugar a que pudiese realizarse el metanálisis de pocos ensayos.
PICO
Resumen en términos sencillos
Tratamiento en pacientes masculinos y femeninos que contraen herpes genital por primera vez (primer episodio de herpes genital)
Pregunta de la revisión
El objetivo de esta investigación fue considerar los efectos positivos y adversos de los tratamientos en la duración de los síntomas en pacientes que presentan su primer episodio de herpes genital.
Antecedentes
El herpes genital es causado por el virus del herpes simple (VHS) que se transmite fundamentalmente por vía sexual (contacto piel con piel). El primer episodio de herpes genital es la primera vez que un paciente presenta los síntomas del herpes genital. La característica principal del herpes genital son lesiones cutáneas dolorosas. El tratamiento se basa en la supresión viral para reducir la duración y la gravedad de los síntomas.
Características de los estudios
Se incluyeron 26 ensayos controlados aleatorios (ECA) con 2084 participantes que consideraron los tratamientos para el primer episodio de herpes genital versus placebo u otro tratamiento. Todos los ensayos incluyeron a pacientes que presentaban su primer episodio de herpes genital y se realizaron en diversos países en todo el mundo. Tres de los ensayos incluían sólo a pacientes mujeres, y en todos los ensayos los participantes habían tenido síntomas durante ocho días o menos. Quince de los 26 ensayos fueron financiados por una compañía farmacéutica.
Resultados clave
Las pruebas están actualizadas hasta abril 2016. Las pruebas indican que el aciclovir oral e intravenoso puede ser efectivo para reducir el número de días de síntomas en pacientes con un primer episodio de herpes genital. El valaciclovir oral mostró una duración similar de los síntomas que el aciclovir. No se hallaron pruebas suficientes para apoyar la administración de tratamientos tópicos. Tampoco hubo pruebas de que alguno de los tratamientos redujera el tiempo entre los episodios para los pacientes con herpes genital. En general las pruebas presentadas son de baja calidad. Los estudios incluidos se realizaron principalmente en los años ochenta, y en ese momento la forma breve en que se presentaron los estudios no permite juzgar la calidad de los estudios incluidos de manera adecuada.
Calidad de la evidencia
Las pruebas proporcionadas por esta revisión son de baja calidad. Aunque hay 26 estudios incluidos, los metanálisis creados en esta revisión tenían como máximo tres estudios incluidos. Este hecho se debió principalmente al número reducido de estudios que consideraron cada tipo diferente de antiviral. También fue poco claro si los estudios incluidos se realizaron de forma adecuada, porque los métodos para cada uno de los estudios individuales no informaron detalles suficientes para juzgar la calidad y la inconsistencia de cada estudio, lo cual también afectó la calidad general de la revisión.
Authors' conclusions
Summary of findings
| Oral acyclovir versus placebo for men and women with their first episode of genital herpes | |||||
| Patient or population: men and women with their first episode of genital herpes | |||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments |
| Risk with oral acyclovir | |||||
| Duration of symptoms from onset of treatment | The mean duration of symptoms from onset of treatment in the intervention group was 3.22 days fewer than that with placebo (5.91 fewer to 0.54 fewer) | ‐ | 82 | ⊕⊕⊝⊝ Low1, 2 | |
| Adverse events | Study population | Not pooled | 130 | ⊕⊝⊝⊝ Very low2, 3,5 | There were no severe adverse events. Adverse events were unable to be pooled as they were only reported in two studies and were not reported in a consistent way. Adverse events recorded for those taking this medication included coryza, dizziness, tiredness, diarrhoea and renal colic |
| Not pooled | |||||
| Duration of lesions from onset of treatment | The mean duration of lesions from onset of treatment in the intervention group was 3.51 fewer days than that with placebo (6.19 fewer to 0.82 fewer) | ‐ | 86 | ⊕⊕⊝⊝ Low1, 2 | |
| Time to recurrence | Data were not analysed using the correct method but statistical analysis did not show any difference in median time to recurrence in the two groups | Not pooled | 198 (2 RCTs) | ⊕⊝⊝⊝ Very low2,4 | |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 for risk of bias. There was unclear risk in both studies for randomisation and allocation concealment. Only one study used blinding and one study was graded high risk for attrition and reporting biases. 4 Downgraded by 2 for risk of bias as both studies were unclear for allocation concealment and randomisation and there is the potential for a substantial effect due to dropouts as actual numbers followed up were not reported 5 Downgraded by 1 for imprecision based on very wide confidence intervals | |||||
| Topical acyclovir versus placebo for men and women with their first episode of genital herpes | ||||||
| Patient or population: men and women with their first episode of genital herpes | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with placebo | Risk with topical acyclovir | |||||
| Duration of symptoms from onset of treatment | The mean duration of symptoms from onset of treatment in the intervention group was 0.61 days fewer than that with placebo (2.16 fewer to 0.95 more) | ‐ | 195 | ⊕⊕⊝⊝ Low1, 2 | One included study had given all subjects oral acyclovir | |
| Duration of lesions from onset of treatment | The mean duration of lesions from onset of treatment in the intervention group was 0.86 days fewer than that with placebo (2.15 fewer to 0.42 more) | ‐ | 195 | ⊕⊕⊝⊝ Low1, 3 | One included study had given all subjects oral acyclovir | |
| Adverse events ‐ pain with topical application | Study population | Study population | RR 0.74 | 247 | ⊕⊕⊝⊝ | |
| 242 per 1000 | 179 per 1000 | |||||
| Moderate | Moderate | |||||
| 235 per 1000 | 174 per 1000 | |||||
| Time to recurrence | Data were not pooled. Time to reccurrence ranged from 70‐116 days | Data were not pooled. Time to recurrence ranged from 70‐116 days | The were no differences reported between the two groups | 129 (3 RCTs) | ⊕⊝⊝⊝ Very low1,4 | Data were not analysed using the correct method. Medians were presented |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded by 1 for risk of bias. All trials had unclear risk of bias for randomisation and allocation concealment. 4 Downgraded by 2 for risk of bias with regard to incomplete data not many participants were followed up. 5 Downgraded by 1 for imprecision based on very wide confidence intervals | ||||||
Background
Description of the condition
Genital herpes is a sexually transmitted infection caused by herpes simplex virus (HSV) type 1 and 2. HSV‐2 infections usually cause more recurrent and severe symptoms, and initial infections (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 (Azwa 2009). The prevalence of genital HSV infection increases with age and numbers of sexual partners, with higher rates in specific ethnic and lower socioeconomic groups (Azwa 2009). The strongest predictor for genital HSV infection is a person's number of lifetime partners (Azwa 2009). 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 symptomatic first‐episode occurrences. The first is a first episode of herpes in non‐primary infection which occurs in a person who was non‐symptomatic when initially infected with HSV, the second is a first episode of herpes in primary infection which is when HSV causes a symptomatic episode in a HSV‐seronegative person. First episode of herpes in non‐primary infections which is in an already infected individual are associated with fewer systemic symptoms, a shorter duration of disease, a shorter duration of viral shedding, and fewer lesions than a first episode of herpes with a primary infection(Azwa 2009). A first episode can last up to two weeks if untreated (Cernik 2008). As symptomatic, first episode herpes with primary infection is usually more severe than a first episode of herpes with a non primary infection, it is important to ascertain that interventions are effective for these individuals experiencing a first episode of herpes with a primary infection.
After an incubation period of one to 26 days, classical primary genital herpes begins with prodromal symptoms, characterised by localised pain or tingling lasting up to 24 hours. Clinical manifestations of herpes are diverse (Corey 1983b). 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 (Corey 1982b). However, infection of the cervix, often subclinical, is common. Men typically develop lesions on the glans, prepuce, or shaft of the penis (Corey 1982b). 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 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 people who present with primary HSV infection. These include central nervous system disease, such as aseptic meningitis, encephalitis, or transverse myelitis; end organ disease including hepatitis or pneumonitis; and disseminated HSV (Corey 1982b).
Description of the intervention
There is no therapy or vaccine to prevent HSV, though the use of condoms offers moderate protection from acquisition (Martin 2009). The aim of treatment is to improve symptoms and time to recovery. Antiviral agents have been shown to reduce the duration and severity of symptoms, reduce healing times, and decrease the duration of viral shedding in first episode genital herpes (Azwa 2009). Which antiviral provides the best treatment and in which form (oral, topical, subcutaneous, intramuscular, or intravenous) needs to be confirmed. Treatment of symptomatic episodes of HSV does not alter the clinical course of the disease and has no effect on the rates of recurrences of genital herpes (Azwa 2009).
Currently, there are three classes of drugs licensed for the treatment of HSV symptomatic episodes, all of which target viral deoxyribonucleic acid (DNA) replication. Guanosine analogues, including acyclovir, valicyclovir, famciclovir, and ganciclovir, are the drugs of choice for the management of first episode HSV. The acyclic nucleotide analogue, cidofovir, and the pyrophosphate analogue, foscarnet, are reserved for use in resistant viruses. Acyclovir, a thymidine nucleoside analogue, 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 analogue, penciclovir (Azwa 2009).
Acyclovir can be administered topically, orally, or intravenously. When administered within 72 hours of the formation of the lesions, acyclovir shortens the course of the first episode attack, prevents new lesion formation, and helps decrease any accompanying constitutional symptoms (Azwa 2009).
Adverse effects caused by Acyclovir, valacyclovir, and famciclovir are rare and include nausea, vomiting, headache, and diarrhoea (Azwa 2009). Ganciclovir (myelosuppressive), foscarnet (nephrotoxic), and cidofovir (nephrotoxic) are very toxic drugs and are not used as a first‐line treatment (Vajpayee 2000).
Imidazoquinolines such as imiquimod and resiquimod have 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 are well known for their antiviral effects, and are also potent cell growth regulators, and have immunomodulation properties (Katze 2002). Some randomised double‐blind placebo‐controlled trials have reported positive results with the use of Interferon 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 2012). Some of the products that have been trialed include Clinacanthus nutans (C. 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).
Imiquimod and its potent analogue (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 tumour necrosis factor‐alpha (TNF‐α), interferon‐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).
Interferon 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 2012).
Why it is important to do this review
HSV is a major global health problem. It is the leading cause of encephalitis and genital ulcerative disease, and a major cofactor for HIV infection (Azwa 2009). The virus can establish latency, reactivate frequently, and be horizontally and vertically transmitted during periods of unrecognised 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 first episode of primary infection 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 first episode of primary infection herpes. Other predictors of neonatal infection include viral shedding during labour, 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 labour should deliver by cesarean section to prevent neonatal HSV infection (Workowski 2010).
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. This review will help to provide clarity on which is the most effective treatment regime in terms of medication, dose, and application by demonstrating a clear picture of the current evidence that exists within the literature. This will in turn help to clarify the situation for health practitioners regarding the extent of improvement of health outcomes for particular treatments, along with their adverse events.
This review addresses first‐episode disease only. A separate Cochrane review addresses the use of oral antiviral therapy for prevention of genital herpes outbreaks in immunocompetent and nonpregnant patients (Le Cleach 2014).
Objectives
To determine the effectiveness and safety of the different existing treatments for first‐episode genital herpes on the duration of symptoms and time to recurrence.
Methods
Criteria for considering studies for this review
Types of studies
We included published and unpublished parallel randomised controlled trials (RCTs) and cluster‐RCTs. We excluded quasi‐RCTs.
Inclusions:
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drug dosing trials;
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suppressive therapy regimens (long‐term therapy) for first episodes.
Exclusions:
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studies of vaccinations;
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studies for which the objective was to look at the treatment for complications of herpes simplex virus (HSV), for example, herpes simplex encephalitis or herpes proctitis.
Types of participants
Men and women, inclusive of pregnant women, with their first episode of genital herpes (including immunocompetent and immunodeficient individuals). We included studies if they included participants with first‐episode disease and data were reported separately for this group.
Types of interventions
We looked at antivirals (both topical and systemic), interferon (both topical and systemic), immune modulators such as imiquimod (topical or analogue, e.g. resiquimod) and natural products which were compared with no treatment, placebo, other medication, or differing drug dosages. The timing of the treatments is in relation to the onset of symptoms. The interventions are:
Antivirals
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antiviral (such as acyclovir: topical and systemic) versus placebo
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antiviral (topical and systemic) versus no treatment
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antiviral (topical and systemic) versus other medication
Interferon (immune modulator)
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Interferon (topical and systemic) versus placebo
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Interferon (topical and systemic) versus no treatment
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Interferon (topical and systemic) versus other medication
Imiquimod (immune modulator)
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imiquimod (topical or analogue) versus placebo
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imiquimod (topical or analogue) versus no treatment
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imiquimod (topical or analogue) versus other medication
Natural product
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natural product versus placebo
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natural product versus no treatment
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natural product versus other medication
Antiviral + natural product
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antiviral + natural product versus placebo
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antiviral + natural product versus no treatment
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antiviral + natural product versus other medication
Dosage studies
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antiviral versus antiviral (both topical or systemic)
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interferon versus interferon (both topical or systemic)
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imiquimod versus imiquimod (both topical and analogue)
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natural product versus natural product
Types of outcome measures
Primary outcomes
1. Duration of symptoms from onset of treatment: symptoms are defined by the trial authors. When several symptoms are reported, we included the longest duration.
2. Time to first recurrence.
3. Adverse events.
Secondary outcomes
4. Duration of lesions from onset of treatment: we defined this as time to complete lesion healing.
5. Neonatal effects: as defined by the trial authors.
6. Caesarean section delivery.
Search methods for identification of studies
RH and VJ identified 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).
Electronic searches
The Trials Search Co‐ordinator (TSC) of the Cochrane Sexually Transmitted Infections Review Group (STIG) conducted a comprehensive search strategy to capture as many relevant RCTs as possible in electronic databases. We used both electronic searching in bibliographic databases and handsearching, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We downloaded and managed the search results using Endnote bibliographic software. We deleted duplicate records of the same study. See Appendix 1 for the electronic search strings.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) Ovid platform (from inception to April 2016), MEDLINE Ovid platform (from inception to April 2016), EMBASE.com (from inception to April 2016), PsycINFO EBSCOHost platform (from inception to April 2016), CINAHL EBSCOHost platform (from inception to April 2016), LILACS iAHx interface (from inception to April 2016) and AMED (from inception to April 201)
We used the Cochrane highly sensitive search strategy for identifying RCTs (sensitivity‐ and precision‐maximising version; 2008 revision) in Ovid format in MEDLINE (Higgins 2011).
Searching other resources
We attempted to identify additional relevant RCTs by using the following methods.
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Searching in Complementary and Alternative Medicines (CAM) Specialised Register (ProCite Database): inception to present.
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Searching in trial registers:
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World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP portal) (http://apps.who.int/trialsearch/): inception to present.
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ClinicalTrials.gov (http://clinicaltrials.gov/): inception to present.
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Searching in Web of Science (http://thomsonreuters.com/web‐of‐science/): inception to present.
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Searching in Proquest Dissertations and Theses (http://search.proquest.com): inception to present.
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Searching for grey literature in System for Information on Grey Literature in Europe 'OpenGrey' (http://www.opengrey.eu/): inception to present.
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Searching by contacting pharmaceutical companies producing 'antiviral agents, interferon, imiquimod, and biological agents' for 'genital herpes'.
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Handsearching conference proceedings from the following meetings:
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International Society for Sexually Transmitted Diseases Research ‐ ISSTDR (http://www.isstdr.org/): 2007, 2009, 2011, 2013, and 2015.
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British Association for Sexual Health and HIV ‐ BASHH (http://www.bashh.org/): 2004, 2006, 2007, 2009, 2013, 2014, and 2015.
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International Congress on Infectious Diseases ‐ ICID (http://www.isid.org/): 2010 and 2012, and 2014.
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International Union against Sexually Transmitted Infections ‐ IUSTI (http://www.iusti.org/): 2011 and 2012.
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International Society for Infectious Diseases ‐ ISID (http://www.isid.org/): 2011.
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International Meeting on Emerging Diseases and Surveillance ‐ IMED (http://www.isid.org/): 2007, 2009, 2011, 2013, and 2014.
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Interscience Conference on Antimicrobial Agents and Chemotherapy ‐ ICAAC (http://www.icaac.org/): 2011, 2012, 2013, 2014, and 2015.
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International Federation of Gynecology and Obstetrics ‐ FIGO (http://www.figo.org/ ): 2012 and 2015.
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Handsearching within previous systematic reviews and other relevant publications on the same topic.
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Handsearching within reference lists of all relevant RCTs identified by others methods.
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Contacting drug companies for trials.
Data collection and analysis
Selection of studies
After all searches were conducted, we checked for duplicates using EndNote. Two review authors (RH, VJ) independently assessed trials for inclusion by scanning the titles and abstracts based on the established inclusion criteria. We then compared which trials had been identified and obtained full‐text articles in order to select the final studies for possible inclusion in the review. A third review author (HR) helped resolve any disagreements regarding study inclusion. We sought additional information from the trial authors if there was insufficient information to make a decision about eligibility. We recorded the selection process in sufficient detail to complete a PRISMA flow diagram (Moher 2009), and 'Characteristics of excluded studies' table. We did not impose any language restrictions.
Data extraction and management
Three review authors (RH, DF, VJ) independently extracted data from eligible studies using a data extraction form that was developed by the review authors (Appendix 2). We resolved any differences by discussion or by consultation (or both) with a third review author (HR, VJ) to reach consensus. Extracted data included study characteristics and outcome data (see data extraction form, Appendix 2). Where there were multiple publications of one study, we used the main trial report as the reference and extracted any additional details from secondary papers. We contacted trial authors if further data was required, such as methods or results so as to confirm the suitability of the study for meta‐analysis. We routinely sought 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 individuals (RH, VJ or DF) independently assessed the quality of each of the selected studies using the Cochrane 'Risk of bias' assessment tool (Higgins 2011). We classified studies as 'low risk of bias', 'high risk of bias', or 'unclear risk of bias', reporting on the following seven domains: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other bias.
We resolved any disagreements regarding bias by consensus or discussion with a third review author (HR or VJ).
We searched for within‐trial selective reporting, such as reporting of outcomes in insufficient detail or trials failing to report obvious outcomes. We sought protocols and compared the outcomes of the protocol with the outcomes in the final study.
The conclusion of all judgements is presented in the 'Risk of bias' table, which by means of sensitivity analysis, is incorporated into the interpretation of review findings.
Measures of treatment effect
We expressed dichotomous data, such as caesarean section delivery, as a risk ratio (RR) and 95% confidence intervals (CIs). We expressed continuous data, such as duration of symptoms, as a mean difference (MD) between treatment groups, with 95% CIs. If similar outcomes were reported on different scales we planned to use the standardised mean difference (SMD). We utilised the most detailed numerical data available that provided a similar way to analyse the included studies (e.g. P values, test statistics) where data required to calculate RRs or MDs were unavailable. We used hazard ratios (HRs) to express time‐to‐event outcomes, where data permitted (duration of symptoms, duration of lesions, time to recurrence). Many studies presented data as medians as the data were heavily skewed. These medians are presented in additional tables.
Unit of analysis issues
In the case of cross‐over trials, we planned to include only the first phase data. However, we did not include any cross‐over trials in this review.
In the case of cluster‐randomised data, we planned to employ the interclass correlation coefficient (ICC) as discussed in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). If the ICC was not available then we planned to borrow a suitable factor from other trials as an estimate of relative variability. We did not, however, have any cluster‐randomised trials.
For adverse events where it was not clear if individuals had suffered from more than one adverse event, we did not generate a summary statistic. If we found studies with more than one intervention versus placebo or a third intervention, we planned to ensure double‐counting of the participants would not have occurred by splitting the comparison group between the two interventions (Higgins 2011).
Dealing with missing data
We attempted to contact the primary trial author for further information when there were missing data. However, due to the age of the included trials, we were unable to get additional information for the majority of trials. We noted characteristics of any participants that left the study; this enabled us to determine if the groups remain balanced. We looked at the method used to impute the missing data if intention‐to‐treat (ITT) analyses were supplied by the primary trial authors.
When there was sufficient detail reported to calculate the MDs but no information on the corresponding standard deviation (SD) was given, we assumed 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. We planned to explore the robustness of this decision separately by sensitivity analysis.
Assessment of heterogeneity
We carried out meta‐analyses when studies were sufficiently homogeneous in terms of their clinical and methodological characteristics. In addition to visual inspection of the forest plots, we used the I2 statistic to quantify any heterogeneity in the meta‐analysis (Higgins 2011). For I2 statistic levels up to 50%, we considered heterogeneity to be mild to moderate. For I2 statistic levels between 50% and 80%, we considered heterogeneity to be moderate and, where possible, we used random‐effects models to allow for heterogeneity. If the I2 statistic exceeded 80%, we considered heterogeneity to be substantial, and did not present pooled results; instead, we planned to report any observations as a narrative (Higgins 2011).
Assessment of reporting biases
We minimised the risk of reporting bias by undertaking a comprehensive search over multiple electronic databases and additional resources for both unpublished and published articles. We did not impose any language restrictions. We were alert for duplication of data. We were unable to construct a funnel plot to assess publication bias, as there were fewer than 10 studies in any analysis (Higgins 2011).
Data synthesis
We carried out statistical analysis using Review Manager 5 software (RevMan 2014). If the studies were sufficiently similar, we combined the data using a fixed‐effect model. If we detected moderate heterogeneity, we used a random‐effects model (Higgins 2011).
We meta‐analysed dichotomous data using the Mantel‐Haenszel method to calculate RRs; and for continuous data we used the MD, or SMD, as appropriate. We meta‐analysed time to recurrence data as HRs using the generic inverse variance method.
We planned to use the Peto odds ratio if the obtained data included rare events (as might be the case for adverse events).
We conducted separate analyses according to the route of drug administration (oral, topical, subcutaneous, intramuscular, or intravenous).
Some of the primary studies did not report combined findings for all first‐episode participants. For example, separate data were reported for male and female participants, or for first episode of primary infection and first episode of non primary infection. We stratified our analyses as required, to facilitate maximum pooling of data.
Subgroup analysis and investigation of heterogeneity
Where data were available, we conducted subgroup analyses to determine the separate evidence within the following subgroups.
-
Gender.
-
Length of treatment (five days or less, more than five days). The rationale for this subgroup was that the usual recommended length of treatment is five days with no evidence of benefit for longer periods of time (Azwa 2009).
-
Type of drug within a class
-
Duration of time between appearance of lesions and initiation of treatment (five days or less, more than five days). The rationale for this subgroup was that it is usually recommended that treatment be initiated as soon as possible once a clinical diagnosis has been made (Azwa 2009).
-
Immunodeficiency e.g. HIV.
-
First episode of primary infection versus first episode of non‐primary infection.
If we detected substantial statistical heterogeneity, we explored clinical and methodological differences between the studies that might account for this. We took any statistical heterogeneity into account when interpreting the results, especially if there was any variation in the direction of effect.
Sensitivity analysis
We conducted sensitivity analyses for the primary outcomes to determine whether the conclusions to arbitrary decisions made regarding the eligibility and analysis were robust. These analyses included consideration of whether the review conclusions would have differed if:
-
eligibility were restricted to studies without high risk of bias;
-
a random‐effects model had been adopted; and
-
imputed data were included by ITT.
Overall quality of the evidence: 'Summary of findings' table
We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of a body of evidence as it relates to the studies which contribute data to the meta‐analyses for the prespecified outcomes. We used methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) using GRADEproGDT software (GRADEproGDT 2015).We justified all decisions to down‐ or up‐grade the quality of studies using footnotes, and we made comments to aid the reader's understanding of the review where necessary.We then imported these tables into Review Manager 5 (RevMan 2014).
We included the following outcomes in the 'Summary of findings' tables: Duration of symptoms from onset of treatment, Adverse events, Duration of lesions from onset of treatment and Time to recurrence.
Results
Description of studies
See Characteristics of included studies and Characteristics of excluded studies tables.
Results of the search
We conducted the searches in April 2016. The searches were broad and included antiviral medications. After de‐duplication we had 3349 studies. After extensive screening and assessment, we identified 26 studies eligible for inclusion in this review (see Figure 1). Two studies are awaiting classification (see Characteristics of studies awaiting classification table). We have not identified any ongoing studies in this area.
Study flow diagram.
Included studies
Design and setting of the included studies
We included 26 studies (documented by 42 publications) which analysed 2084 participants. Most of the studies were conducted in the US (Adams 1976; Bryson 1983; Corey 1982a; Corey 1982b; Corey 1983; Levin 1989; Mertz 1984; Pazin 1987; Peacock 1988; Silvestri 1982; Wald 1994), and the UK (Csonka 1984; Fiddian 1983; Kinghorn 1986a; Kinghorn 1986b; Mindel 1982; Mindel 1986; Mindel 1987), with additional studies in New Zealand (Batcheler 1986), Canada (Mendelson 1986), China (Lai 2000), Sweden (Nilsen 1982), Mexico (Zavala 1988), and Japan (Niimura 1996); one multicentre study included participants from the US, UK, and Australia (Fife 1997). The largest study included 643 participants (Fife 1997), and the smallest study included 11 (Csonka 1984). Overall, the studies were not recent, with the oldest study published in 1976 (Adams 1976), and the newest study published in 2000 (Lai 2000).
Sixteen studies stated that they received commercial funding (Corey 1982a; Corey 1982b; Corey 1983; Fiddian 1983; Fife 1997; Kinghorn 1986a; Kinghorn 1986b; Levin 1989; Mendelson 1986; Mertz 1984; Mindel 1982; Mindel 1986; Mindel 1987; Nilsen 1982; Peacock 1988; Wald 1994). Four studies apparently received no commercial funding (Adams 1976; Csonka 1984; Pazin 1987; Silvestri 1982). Six studies did not mention their funding source (Altomare 1985; Batcheler 1986; Bryson 1983; Lai 2000; Niimura 1996; Zavala 1988).
Participants in the included studies
Three studies included only women (Batcheler 1986; Mindel 1986; Pazin 1987), and the remaining 23 studies included men and women.
The duration of symptoms required for participant eligibility differed between studies. These criteria are presented in Table 1.
| Time | Less than 24 hrs | Less than 2 days | Less than 3 days | Less than 4 days | Less than 5 days | Less than 6 days | Less than 7 days | Less than 8 days | Did not state |
| Studies of oral antivirals | Niimura 1996 included from day 2, 3, 4, 5, 6, 7 or more, but subgrouped data of results was not available | ||||||||
| Studies of topical antivirals | |||||||||
| Studies of intravenous antivirals | Severe GH | ||||||||
| Studies of topical interferon | |||||||||
| Studies of IM/SC interferon | Pazin 1987 (IM) | Levin 1989 (IM) | Mendelson 1986 (SC) | ||||||
| Studies of adenosine arabinoside | |||||||||
| Studies of topical carbenoxolone versus topical cicloxone | |||||||||
| Studies of ribavirin | |||||||||
| Studies of topical idoxuridine versus dimethyl sulfoxide | |||||||||
| Studies of oral inosine pranobex | |||||||||
| Studies of topical tromantadine |
GH: genital herpes
IM: intramuscular
SC: subcutaneous
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Adams 1976 and Altomare 1985 included participants with onset of symptoms of less than two days.
-
Fife 1997, Pazin 1987, and Zavala 1988 included participants with onset of symptoms of less than three days.
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Levin 1989 included participants with onset of symptoms of less than four days.
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Csonka 1984, Fiddian 1983, Lai 2000, Mendelson 1986, Mindel 1986, Mindel 1987, Nilsen 1982, and Wald 1994 included participants with onset of symptoms of less than five days.
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Bryson 1983, Corey 1982a, Corey 1982b, Kinghorn 1986a, Kinghorn 1986b, Mertz 1984, and Mindel 1982 included participants with onset of symptoms of less than six days.
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Corey 1983 and Peacock 1988 included participants with onset of symptoms of less than seven days.
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Silvestri 1982 included participants with onset of symptoms of less than eight days.
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Batcheler 1986 did not state how many days of symptoms their participants had before treatment
-
Niimura 1996 included from day 2, 3, 4, 5, 6, 7 or more, but subgrouped data of results was not available.
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Bryson 1983, Corey 1982a, and Corey 1982b subgrouped by antibody status (first episode of primary infection and first episode of non‐primary infection).
-
It is important to note that Mindel 1982 only included participants with severe first episode genital herpes.
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Adams 1976, Bryson 1983, Fiddian 1983, Kinghorn 1986b, and Nilsen 1982 looked at both males and females and did not provide results subgrouped by antibody status.
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The remaining studies did not report results by either gender or antibody status.
Interventions in the included studies
Antiviral versus placebo
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Oral acyclovir versus placebo (Bryson 1983; Kinghorn 1986b; Mertz 1984; Nilsen 1982). Some participants in both arms of Kinghorn 1986b also received co‐trimoxazole. The oral dose of acyclovir was 1 gm daily in most studies.
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Oral ribavirin versus placebo (Zavala 1988).
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Intravenous acyclovir versus placebo (Corey 1983; Mindel 1982; Peacock 1988).
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Topical acyclovir versus placebo (Corey 1982a; Corey 1982b; Fiddian 1983; Kinghorn 1986a).
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Topical cycloxolone versus placebo (Csonka 1984).
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Topical carbenoxolone versus placebo (Csonka 1984).
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Topical tromantadine versus placebo (Altomare 1985).
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Topical adenosine arabinoside versus placebo (Adams 1976).
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Topical idoxuridine in dimethyl sulfoxide versus dimethyl sulfoxide alone or saline (Silvestri 1982).
Antiviral versus other antiviral
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Topical 2% carbenoxolone cream versus 2% cicloxolone cream (Csonka 1984).
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Oral acyclovir versus inosine prabonex (with or without oral acyclovir in control arm) (Mindel 1987).
Antiviral regimen comparisons
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Long versus short course oral acyclovir (Mindel 1986).
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High (4 gm/day) versus standard dose (1 gm/day) oral acyclovir (Wald 1994).
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Famciclovir at doses, 125 mg, 250 mg and 500 mg (Niimura 1996).
Antiviral versus interferon
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Topical acyclovir versus intramuscular interferon (Levin 1989).
Interferon versus placebo
-
Intramuscular interferon versus placebo (Pazin 1987).
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Topical interferon versus placebo (Batcheler 1986).
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Subcutaneous interferon versus placebo (Mendelson 1986).
We did not find any studies of imiquimod, antiviral + natural product, or natural products that met the inclusion criteria.
Outcomes in the included studies
Primary outcomes
1. Duration of symptoms from onset of treatment
Most studies reported duration of symptoms, but many either reported only median values (Corey 1983; Fiddian 1983; Mertz 1984; Mindel 1982; Mindel 1986; Mindel 1987; Nilsen 1982; Peacock 1988; Wald 1994), or reported dichotomous data (e.g. number healed by six days) (Csonka 1984; Niimura 1996). We could not meta‐analyse these data.
Other studies reported means, but some failed to report standard deviations (SDs) or standard errors (SEs) (Adams 1976; Bryson 1983; Fife 1997; Mendelson 1986; Silvestri 1982), and so we had to impute the SD or report the data in additional tables. Only one study reported hazard ratios for this outcome (Fife 1997).
2. Time to first recurrence
Nine studies reported time to first recurrence (Bryson 1983; Corey 1982a; Corey 1982b; Mendelson 1986; Mertz 1984; Mindel 1987; Pazin 1987; Peacock 1988; Wald 1994), but none reported hazard ratios. Six of these studies reported median time to first recurrence (Bryson 1983; Corey 1982a; Corey 1982b; Mertz 1984; Mindel 1987; Wald 1994). Mean times were given by Peacock 1988, but the remaining two studies just declared there were no differences in time to first recurrence between the two groups and did not provide numerical data (Mendelson 1986; Pazin 1987). The proportion of participants who were adequately followed up varied across studies, but was around 80% in those that declared numbers of patients followed up (Corey 1982a; Corey 1982b; Wald 1994); however, the majority of studies did not declare the number of patients adequately followed up.
3. Adverse events
Nearly all studies reported adverse events. Many failed to report comparative data, but this was often because (as they reported in the text) there were no adverse events reported in either arm. Although, one study reported other outcomes separately for first‐episode participants, for this particular outcome separate data were not provided (Altomare 1985) .
Secondary outcomes
1. Duration of lesions from onset of treatment
Most studies reported duration of lesions, although as noted above, many reported data unsuitable for meta‐analysis.
2. Neonatal effects
No studies reported this outcome.
3. Caesarean section delivery
No studies reported this outcome.
Excluded studies
We excluded 106 studies; the reasons are reported in the Characteristics of excluded studies table. Common reasons for exclusion are that the studies were not looking at first‐episode genital herpes, or the study design did not appear to be randomised.
We excluded seven studies due to suspected fraudulent publication (Syed 1995a; Syed 1995b; Syed 1995c; Syed 1997a; Syed 1997b; Syed 1998a; Syed 1998b). When we attempted to gain more information from T. A. Syed regarding his studies, we discovered that he is currently serving a prison sentence for 64 counts including practicing medicine without a license, grand theft, perjury, and forgery. It appears he was never employed at universities he claimed the research was from. Other authors listed on his studies were unable to be identified. For these reasons we have chosen not to include these studies despite the fulfilment of the inclusion criteria of this review. Our Review Group has contacted all relevant journals where his studies were published to highlight this information.
Risk of bias in included studies
We rated most of the studies at unclear risk of bias in most domains. We attempted to contact all trial authors for more information about randomisation and blinding procedures. For a graphical representation of the results of the risk of bias assessment see Figure 2 and Figure 3 .
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Generation of random sequence
Only two studies (8%) reported acceptable methods of random sequence generation (Altomare 1985; Levin 1989). We judged one study (4%) to be at high risk of bias (Niimura 1996), and the remaining studies (88%) at unclear risk of bias in this domain.
Allocation concealment
Only one study (4%) reported acceptable methods of allocation concealment (Silvestri 1982). We judged one study (4%) to be at high risk of bias (Niimura 1996), and the remaining studies (92%) at unclear risk of bias in this domain.
Blinding
Twelve studies (46%) described acceptable methods of blinding of participants and study personnel (Adams 1976; Altomare 1985; Corey 1982a; Corey 1982b; Corey 1983; Fife 1997; Kinghorn 1986a; Kinghorn 1986b; Mendelson 1986; Mindel 1982; Pazin 1987; Silvestri 1982). We judged two studies (8%) at high risk of bias in this domain (Lai 2000; Niimura 1996), and the remaining studies (46%) at unclear risk; many of these studies mentioned that they were double‐blinded but failed to provide further details.
Only three studies (12%) described acceptable methods of blinding of outcome assessment (Fife 1997; Mendelson 1986; Pazin 1987). We judged two studies (8%) at high risk of bias in this domain (Lai 2000; Niimura 1996), and the remaining studies (80%) at unclear risk; many of these studies mentioned that they were double‐blinded but failed to provide further details.
Incomplete outcome data
Fifteen studies (58%) analysed all or most randomised participants for at least two of our primary outcomes and we judged these at low risk of attrition bias (Batcheler 1986; Corey 1983; Fiddian 1983; Fife 1997; Kinghorn 1986a; Kinghorn 1986b; Lai 2000; Niimura 1996; Mendelson 1986; Mindel 1982; Mindel 1986; Nilsen 1982; Pazin 1987; Peacock 1988; Zavala 1988). We judged seven studies (27%) at high risk of bias, in most cases because they failed to analyse a high proportion (< 20%) of randomised participants (Adams 1976; Bryson 1983; Corey 1982b; Csonka 1984; Levin 1989; Silvestri 1982; Wald 1994). We judged the remaining studies (15%) at unclear risk of bias in this domain (Altomare 1985; Corey 1982a; Mertz 1984; Mindel 1987).
In the studies reporting time to first recurrence, the proportion of participants who were adequately followed‐up varied across the studies see Description of studies.
Selective reporting
We judged one study (4%) at high risk of bias in this domain as it was unclear why outcomes were not reported for one group of randomised participants (Bryson 1983); we judged all other studies (96%) at unclear risk of selective reporting, as study protocols were not available and there was no statement in the publication stating that all measured outcomes had been reported. Therefore it was unclear whether all prespecified outcomes were reported.
Other potential sources of bias
We judged two studies (8%) at high risk of bias for this domain. One study was due to baseline imbalance (Wald 1994), and one study was due to the data and analyses being undertaken by the funder (Niimura 1996). We rated three studies (12%) at unclear risk of other bias, for example, due to changes in the intervention during the study, or possible co‐intervention (Adams 1976; Altomare 1985; Kinghorn 1986a). We judged all other studies (80%) at low risk of bias in this domain, as no potential source of other bias was identified.
Effects of interventions
See: Summary of findings for the main comparison Oral acyclovir versus placebo for men and women with their first episode of genital herpes; Summary of findings 2 Topical acyclovir versus placebo for men and women with their first episode of genital herpes
Antiviral versus placebo
1.1 Oral acyclovir versus placebo
Four studies with 227 participants were included in this comparison (Bryson 1983; Kinghorn 1986b; Mertz 1984; Nilsen 1982).
Primary outcomes
1.1.1 Duration of symptoms from onset of treatment
When two studies were pooled, symptom duration was significantly shorter in the acyclovir group (Bryson 1983; Kinghorn 1986b) (mean difference (MD) ‐3.22 days, 95% confidence interval (CI) ‐5.91 to ‐0.54; two RCTs, 82 participants, I2 statistic = 52%) (Analysis 1.1; Figure 4). There was moderate heterogeneity for this outcome for which there was no clear explanation. Use of a random‐effects model did not affect the significance of the findings.
Forest plot of comparison: 1 Oral acyclovir versus placebo, outcome: 1.1 Duration of symptoms from onset of treatment.
Two studies reported medians only (Mertz 1984; Nilsen 1982). One found that the duration of symptoms was significantly shorter in the acyclovir group than in the placebo group among participants (n = 101) with first episode of primary infection (P < 0.5) (Mertz 1984). There was no significant difference between the groups in participants with first episode of non‐primary infection (n = 13). The other study found that the duration of symptoms was significantly shorter in the acyclovir group (Nilsen 1982) (n = 31, P < 0.05). See Table 2.
| Acyclovir | Placebo | ||||||
| Outcome | Study | Median (days) | No. participants | Median (days) | No. participants | P value | Favours intervention |
| Duration of symptoms from onset of treatment | 4 | 17 | 9 | 14 | < 0.05 | ✓ | |
| Duration of symptoms from onset of treatment by antibody status | |||||||
| Primary | 5 | 52 | 7 | 49 | < 0.05 | ✓ | |
| Non‐primary | 2 | 9 | 4 | 15 | > 0.1 | ✕ | |
| Duration of symptoms from onset of treatment by gender | |||||||
| Females | 5 | 10 | 8 | 7 | NS | ✕ | |
| Males | 3 | 7 | 9 | 7 | < 0.05 | ✓ | |
| Duration of lesions from onset of treatment | 6 | 17 | 11 | 14 | < 0.01 | ✓ | |
| Duration of lesions from onset of treatment by antibody status | |||||||
| Primary | 12 | 61 | 16 | 58 | < 0.01 | ✓ | |
| Non‐primary | 9 | 12 | 13 | 19 | > 0.1 | ✕ | |
| Duration of lesions from onset of treatment by gender | |||||||
| Females | 4.5 | 10 | 6 | 7 | < 0.05 | ✓ | |
| Males | 7 | 7 | 11 | 7 | 0.06 | ✕ | |
| Time to recurrence | ✕ | ||||||
| Participants with 4‐9 month follow‐up | 94 | Unclear | 101 | Unclear | NS | ✕ | |
| HSV‐2 group | 71 | Unclear | 108 | Unclear | NS | ✕ | |
Mertz 1984: Duration of symptoms refers specifically to pain
HSV‐2: herpes simplex virus type 2
NS: not statistically significant
✓: favours intervention
✕: does not favour intervention
Due to the moderate heterogeneity (52%), we used a random‐effects model for this analysis. The evidence for this outcome was of low quality. We downgraded the quality of evidence due to the risk of bias of associated studies and because this finding is based on very low sample numbers (summary of findings Table for the main comparison).
Subgroup analysis by gender
When we pooled Bryson 1983 and Kinghorn 1986b, and considered men and women separately, for males there is a difference in the duration of symptoms after treatment with acyclovir (MD ‐2.10 days, 95% CI ‐4.28 to 0.09; 2 RCTs, 33 men, I2 statistic = 0%). In females there was high heterogeneity between the two trials included in the meta analysis and it did not show any statistical difference between those taking acyclovir and those taking placebo (MD ‐4.13 days, 95% CI ‐10.15 to 1.89; 2 RCTs, 49 women, I2 statistic = 71%). However overall, we did not observe any statistical difference between men and women (Test for subgroup differences: Chi2 = 0.39, P = 0.53) for the duration of symptoms from onset of treatment.
When median duration of symptoms was subgrouped by gender in Nilsen 1982, findings remained statistically significant among males (n = 14, P < 0.05) but not among females (n = 17). See Table 2.
These subgroup findings should be regarded with caution and are as a result of low to very low quality evidence due to the small sample sizes, heterogeneity in one of the female subgroups, and inconsistency in the findings.
Subgroup analysis by antibody status (first episode of primary infection or first episode of non‐primary infection)
No data were available to allow subgrouping by antibody status. However, one study that had reported medians did report these two groups separately (Mertz 1984). This study showed a significant reduction in duration of symptoms for those undergoing their first episode of primary infection as indicated by their antibody status. In those whose antibody status indicated a previous infection, there was no observed reduction (Table 2).
1.1.2 Time to first recurrence
No studies reported hazard ratios. Two studies reported no significant difference between the two groups in the median days to recurrence among participants with adequate follow‐up (Bryson 1983; Mertz 1984). See Table 2.
1.1.3 Adverse events
Very few adverse events were reported (Analysis 1.2). Reported events included headache, nausea, heartburn, fatigue, and sore throat. Two studies reported that no adverse events occurred in either group (Bryson 1983; Kinghorn 1986b). This evidence was of low quality as there was a high level of heterogeneity and the risk of bias of the included studies was unclear for most of the domains (summary of findings Table for the main comparison).
Secondary outcomes
1.1.4 Duration of lesions from onset of treatment
When we pooled two studies (Bryson 1983; Kinghorn 1986b), lesion duration was significantly shorter in the acyclovir group (MD ‐3.51 days, 95% CI ‐6.19 to ‐0.82; two RCTs, 86 participants, I2 statistic = 0%, Analysis 1.3).
Two studies reported medians only (Mertz 1984; Nilsen 1982). One study found that the duration of lesions was significantly shorter in the acyclovir group than in the placebo group among participants (n = 119) with first episode of primary infection (P < 0.01) (Mertz 1984). There was no significant difference between the groups for participants with first episode of non‐primary infections (n = 31). The other study found that the duration of symptoms was significantly shorter in the acyclovir group (n = 31, P < 0.01) (Nilsen 1982). See Table 2. These findings should be regarded with caution due to the low quality evidence shown here. This is a result of small sample sizes and high levels of bias associated with the included studies (summary of findings Table for the main comparison).
Subgroup analysis by gender
When we pooled Bryson 1983 and Kinghorn 1986b, and considered men and women separately, for males there is a difference in the duration of lesions after treatment with acyclovir (MD ‐5.74 days, 95% CI ‐9.80 to ‐1.69; 35 men, I2 statistic = 0%). In females the meta analysis did not show any statistical difference between those taking acyclovir and those taking placebo for duration of lesions (MD ‐1.74 days, 95% CI ‐5.34 to 1.85; 51 women, I2 statistic = 0%). However overall, we did not observe any statistical difference between men and women (Test for subgroup differences: Chi2 = 2.10, P = 0.15) for the duration of lesions from onset of treatment.
However, when findings were subgrouped by gender in Nilsen 1982 (data supplied as medians), among males there was no difference between the acyclovir and placebo groups (n = 14, P = 0.06), but among females there was a significantly shorter lesion duration in the acyclovir group (n = 17, P < 0.05). See Table 2.
These subgroup findings should be regarded with caution due to the low grade of the evidence as a result of small sample sizes and inconsistency in the findings.
Subgroup analysis by antibody status (first episode of primary infection or first episode of primary non‐primary infection)
No data were available to allow subgrouping by antibody status. However, one study that had reported medians did report these two groups separately (Mertz 1984). This study showed a significant reduction in duration of lesions for those undergoing their first episode of primary infection, as indicated by their antibody status. In those whose antibody status indicated they were having a first episode of non primary infection, there was no observed reduction (Table 2).
No other secondary outcomes were reported.
1.2 Oral ribavirin versus placebo
One study made this comparison (Zavala 1988). The study was in Spanish, and the data were provided by a translator.
Primary outcomes
1.2.1 Duration of symptoms from onset of treatment
The mean duration of symptoms from the onset of treatment for the treatment group of 30 patients was 5.7 days, and for the placebo group of 30 patients was 15.5 days. No standard errors were provided, so we have reported the available data in Table 3.
| Oral ribavirin | Placebo | |||||
| Outcome | Study | Mean (days) | No. participants | Mean (days) | No. participants | Favours intervention |
| Duration of symptoms from the onset of treatment | 5.7 | 30 | 15.5 | 30 | ✓ | |
✓: favours intervention
Our other primary outcomes were not reported.
Secondary outcomes
Our other secondary outcomes were not reported.
1.3 Intravenous acyclovir versus placebo
Three studies compared this outcome (Corey 1983; Mindel 1982; Peacock 1988). Nearly all outcomes were reported as median values. Peacock 1988 reported mean values for time to first recurrence but did not report standard deviations. Mindel 1982 only included patients with severe first episode of primary infection genital herpes that warranted hospital admission.
Primary outcomes
1.3.1 Duration of symptoms from onset of treatment
Two studies reported a shorter median duration of symptoms in the acyclovir group (Mindel 1982: n = 30, P < 0.05; Peacock 1988: n = 82, P = 0.019). The third study reported no significant difference between the groups (Corey 1983: n = 31, P = 0.17). See Table 4.
| Acyclovir | Placebo | ||||||
| Outcome | Study | Median (days) | No. participants | Median (days) | No. participants | P value | Favours intervention |
| Duration of symptoms from onset of treatment ‐ all | |||||||
| 6.5 | 15 | 8.5 | 15 | < 0.05 | ✓ | ||
| 4.3 | 42 | 4.8 | 40 | 0.019 | ✓ | ||
| 4 | 15 | 7 | 16 | 0.17 | ✕ | ||
| Duration of symptoms from onset of treatment by antibody status | |||||||
| Primary | 6.3 | 12 | 8.8 | 8 | NS | ✕ | |
| 4.2 | 10.6 | 0.009 | ✓ | ||||
| 3 | 14 | 7 | 13 | 0.17 | ✕ | ||
| Non‐primary | 4.4 | 3.8 | 0.55 | ✓ | |||
| Duration of symptoms from onset of treatment by gender | |||||||
| Female | 6.8 | 12 | 7.3 | 12 | NS | ✕ | |
| Duration of lesions from onset of treatment | |||||||
| 7.0 | 15 | 14.0 | 15 | < 0.001 | ✓ | ||
| 8.4 | 42 | 11.5 | 40 | 0.02 | ✓ | ||
| 9 | 15 | 21 | 16 | 0.002 | ✓ | ||
| Duration of lesions from onset of treatment by antibody status | |||||||
| Primary | 9.0 | 12 | 15.0 | 8 | < 0.05 | ✓ | |
| 8.3 | 22 | 14.2 | 22 | 0.015 | ✓ | ||
| 9 | 14 | 21 | 13 | 0.007 | ✓ | ||
| Non‐primary | 8.4 | 20 | 8.2 | 18 | NS | ✕ | |
| Duration of lesions from onset of treatment by gender | |||||||
| Female | 7.0 | 12 | 12.5 | 12 | < 0.05 | ✓ | |
| Time to first recurrence by HSV type | |||||||
| HSV‐1 | 279 | 7 | 184 | 7 | 0.4 | ✕ | |
| HSV‐2 | 64 | 23 | 74 | 23 | 0.4 | ✕ |
Duration of symptoms: Peacock 1988 refers specifically to pain; Corey 1983 refers to constitutional symptoms
HSV‐1: herpes simplex virus type 1
HSV‐2: herpes simplex virus type 2
NS: not statistically significant
✓: favours intervention
✕: does not favour intervention
Subgroup analysis by gender
One study reported data for females only (n = 24) and found no significant difference between the acyclovir and the placebo group (Mindel 1982; Table 4).
Subgroup analysis by antibody status (first episode of primary infection or first episode of non‐primary infection)
One study reported data separated into first episode of primary infection and first episode of non‐primary infection based on antibody status (Peacock 1988). Acyclovir reduced the symptoms in the first episode of primary infection group only, and no difference was seen in the first episode of non‐primary infection group (Table 4).
1.3.2 Time to first recurrence
One study reported mean time to first recurrence (Peacock 1988). No measurement of error was provided for this information but this study observed a mean time to first recurrence in the acyclovir group of 89 days and 93 days in the placebo group.
Corey 1983 and Mindel 1982 combined their data in a follow‐up publication, subgrouped into participants with HSV‐1 infection (n = 14) and those with HSV‐2 infection (n = 46). They reported no significant difference (P = 0.04) between the groups in median time to first recurrence. See Table 4.
1.3.3 Adverse events
None of the three studies reported a difference between the groups in the rate of adverse events, though sample sizes were small for individual outcomes (Analysis 2.1). Reported events included mild phlebitis or pain at the infusion site, rashes, abnormal liver function tests, nausea, vomiting, and dizziness. Some of these effects were attributed to co‐administration of codeine.
Secondary outcomes
1.3.4 Duration of lesions from onset of treatment
All three studies reported a shorter median duration of lesions in the acyclovir group (Mindel 1982: n = 30, P < 0.001; Peacock 1988: n = 82, P = 0.02; Corey 1983: n = 31, P = 0.002). See Table 4.
Subgrouped by gender
One study reported data for females only (n = 24) and found a significantly shorter median duration of lesions in the acyclovir group (P < 0.05) (Mindel 1982; Table 4).
Subgroup analysis by antibody status (first episode of primary infection or first episode of non‐primary infection)
One study reported data separated into first episode of primary infection and first episode of non‐primary infection based on antibody status. Acyclovir reduced the duration of lesions in the first episode of primary infection group (P < 0.015) but not in the first episode of non‐primary infection group (Peacock 1988; Table 4).
No other secondary outcomes were reported.
1.4 Topical acyclovir versus placebo
Four studies made this comparison (Corey 1982a; Corey 1982b; Fiddian 1983; Kinghorn 1986a). It should be noted that in the Kinghorn 1986a study all participants received oral acyclovir in addition to the topical acyclovir or placebo.
Primary outcomes
1.4.1 Duration of symptoms from onset of treatment
When three studies were pooled, there was no difference between the groups in symptom duration (Corey 1982a; Corey 1982b; Kinghorn 1986a) (MD ‐0.61 days, 95% CI ‐2.16 to 0.95; 3 RCTs, 195 participants, I2 statistic = 56%; Analysis 3.1; Figure 5). As there was moderate heterogeneity for this analysis for which there was no obvious explanation, we used a random‐effects model.
Forest plot of comparison: 4 Topical acyclovir versus placebo, outcome: 4.1 Duration of symptoms from onset of treatment.
One study reported medians only (Fiddian 1983). The duration of symptoms was significantly shorter in the acyclovir group than in the placebo group (n = 101, P = 0.01; see Table 5). We graded this evidence as low quality due to the high risk of bias associated with the included studies and the reasonably high heterogeneity (summary of findings Table 2).
| Topical acyclovir | Topical placebo | ||||||
| Outcome | Study | Median (days) | No. participants | Median (days) | No. participants | P value | Favours intervention |
| Duration of symptoms from onset of treatment ‐ all | |||||||
| 5 | 54 | 8 | 47 | 0.01 | ✓ | ||
| Duration of symptoms from onset of treatment by gender | |||||||
| Females | 6 | 35 | 9 | 31 | < 0.05 | ✓ | |
| Males | 3.5 | 19 | 6 | 16 | > 0.1 | ✕ | |
| Duration of lesions from onset of treatment ‐ all | |||||||
| 8 | 54 | 13 | 47 | 0.01 | ✓ | ||
| Duration of lesions from onset of treatment by gender | |||||||
| Females | 8 | 35 | 13 | 31 | < 0.001 | ✓ | |
| Males | 8 | 19 | 11 | 16 | < 0.01 | ✓ | |
| Time to first recurrence | |||||||
| 116 | 116 | ✕ | |||||
| 79 | 79 | ✕ | |||||
✓: favours intervention
✕: does not favour intervention
Subgrouped analysis gender
Kinghorn 1986a analysed females separately and found no difference between the acyclovir and placebo groups (MD 0.50 days, 95% CI ‐1.35 to 2.35; 35 women). (See Analysis 3.2; Figure 6). In the study that reported median values only, there was no statistically significant difference between the groups among men (Fiddian 1983, n = 35), but symptom duration was significantly shorter in the acyclovir group among women (Fiddian 1983, 64 women, P < 0.05). See Table 5.
Forest plot of comparison: 4 Topical acyclovir versus placebo, outcome: 4.2 Duration of symptoms from onset of treatment by gender.
1.4.2 Time to first recurrence
Corey 1982b reported no difference in the median time to recurrence among 58 participants (84% of total) who had adequate follow‐up; the median was 79 days in both groups, but it was unclear how many in each group were followed up. No further information about time to recurrence was available.
Corey 1982a reported no difference in the median time to recurrence among 25 participants (78% of total) with HSV‐2 infection who had adequate follow up; the median was 116 days in both groups, but it was unclear how many in each group were followed up. No further information about time to recurrence was available.
Kinghorn 1986a also failed to show a difference between those on topical acyclovir and those receiving placebo in those who had had a recurrence in the six months following treatment (risk ratio (RR) 1.2, 95% CI 0.6 to 2.3; P = 0.6). Of the 46 patients who completed follow‐up, 11 (50%) out of 22 who received acyclovir compared with 10 (42%) out of 24 treated with placebo had a recurrence within six months of their first episode.
1.4.3 Adverse events
None of the studies reported a difference between the groups in the rate of adverse events, though sample sizes were small for individual outcomes (Analysis 3.5, Figure 7). Reported events included pain with topical application, rashes, and itching. This evidence is of moderate quality with the only concern being in regard to the risk of bias associated with the included studies (summary of findings Table 2).
Forest plot of comparison: 4 Topical acyclovir versus placebo, outcome: 4.3 Adverse events.
Secondary outcomes
1.4.4 Duration of lesions from onset of treatment by antibody status
When Corey 1982a, Corey 1982b, and Kinghorn 1986a were pooled there was no difference between the groups in lesion duration (MD ‐0.86 days, 95% CI ‐2.15 to 0.42; 195 participants, I2 statistic = 51%, Analysis 3.3; Figure 8). As there was moderate heterogeneity for this outcome for which there was no clear explanation we used a random‐effects model.
Forest plot of comparison: 4 Topical acyclovir versus placebo, outcome: 4.4 Duration of lesions from onset of treatment by antibody status.
The study which reported medians only found that the duration of symptoms was significantly shorter in the acyclovir group than in the placebo group (Fiddian 1983, n = 101, P = 0.01; see Table 5). As a result of the substantial heterogeneity and the risk of bias of included studies we have judged this evidence as low quality (summary of findings Table 2).
Subgroup analysis by gender
Kinghorn 1986a analysed females as a separate subgroup and found no difference between the acyclovir and placebo groups (MD ‐0.10 days, 95% CI 1.78 to 1.58; 35 women). See Analysis 3.4.
The study which reported medians only found a significantly shorter lesion duration in the acyclovir group among men (Fiddian 1983) (n = 35, P < 0.01) and also among women (64 women, P < 0.001). See Table 5.
No other secondary outcomes were reported.
1.5 Topical 2% cicloxolone cream versus placebo
One small three‐arm study made this comparison (Csonka 1984). It included a total of only 19 participants with first‐episode disease, of whom only 11 (57%) were included in the analysis.
Primary outcomes
1.5.1 Duration of symptoms from onset of treatment
There was no difference between the groups in the duration of symptoms at five or seven days. However, no conclusions can be drawn, as analysis included only five participants in the cicloxolone group and four in the placebo group. See Analysis 4.1 and Analysis 4.2.
1.5.2 Time to first recurrence
This outcome was not reported.
5.3 Adverse events
No comparative data were reported among participants with first‐episode disease. Among all participants with either first‐episode or recurrent genital herpes, one in each group had slight irritation after application of the cream. The reaction was not sufficiently severe to discontinue treatment.
Secondary outcomes
1.5.4 Duration of lesions from onset of treatment
There was no difference between the groups in the duration of lesions at five or seven days. However, no conclusions can be drawn as analysis included only five participants in the cicloxolone group and four in the placebo group. See Analysis 4.3 and Analysis 4.4.
No other secondary outcomes were reported.
1.6 Topical carbenoxolone sodium cream versus placebo
One small three‐arm study made this comparison (Csonka 1984). It included a total of only 19 participants with first‐episode disease, of whom only 11 (57%) were included in analysis.
Primary outcomes
1.6.1 Duration of symptoms from onset of treatment
There was no difference between the groups in the duration of symptoms at five or seven days. However, no conclusions can be drawn as there were only two participants in the carbenoxolone group and four in the placebo group. See Analysis 5.1 and Analysis 5.2.
1.6.2 Time to first recurrence
This outcome was not reported.
1.6.3 Adverse events
No comparative data were reported among participants with first‐episode disease. Among all participants with either first‐episode or recurrent genital herpes, one in each group had slight irritation after application of the cream; the reaction was not severe enough to discontinue treatment.
Secondary outcomes
1.6.4 Duration of lesions from onset of treatment
There was no difference between the groups in the duration of lesions at five or seven days. However, no conclusions can be drawn as there were only two participants in the carbenoxolone group and four in the placebo group. See Analysis 5.3 and Analysis 5.4.
Our other secondary outcomes were not reported.
1.7 Topical adenosine arabinoside versus placebo or no treatment
One study made this comparison (Adams 1976). Partway through this study the intervention was changed from adenosine arabinoside topical ointment to gel that was applied topically and intravaginally. Due to poor reporting of study methods, we could not extract data for analysis. The study authors concluded that the intervention was ineffective in both men and women. Available data are presented in Table 6.
| Adenine arabinoside | Placebo | No treatment | Untreated (no contraception) | |||||||
| Study | Mean (days) | No. participants | Mean (days) | No. participants | Mean (days) | No. participants | Mean (days) | No. participants | Favours intervention | |
| Duration of symptoms from onset of treatment by gender | ||||||||||
| Females | 10.4 | 8 | 6.8 | 10 | 8.8 | 4 | 7.0 | 5 | ✕ | |
| Males | 7.8 | 9 | 6.3 | 9 | 6.5 | 4 | ✕ | |||
| Duration of lesions from onset of treatment by gender | ||||||||||
| Females | 16.1 | 8 | 11 | 10 | 10 | 4 | 13.6 | 5 | ✕ | |
| Males | 11.9 | 9 | 13.1 | 9 | 11.5 | 4 | ✕ | |||
✕: does not favour intervention
1.8 Topical 30% idoxuridine in dimethyl sulfoxide versus dimethyl sulfoxide alone or saline
One study made this comparison but data were not in a format that we could use in a meta‐analysis (Silvestri 1982).
Primary outcomes
1.8.1 Duration of symptoms from onset of treatment
There was no difference between the groups in the mean duration of symptoms. See Table 7.
| Topical 30% idoxuridine | Control* | |||||
| Outcome | Study | Mean (days) | No. participants | Mean (days) | No. participants | Favours intervention |
| Duration of symptoms from the onset of treatment ‐ all | ||||||
| 10.7 | 9 | 12.9 | 23 | ✕ | ||
| Duration of lesions from the onset of treatment ‐ all | ||||||
| 19.6 | 9 | 17.9 | 23 | ✕ | ||
| Adverse effects | Events | No. Participants | Events | No. participants | ||
| Burning on application | 5 | 9 | 6 | 23 | ✕ | |
*Control: either dimethyl sulfoxide alone or saline alone
✕: does not favour intervention
Time to first recurrence
This outcome was not reported.
1.8.2 Adverse events
There was no difference between the groups in the rate of adverse events. Burning on application was reported in both study groups. See Table 7.
Secondary outcomes
1.8.3 Duration of lesions from onset of treatment
There was no difference between the groups in the duration of symptoms. See Table 7.
Our other secondary outcomes were not reported.
1.9 Topical tromantadine versus placebo
One small study made this comparison (Altomare 1985). It included 14 males and seven female participants.
Primary outcomes
1.9.1 Duration of symptoms from onset of treatment
Duration of symptoms and duration of lesions were reported as a combined outcome in this study and data were dichotomous. There was no difference between the groups at three days (Analysis 6.1), six days (Analysis 6.2), or nine days (Analysis 6.3) from onset of treatment, but at 12 days the intervention group were significantly more likely to have healed (RR 2.27, 95% CI 1.04 to 4.97; 1 RCT, 21 participants) (Analysis 6.4).
1.9.2 Time to first recurrence
This outcome was not reported.
1.9.3 Adverse events
Adverse events were poorly reported in this study and no reliable comparative data were available for first‐episode participants.
Secondary outcomes
Other secondary outcomes were not reported.
2. Antiviral versus other antiviral
2.1 Oral valaciclovir versus acyclovir
Two studies made this comparison (Fife 1997; Lai 2000). One was a large study which used survival analysis and reported hazard ratios (Fife 1997), and the other small study which reported mean values (Lai 2000).
Primary outcomes
2.1.1 Duration of symptoms from onset of treatment
Both studies reported that there was no difference between the oral valaciclovir group and the oral acyclovir group in the duration of symptoms (hazard ratio (HR) 1.02, 95% CI 0.85 to 1.22; 1 RCT, 643 participants, Analysis 7.1; MD 0.30 days, 95% CI ‐0.81 to 1.41; 1 RCT, 28 participants, Analysis 7.2).
2.1.2 Time to first recurrence
This outcome was not reported.
2.1.3 Adverse events
There was no difference between the groups in the rate of adverse events. Reported events included nausea and headache, however they were uncommon in both arms of the included studies. See Analysis 7.3.
Secondary outcomes
2.1.4 Duration of lesions from onset of treatment
One study reported this outcome (Fife 1997). There was no significant difference between the groups in the duration of lesions (HR 1.08, 95% CI 0.92 to 1.27; 1 RCT, 643 participants; Analysis 7.4)
Our other secondary outcomes were not reported.
2.2 Topical carbenoxolone sodium versus topical cicloxolone
One small three‐arm study made this comparison (Csonka 1984). It included a total of only 19 participants with first‐episode disease, of whom only 11 (57%) were included in the analysis.
Primary outcomes
2.2.1 Duration of symptoms from onset of treatment
There was no difference between the groups in the duration of symptoms at five or seven days. However, no conclusions can be drawn as analysis included only two participants in the carbenoxolone group and five participants in the cicloxolone group. See Analysis 8.1.
2.2.2 Time to first recurrence
This outcome was not reported.
2.2.3 Adverse events
No comparative data were reported among participants with first‐episode disease. Among all participants with either first‐episode or recurrent genital herpes, one in each group had slight irritation after application of the cream. The reaction was not sufficiently severe to discontinue treatment.
Secondary outcomes
2.2.4 Duration of lesions from onset of treatment
There was no difference between the groups in the duration of lesions at five or seven days. However, no conclusions can be drawn as analysis included only two participants in the carbenoxolone group and five participants in the cicloxolone group. See Analysis Analysis 8.2.
Our other secondary outcomes were not reported.
2.3 Oral acyclovir alone versus inosine prabonex with or without acyclovir
One study with 52 participants compared acyclovir alone versus inosine prabonex with or without acyclovir (Mindel 1987). It reported median values.
Primary outcomes
2.3.1 Duration of symptoms from onset of treatment
There was no significant difference between any of the groups in duration of symptoms. See Table 8.
| Acyclovir | Inosine pranobex | Both | |||||||
| Study | Median (days) | No. participants | Median (days) | No. participants | Median (days) | No. participants | P value | Favours Acyclovir | |
| Duration of symptoms from onset of treatment ‐ all | |||||||||
| 7 (range 3 to 19) | 24 | 8 (range 4 to 23) | 28 | 7 (range 3 to 19) | 25 | Acyclovir versus inosine: NS Acyclovir versus both: NS | ✕ | ||
| Duration of symptoms from onset of treatment by gender | |||||||||
| Females | 7 (range 3 to 19) | 9.5 (range 4 to 23) | 7 (range 3 to 19) | Acyclovir versus inosine: P < 0.05 Acyclovir versus both: NS | ✓ | ||||
| Duration of lesions from onset of treatment ‐ all | |||||||||
| 9 (range 4 to 24) | 24 | 13 (range 1 to 26) | 28 | 9 (range 5 to 18) | 25 | Acyclovir versus inosine: P < 0.05 Acyclovir versus both: NS | ✓ | ||
| Duration of lesions from onset of treatment by gender | |||||||||
| Females | 9.5 (range 4 to 24) | 13 (range 1 to 26) | 9 (range 5 to 18) | Acyclovir versus inosine: NS Acyclovir versus both: NS | ✕ | ||||
| Time to recurrence | |||||||||
| 187.4 | 142.5 | 132.7 | NS | ✕ | |||||
NS: not statistically significant
✓: favours acyclovir
✕: does not favour acyclovir
Subgroup analysis by gender
When analysis was restricted to women only, duration of symptoms was significantly shorter in the acyclovir‐only group (n = 21) than in the inosine prabonex‐only group (n = 24) (P < 0.05), but did not differ from the group receiving both interventions (n = 21). See Table 8.
2.3.2 Time to first recurrence
The authors reported that there was no significant difference between the groups in time to first recurrence. It was not stated what proportion of participants were followed up for this outcome. See Table 8.
2.3.3 Adverse events
The study authors stated that no adverse effects were noted.
Secondary outcomes
2.3.4 Duration of lesions from onset of treatment
Duration of lesions was significantly shorter in the group receiving acyclovir only (n = 24) than in those receiving inosine prabonex only (n = 28). There was no difference between the groups when the group receiving acyclovir only (n = 24) was compared with those receiving acyclovir plus inosine prabonex (n = 49). See Table 8.
Subgroup analysis by gender
When analysis was restricted to women only, duration of lesions did not significantly differ between any of the groups. See Table 8.
Our other secondary outcomes were not reported.
3. Antiviral regimen comparisons
3.1 Long course versus short course acyclovir
One study made this comparison (Mindel 1986; n = 60). It reported median values. Sixty women were treated with either oral acyclovir for 42 days or oral acyclovir for five days followed by placebo for 37 days.
Primary outcomes
3.1.1 Duration of symptoms from onset of treatment
There was no significant difference between the groups in duration of symptoms (Table 9).
| Long course acyclovir | Short course acyclovir | ||||||
| Outcome | Study | Median (days) | No. participants | Median (days) | No. participants | P value | Favours long course acyclovir |
| Duration of symptoms from onset of treatment by gender | |||||||
| Female | 11 (range 1 to 31) | 30 | 11 (range 2 to 28) | 30 | NS | ✕ | |
| Duration of lesions from onset of treatment by gender | |||||||
| Female | 11 (range 5 to 34) | 30 | 11 (range 5 to 32) | 30 | NS | ✕ | |
NS: not statistically significant
✕: does not favour long course acyclovir
3.1.2 Time to first recurrence
The median time to first recurrence in the long course group was 66.5 days, and 24 days in the short course group (P < 0.0001). However the study authors reported that the difference between the groups was only significant during the treatment period (42 days) and not for longer follow‐up.
3.1.3 Adverse events
There was no difference between the groups in the rate of adverse events, which were uncommon in both groups. Reported events included constipation, diarrhoea, and bilirubin elevation. See Analysis 9.1.
Secondary outcomes
3.1.4 Duration of lesions from onset of treatment
There was no significant difference between the groups in duration of lesions (Table 9).
Our other secondary outcomes were not reported.
3.2 High dose versus standard dose acyclovir
One study made this comparison (Wald 1994; n = 56). It reported median values. Participants were treated with either oral acyclovir 1 gm daily or 4 gm daily for five days.
Primary outcomes
3.2.1 Duration of symptoms from onset of treatment
There was no significant difference between the groups in duration of symptoms. See Table 10.
| High dose acyclovir | Low dose acyclovir | ||||||
| Outcome | Study | Median (days) | No. participants | Median (days) | No. participants | P value | Favours high dose acyclovir |
| Duration of symptoms from onset of treatment ‐ all | |||||||
| 7 (range 5 to 10) | 59 | 9 (range 7 to 12) | 28 | NS | ✕ | ||
| Duration of lesions from onset of treatment ‐ all | |||||||
| 11 (range 8 to 14) | 59 | 10 (range 7 to 11) | 28 | NS | ✕ | ||
| Time to recurrence ‐ all | |||||||
| 45 (range 20 to 128) | See footnote | 53 (range 11 to 196) | See footnote | NS | ✕ | ||
Recurrence occurred in 80% of participants
NS: not statistically significant
✕: does not favour high dose acyclovir
3.2.2 Time to first recurrence
There was no significant difference between the groups in time to first recurrence. See Table 10.
3.2.3 Adverse events
There was no statistically significant difference between the groups in the rate of adverse events (RR 7.08, 95% CI 0.41 to 121.05), but all reported events occurred in the intervention group (gastric disturbance in seven participants and headache in two participants). See Analysis 9.2.
Secondary outcomes
3.2.4 Duration of lesions from onset of treatment
There was no significant difference between the groups in duration of lesions. See Table 10.
Our other secondary outcomes were not reported.
3.3 High dose versus standard dose famciclovir
One study looked at different dosing regimens of famciclovir (Niimura 1996).
Primary outcomes
3.3.1 Duration of symptoms from onset of treatment
There was no significant difference between the groups in duration of symptoms. See Analysis 13.1.
3.3.2 Time to first recurrence
There were no studies that looked at this outcome.
3.3.3 Adverse events
There were no studies that looked at this outcome.
Secondary outcomes
3.3.4 Duration of lesions from onset of treatment
There was no significant difference between the groups in visibility of lesions at day 5. See Analysis 13.2.
No other secondary outcomes were reported.
4 Antiviral versus interferon
4.1 Topical acyclovir versus intramuscular interferon
One study with 105 participants made this comparison (Levin 1989).
Primary outcomes
4.1.1 Duration of symptoms from onset of treatment
There was no difference between the groups in symptom duration (MD 1.03 days, 95% CI ‐0.85 to 2.91; 1 RCT, 105 participants; Analysis 10.1).
4.1.2 Time to first recurrence
This outcome was not reported.
4.1.3 Adverse events
Compared to the topical acyclovir group, the intramuscular interferon group reported higher rates of visual disturbances (RR 2.76, 95% CI 1.23 to 6.19), dizziness (RR 6.83, 95% CI 1.59 to 29.25), nausea (RR 1.81, 95% 1.10 to 2.96), anorexia (RR 1.74, 95% CI 1.10 to 2.75), sweating (RR 19.31, 95% CI 1.14 to 327.34), fever (RR 3.82, 95% CI 2.36 to 6.18), fatigue (RR 1.44, 95% CI 1.09 to 1.90), chills (RR 3.13, 95% CI 1.99 to 4.91), headache (RR 1.57, 95% CI 1.14 to 2.17), myalgia (RR 1.74, 95% CI 1.30 to 2.34), and neutropenia (RR 5.69, 95% CI 2.33 to 13.90). There was no difference between the groups in rates of diarrhoea or vomiting (Analysis 10.2).
Secondary outcomes
4.1.4 Duration of lesions from onset of treatment
There was no difference between the groups in lesion duration (MD 1.58, 95% CI ‐0.38 to 3.54; 1 RCT, 105 participants; Analysis 10.3).
Our other secondary outcomes were not reported.
5 Interferon versus placebo
5.1 Topical interferon cream versus placebo
Batcheler 1986 reported this comparison. Only females (n = 36) were included in this study. Data were unsuitable for analysis as no standard errors were reported.
Primary outcomes
5.1.1 Duration of symptoms from onset of treatment
This outcome was reported for only 30 (83%) of the participants. The authors stated that there was no significant difference between the groups. See Table 11.
| Topical interferon | Placebo | |||||
| Outcome | Study | Mean (days) | No. participants | Mean (days) | No. participants | Favours intervention |
| Duration of symptoms from the onset of treatment | ||||||
| 7.25 | 12 | 6.33 | 18 | X | ||
| Duration of lesions from the onset of treatment | ||||||
| 8.06 | 16 | 6.52 | 19 | X | ||
✓: favours intervention
✕: does not favour intervention
5.1.2 Time to first recurrence
This outcome was not reported.
5.1.3 Adverse events
The authors reported that there were no adverse events in either study arm.
Secondary outcomes
5.1.4 Duration of lesions from onset of treatment
The authors stated that there was no significant difference between the groups (see Table 11).
Our other secondary outcomes were not reported.
5.2 Subcutaneous interferon versus placebo
One study reported this comparison (Mendelson 1986). It included 31 participants.
Primary outcomes
5.2.1 Duration of symptoms from onset of treatment
The authors stated that there was no significant difference between the groups (Analysis 11.1).
5.2.2 Time to first recurrence
The authors stated that there was no difference between the groups in time to first recurrence, but no numerical data were presented for this outcome.
5.2.3 Adverse effects
Compared to the placebo group, the subcutaneous interferon group reported higher rates of fever (RR 12.86, 95% CI 1.91 to 86.44), headache (RR 3.57, 95% CI 1.23 to 10.36), chills (RR 5.89, 95% CI 1.58 to 22.03), anorexia (RR 8.57. 95% CI 1.22 to 60.07), and neutropenia (RR 29.00, 95% CI 1.90 to 443.25). There was no difference between the groups in rates of myalgia, nausea, vomiting, fatigue, and diarrhoea (see Analysis 11.2).
Secondary outcomes
5.2.4 Duration of lesions from onset of treatment
The authors stated that there was no significant difference between the groups (Analysis 11.3).
Our other secondary outcomes were not reported.
5.3 Intramuscular interferon versus placebo
One study reported this comparison (Pazin 1987). The study included 69 participants, all women.
Primary outcomes
5.3.1 Duration of symptoms from onset of treatment
Data were reported in graphical form. The study authors reported that although the mean duration of pain in the intervention group was consistently two days shorter than in the placebo group, the difference was not significant.
5.3.2 Time to first recurrence
The study authors stated that life table analysis showed no difference between the groups in time to first recurrence. Eighty per cent of participants were followed for at least 230 days.
5.3.3 Adverse events
Compared to the placebo group, the interferon group had increased rates of transient neutropenia (RR 23.91, 95% CI 1.48 to 385.85; 1 RCT, n = 64) and thrombocytopenia (RR 11.51, 95% CI 0.68 to 196.20). See Analysis 12.1.
Secondary outcomes
5.3.4 Duration of lesions from onset of treatment
The study authors stated that there was no significant difference between the groups in duration of lesions. See Table 12.
| Intramuscular interferon | Placebo | ||||||
| Outcome | Study | Median (days) | No. participants | Median (days) | No. participants | P value | Favours intervention |
| Duration of lesions from onset of treatment ‐ women | |||||||
| 16 | 34 | 22 | 30 | P < 0.05 for days 18 to 20 only | ✕ | ||
✕: does not favour intervention
Our other secondary outcomes were not reported.
6 Natural products
There were no included studies that looked at this comparison.
Sensitivity Analysis
It was not possible to conduct a sensitivity analysis by excluding studies at high risk of bias, as the included studies did not differ substantially with respect to risk of bias. Nearly all studies were at unclear risk of bias in most domains. Use of a random‐effects model did not change the statistical significance of any of the findings, with the exception of the female subgroup in Analysis 1.1; Figure 4.
Discussion
Summary of main results
See summary of findings Table for the main comparison, summary of findings Table 2.
There were four randomised controlled studies that compared oral acyclovir with placebo for first‐episode genital herpes. The dose of acyclovir was 200 mg given five times daily for either 5, 7, or 10 days. The pooled data from two studies showed that symptom duration, including lesion duration, was significantly shorter in the acyclovir group (mean difference (MD) ‐3.3 days, 95% CI ‐4.94 to ‐1.46). There was no difference in time to first recurrence. Few adverse effects were reported. One study that compared short duration (5 days) with longer duration (42 days) acyclovir found no difference in symptom duration. Similarly, high dose acyclovir (4 gm x 4 days) did not show any difference in symptom duration compared to standard dose (1 gm x 4 days). The two studies that compared oral acyclovir (200 mg x 5 daily) with oral valaciclovir (300 mg or 500 mg x 2 daily) found no difference in symptom duration. One study of varying regimes of famciclovir (125 mg, 250 mg, or 500 mg X 3 daily) also found no difference in symptom duration. Of the three studies comparing intravenous acyclovir with placebo, two reported shorter median symptom duration and all three a shorter median duration of lesions. Four studies compared topical acyclovir with placebo. Pooled data from three studies showed no difference in symptom duration.
Placebo controlled studies of other antivirals such as cicloxolone, carbenoxolone, adenosine arabinoside, idoxuridine, and tromantadine were either too small or had such poor reporting of study methods to enable any meaningful conclusions. The one study comparing oral acyclovir with inosine prabonex found no overall difference in symptom duration or time to first recurrence, however the duration of lesions was shorter for the acyclovir group. When topical acycylovir, not shown to be beneficial in the previous randomised placebo‐controlled studies, was compared to interferon, in one study, there was no difference in symptom duration. The authors of a study comparing topical interferon cream with placebo reported no difference in symptom duration. Similarly, two studies comparing subcutaneous interferon or intramuscular interferon with placebo also found no benefit. One study of topical proflavine with light exposure and another of the antibiotic, co‐trimoxazole also showed no benefit when compared with placebo.
Overall completeness and applicability of evidence
Many of the included studies in this review were old with data reporting median values that precluded us from being able to pool the data. In addition, the age of the studies also meant that when data were missing, we were unable to obtain additional information. There were no studies comparing either valaciclovir or famciclovir with placebo and no studies comparing famciclovir with acyclovir. We were also lacking studies comparing imiquimod to placebo, no treatment or other medications and studies looking at the use of natural products.
None of the included studies contained pregnant women as part of the participant group. For this reason we were unable to assess the effects of these medications on outcomes looking at neonatal effects and rates of caesarean section delivery. In addition, for the primary outcome of time to first recurrence the available data was limited and not presented in the appropriate form to allow meta‐analysis.
Few studies with acyclovir had antibody levels and so we were unable to confirm that this was a first episode of primary infection. In the one study where this information was available, symptom duration appeared to be reduced only for those with a first episode of primary infection. Whether gender affects the efficacy of acyclovir for symptom duration is not clear due to small sample sizes.
Our intention was to perform subgroup analyses on the following variables gender, length of treatment, type of drug within a class, duration of time between appearance of lesions and initiation of treatment, immunodeficiency and first episode of primary infection versus first episode of non‐primary infection. The was insufficient data to explore the majority of these subgroups and those subgroups we were able to present (gender and first episode of primary infection vs first episode of non primary infection) only contained a limited number of small studies.
Quality of the evidence
We judged most of the studies at unclear risk of bias in most domains. This is in large due to the age of the included studies and the brief reporting of the methods in the included studies. This does not necessarily imply that the studies were of poor quality, but rather that we did not have the information that we required to be able to classify these studies as either low or high risk. In addition to the unclear risk of bias information, there were very few studies that we were able to include in the meta‐analysis. Because of the low number of studies that were able to inform the meta‐analysis the confidence intervals were relatively wide and so for this reason we downgraded the level of evidence for reasons of imprecision. This, in combination with some apparent heterogeneity, led us to grade most of the evidence as low.
Potential biases in the review process
As some of these trials were carried out before there was an international requirement for trial registration, it is possible that some studies may have been missed. However, we were unable to construct a funnel plot to assess publication bias, as there were fewer than 10 studies in any analysis.
Agreements and disagreements with other studies or reviews
Other reviews state that antiviral therapy with oral acyclovir, its prodrug valacyclovir, or with famciclovir, is effective in treating first‐episode genital herpes. All three drugs were found to be equipotent; however, acyclovir is less well absorbed and requires a more frequent dosing schedule. There is agreement that topical antivirals have limited effectiveness (Leung 2000; Patel 2002). The only indication for the use of intravenous therapy is when the patient is unable to swallow or tolerate oral medication. None of these treatments influence subsequent recurrence. All of the studies in this review used acyclovir 200 mg five times daily for either 5, 7, or 10 days. However, current guidelines also recommend 400 mg three times a day for seven days (CDC 2015) or five days (IUSTI 2010). These guidelines recommend that treatment should be commenced within five days of the start of the episode or while new lesions are still forming.
Study flow diagram.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Forest plot of comparison: 1 Oral acyclovir versus placebo, outcome: 1.1 Duration of symptoms from onset of treatment.
Forest plot of comparison: 4 Topical acyclovir versus placebo, outcome: 4.1 Duration of symptoms from onset of treatment.
Forest plot of comparison: 4 Topical acyclovir versus placebo, outcome: 4.2 Duration of symptoms from onset of treatment by gender.
Forest plot of comparison: 4 Topical acyclovir versus placebo, outcome: 4.3 Adverse events.
Forest plot of comparison: 4 Topical acyclovir versus placebo, outcome: 4.4 Duration of lesions from onset of treatment by antibody status.
Comparison 1 Oral acyclovir versus placebo, Outcome 1 Duration of symptoms from onset of treatment.
Comparison 1 Oral acyclovir versus placebo, Outcome 2 Adverse events.
Comparison 1 Oral acyclovir versus placebo, Outcome 3 Duration of lesions from onset of treatment.
Comparison 2 Intravenous acyclovir versus placebo, Outcome 1 Adverse events.
Comparison 3 Topical acyclovir versus placebo, Outcome 1 Duration of symptoms from onset of treatment.
Comparison 3 Topical acyclovir versus placebo, Outcome 2 Duration of symptoms from onset of treatment by gender.
Comparison 3 Topical acyclovir versus placebo, Outcome 3 Duration of lesions from onset of treatment by antibody status.
Comparison 3 Topical acyclovir versus placebo, Outcome 4 Duration of lesions from onset of treatment by gender.
Comparison 3 Topical acyclovir versus placebo, Outcome 5 Adverse events.
Comparison 4 Topical 2% cicloxolone cream versus placebo, Outcome 1 Symptom‐free by end of 5 days.
Comparison 4 Topical 2% cicloxolone cream versus placebo, Outcome 2 Symptom‐free by end of 7 days.
Comparison 4 Topical 2% cicloxolone cream versus placebo, Outcome 3 Lesion‐free by end of 7 days.
Comparison 4 Topical 2% cicloxolone cream versus placebo, Outcome 4 Lesion‐free by end of 5 days.
Comparison 5 Topical carbenoxolone sodium cream versus placebo, Outcome 1 Symptom‐free by end of 5 days.
Comparison 5 Topical carbenoxolone sodium cream versus placebo, Outcome 2 Symptom‐free by end of 7 days.
Comparison 5 Topical carbenoxolone sodium cream versus placebo, Outcome 3 Lesion‐free by end of 7 days.
Comparison 5 Topical carbenoxolone sodium cream versus placebo, Outcome 4 Lesion‐free by end of 5 days.
Comparison 6 Topical tromantadine versus placebo, Outcome 1 Symptom and lesion‐free by end of 3 days.
Comparison 6 Topical tromantadine versus placebo, Outcome 2 Symptom and lesion‐free by end of 6 days.
Comparison 6 Topical tromantadine versus placebo, Outcome 3 Symptom and lesion‐free by end of 9 days.
Comparison 6 Topical tromantadine versus placebo, Outcome 4 Symptom and lesion‐free by end of 12 days.
Comparison 7 Oral valaciclovir versus acyclovir, Outcome 1 Duration of symptoms from onset of treatment.
Comparison 7 Oral valaciclovir versus acyclovir, Outcome 2 Duration of symptoms from onset of treatment.
Comparison 7 Oral valaciclovir versus acyclovir, Outcome 3 Adverse events.
Comparison 7 Oral valaciclovir versus acyclovir, Outcome 4 Duration of lesions from onset of treatment.
Comparison 8 Topical carbenoxolone sodium versus topical cicloxolone, Outcome 1 Symptom‐free by end of 7 days.
Comparison 8 Topical carbenoxolone sodium versus topical cicloxolone, Outcome 2 Lesion‐free by end of 7 days.
Comparison 9 Oral acyclovir regimen comparisons, Outcome 1 Long versus standard course: adverse events.
Comparison 9 Oral acyclovir regimen comparisons, Outcome 2 HIgh versus low dose: adverse events.
Comparison 10 Topical acyclovir versus intramuscular interferon, Outcome 1 Duration of symptoms from onset of treatment by antibody status.
Comparison 10 Topical acyclovir versus intramuscular interferon, Outcome 2 Adverse events.
Comparison 10 Topical acyclovir versus intramuscular interferon, Outcome 3 Duration of lesions from onset of treatment by antibody status.
Comparison 11 Subcutaneous interferon versus placebo, Outcome 1 Duration of symptoms from onset of treatment.
Comparison 11 Subcutaneous interferon versus placebo, Outcome 2 Adverse events.
Comparison 12 Intramuscular interferon versus placebo, Outcome 1 Adverse events.
Comparison 13 High dose famciclovir versus low dose famciclovir, Outcome 1 Participants symptoms resolved at day 5.
Comparison 13 High dose famciclovir versus low dose famciclovir, Outcome 2 Lesions not visible at day 5.
| Oral acyclovir versus placebo for men and women with their first episode of genital herpes | |||||
| Patient or population: men and women with their first episode of genital herpes | |||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments |
| Risk with oral acyclovir | |||||
| Duration of symptoms from onset of treatment | The mean duration of symptoms from onset of treatment in the intervention group was 3.22 days fewer than that with placebo (5.91 fewer to 0.54 fewer) | ‐ | 82 | ⊕⊕⊝⊝ Low1, 2 | |
| Adverse events | Study population | Not pooled | 130 | ⊕⊝⊝⊝ Very low2, 3,5 | There were no severe adverse events. Adverse events were unable to be pooled as they were only reported in two studies and were not reported in a consistent way. Adverse events recorded for those taking this medication included coryza, dizziness, tiredness, diarrhoea and renal colic |
| Not pooled | |||||
| Duration of lesions from onset of treatment | The mean duration of lesions from onset of treatment in the intervention group was 3.51 fewer days than that with placebo (6.19 fewer to 0.82 fewer) | ‐ | 86 | ⊕⊕⊝⊝ Low1, 2 | |
| Time to recurrence | Data were not analysed using the correct method but statistical analysis did not show any difference in median time to recurrence in the two groups | Not pooled | 198 (2 RCTs) | ⊕⊝⊝⊝ Very low2,4 | |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 for risk of bias. There was unclear risk in both studies for randomisation and allocation concealment. Only one study used blinding and one study was graded high risk for attrition and reporting biases. 4 Downgraded by 2 for risk of bias as both studies were unclear for allocation concealment and randomisation and there is the potential for a substantial effect due to dropouts as actual numbers followed up were not reported 5 Downgraded by 1 for imprecision based on very wide confidence intervals | |||||
| Topical acyclovir versus placebo for men and women with their first episode of genital herpes | ||||||
| Patient or population: men and women with their first episode of genital herpes | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with placebo | Risk with topical acyclovir | |||||
| Duration of symptoms from onset of treatment | The mean duration of symptoms from onset of treatment in the intervention group was 0.61 days fewer than that with placebo (2.16 fewer to 0.95 more) | ‐ | 195 | ⊕⊕⊝⊝ Low1, 2 | One included study had given all subjects oral acyclovir | |
| Duration of lesions from onset of treatment | The mean duration of lesions from onset of treatment in the intervention group was 0.86 days fewer than that with placebo (2.15 fewer to 0.42 more) | ‐ | 195 | ⊕⊕⊝⊝ Low1, 3 | One included study had given all subjects oral acyclovir | |
| Adverse events ‐ pain with topical application | Study population | Study population | RR 0.74 | 247 | ⊕⊕⊝⊝ | |
| 242 per 1000 | 179 per 1000 | |||||
| Moderate | Moderate | |||||
| 235 per 1000 | 174 per 1000 | |||||
| Time to recurrence | Data were not pooled. Time to reccurrence ranged from 70‐116 days | Data were not pooled. Time to recurrence ranged from 70‐116 days | The were no differences reported between the two groups | 129 (3 RCTs) | ⊕⊝⊝⊝ Very low1,4 | Data were not analysed using the correct method. Medians were presented |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded by 1 for risk of bias. All trials had unclear risk of bias for randomisation and allocation concealment. 4 Downgraded by 2 for risk of bias with regard to incomplete data not many participants were followed up. 5 Downgraded by 1 for imprecision based on very wide confidence intervals | ||||||
| Time | Less than 24 hrs | Less than 2 days | Less than 3 days | Less than 4 days | Less than 5 days | Less than 6 days | Less than 7 days | Less than 8 days | Did not state |
| Studies of oral antivirals | Niimura 1996 included from day 2, 3, 4, 5, 6, 7 or more, but subgrouped data of results was not available | ||||||||
| Studies of topical antivirals | |||||||||
| Studies of intravenous antivirals | Severe GH | ||||||||
| Studies of topical interferon | |||||||||
| Studies of IM/SC interferon | Pazin 1987 (IM) | Levin 1989 (IM) | Mendelson 1986 (SC) | ||||||
| Studies of adenosine arabinoside | |||||||||
| Studies of topical carbenoxolone versus topical cicloxone | |||||||||
| Studies of ribavirin | |||||||||
| Studies of topical idoxuridine versus dimethyl sulfoxide | |||||||||
| Studies of oral inosine pranobex | |||||||||
| Studies of topical tromantadine | |||||||||
| GH: genital herpes | |||||||||
| Acyclovir | Placebo | ||||||
| Outcome | Study | Median (days) | No. participants | Median (days) | No. participants | P value | Favours intervention |
| Duration of symptoms from onset of treatment | 4 | 17 | 9 | 14 | < 0.05 | ✓ | |
| Duration of symptoms from onset of treatment by antibody status | |||||||
| Primary | 5 | 52 | 7 | 49 | < 0.05 | ✓ | |
| Non‐primary | 2 | 9 | 4 | 15 | > 0.1 | ✕ | |
| Duration of symptoms from onset of treatment by gender | |||||||
| Females | 5 | 10 | 8 | 7 | NS | ✕ | |
| Males | 3 | 7 | 9 | 7 | < 0.05 | ✓ | |
| Duration of lesions from onset of treatment | 6 | 17 | 11 | 14 | < 0.01 | ✓ | |
| Duration of lesions from onset of treatment by antibody status | |||||||
| Primary | 12 | 61 | 16 | 58 | < 0.01 | ✓ | |
| Non‐primary | 9 | 12 | 13 | 19 | > 0.1 | ✕ | |
| Duration of lesions from onset of treatment by gender | |||||||
| Females | 4.5 | 10 | 6 | 7 | < 0.05 | ✓ | |
| Males | 7 | 7 | 11 | 7 | 0.06 | ✕ | |
| Time to recurrence | ✕ | ||||||
| Participants with 4‐9 month follow‐up | 94 | Unclear | 101 | Unclear | NS | ✕ | |
| HSV‐2 group | 71 | Unclear | 108 | Unclear | NS | ✕ | |
| Mertz 1984: Duration of symptoms refers specifically to pain | |||||||
| Oral ribavirin | Placebo | |||||
| Outcome | Study | Mean (days) | No. participants | Mean (days) | No. participants | Favours intervention |
| Duration of symptoms from the onset of treatment | 5.7 | 30 | 15.5 | 30 | ✓ | |
| ✓: favours intervention | ||||||
| Acyclovir | Placebo | ||||||
| Outcome | Study | Median (days) | No. participants | Median (days) | No. participants | P value | Favours intervention |
| Duration of symptoms from onset of treatment ‐ all | |||||||
| 6.5 | 15 | 8.5 | 15 | < 0.05 | ✓ | ||
| 4.3 | 42 | 4.8 | 40 | 0.019 | ✓ | ||
| 4 | 15 | 7 | 16 | 0.17 | ✕ | ||
| Duration of symptoms from onset of treatment by antibody status | |||||||
| Primary | 6.3 | 12 | 8.8 | 8 | NS | ✕ | |
| 4.2 | 10.6 | 0.009 | ✓ | ||||
| 3 | 14 | 7 | 13 | 0.17 | ✕ | ||
| Non‐primary | 4.4 | 3.8 | 0.55 | ✓ | |||
| Duration of symptoms from onset of treatment by gender | |||||||
| Female | 6.8 | 12 | 7.3 | 12 | NS | ✕ | |
| Duration of lesions from onset of treatment | |||||||
| 7.0 | 15 | 14.0 | 15 | < 0.001 | ✓ | ||
| 8.4 | 42 | 11.5 | 40 | 0.02 | ✓ | ||
| 9 | 15 | 21 | 16 | 0.002 | ✓ | ||
| Duration of lesions from onset of treatment by antibody status | |||||||
| Primary | 9.0 | 12 | 15.0 | 8 | < 0.05 | ✓ | |
| 8.3 | 22 | 14.2 | 22 | 0.015 | ✓ | ||
| 9 | 14 | 21 | 13 | 0.007 | ✓ | ||
| Non‐primary | 8.4 | 20 | 8.2 | 18 | NS | ✕ | |
| Duration of lesions from onset of treatment by gender | |||||||
| Female | 7.0 | 12 | 12.5 | 12 | < 0.05 | ✓ | |
| Time to first recurrence by HSV type | |||||||
| HSV‐1 | 279 | 7 | 184 | 7 | 0.4 | ✕ | |
| HSV‐2 | 64 | 23 | 74 | 23 | 0.4 | ✕ | |
| Duration of symptoms: Peacock 1988 refers specifically to pain; Corey 1983 refers to constitutional symptoms HSV‐1: herpes simplex virus type 1 | |||||||
| Topical acyclovir | Topical placebo | ||||||
| Outcome | Study | Median (days) | No. participants | Median (days) | No. participants | P value | Favours intervention |
| Duration of symptoms from onset of treatment ‐ all | |||||||
| 5 | 54 | 8 | 47 | 0.01 | ✓ | ||
| Duration of symptoms from onset of treatment by gender | |||||||
| Females | 6 | 35 | 9 | 31 | < 0.05 | ✓ | |
| Males | 3.5 | 19 | 6 | 16 | > 0.1 | ✕ | |
| Duration of lesions from onset of treatment ‐ all | |||||||
| 8 | 54 | 13 | 47 | 0.01 | ✓ | ||
| Duration of lesions from onset of treatment by gender | |||||||
| Females | 8 | 35 | 13 | 31 | < 0.001 | ✓ | |
| Males | 8 | 19 | 11 | 16 | < 0.01 | ✓ | |
| Time to first recurrence | |||||||
| 116 | 116 | ✕ | |||||
| 79 | 79 | ✕ | |||||
| ✓: favours intervention | |||||||
| Adenine arabinoside | Placebo | No treatment | Untreated (no contraception) | |||||||
| Study | Mean (days) | No. participants | Mean (days) | No. participants | Mean (days) | No. participants | Mean (days) | No. participants | Favours intervention | |
| Duration of symptoms from onset of treatment by gender | ||||||||||
| Females | 10.4 | 8 | 6.8 | 10 | 8.8 | 4 | 7.0 | 5 | ✕ | |
| Males | 7.8 | 9 | 6.3 | 9 | 6.5 | 4 | ✕ | |||
| Duration of lesions from onset of treatment by gender | ||||||||||
| Females | 16.1 | 8 | 11 | 10 | 10 | 4 | 13.6 | 5 | ✕ | |
| Males | 11.9 | 9 | 13.1 | 9 | 11.5 | 4 | ✕ | |||
| ✕: does not favour intervention | ||||||||||
| Topical 30% idoxuridine | Control* | |||||
| Outcome | Study | Mean (days) | No. participants | Mean (days) | No. participants | Favours intervention |
| Duration of symptoms from the onset of treatment ‐ all | ||||||
| 10.7 | 9 | 12.9 | 23 | ✕ | ||
| Duration of lesions from the onset of treatment ‐ all | ||||||
| 19.6 | 9 | 17.9 | 23 | ✕ | ||
| Adverse effects | Events | No. Participants | Events | No. participants | ||
| Burning on application | 5 | 9 | 6 | 23 | ✕ | |
| *Control: either dimethyl sulfoxide alone or saline alone | ||||||
| Acyclovir | Inosine pranobex | Both | |||||||
| Study | Median (days) | No. participants | Median (days) | No. participants | Median (days) | No. participants | P value | Favours Acyclovir | |
| Duration of symptoms from onset of treatment ‐ all | |||||||||
| 7 (range 3 to 19) | 24 | 8 (range 4 to 23) | 28 | 7 (range 3 to 19) | 25 | Acyclovir versus inosine: NS Acyclovir versus both: NS | ✕ | ||
| Duration of symptoms from onset of treatment by gender | |||||||||
| Females | 7 (range 3 to 19) | 9.5 (range 4 to 23) | 7 (range 3 to 19) | Acyclovir versus inosine: P < 0.05 Acyclovir versus both: NS | ✓ | ||||
| Duration of lesions from onset of treatment ‐ all | |||||||||
| 9 (range 4 to 24) | 24 | 13 (range 1 to 26) | 28 | 9 (range 5 to 18) | 25 | Acyclovir versus inosine: P < 0.05 Acyclovir versus both: NS | ✓ | ||
| Duration of lesions from onset of treatment by gender | |||||||||
| Females | 9.5 (range 4 to 24) | 13 (range 1 to 26) | 9 (range 5 to 18) | Acyclovir versus inosine: NS Acyclovir versus both: NS | ✕ | ||||
| Time to recurrence | |||||||||
| 187.4 | 142.5 | 132.7 | NS | ✕ | |||||
| NS: not statistically significant | |||||||||
| Long course acyclovir | Short course acyclovir | ||||||
| Outcome | Study | Median (days) | No. participants | Median (days) | No. participants | P value | Favours long course acyclovir |
| Duration of symptoms from onset of treatment by gender | |||||||
| Female | 11 (range 1 to 31) | 30 | 11 (range 2 to 28) | 30 | NS | ✕ | |
| Duration of lesions from onset of treatment by gender | |||||||
| Female | 11 (range 5 to 34) | 30 | 11 (range 5 to 32) | 30 | NS | ✕ | |
| NS: not statistically significant | |||||||
| High dose acyclovir | Low dose acyclovir | ||||||
| Outcome | Study | Median (days) | No. participants | Median (days) | No. participants | P value | Favours high dose acyclovir |
| Duration of symptoms from onset of treatment ‐ all | |||||||
| 7 (range 5 to 10) | 59 | 9 (range 7 to 12) | 28 | NS | ✕ | ||
| Duration of lesions from onset of treatment ‐ all | |||||||
| 11 (range 8 to 14) | 59 | 10 (range 7 to 11) | 28 | NS | ✕ | ||
| Time to recurrence ‐ all | |||||||
| 45 (range 20 to 128) | See footnote | 53 (range 11 to 196) | See footnote | NS | ✕ | ||
| Recurrence occurred in 80% of participants | |||||||
| Topical interferon | Placebo | |||||
| Outcome | Study | Mean (days) | No. participants | Mean (days) | No. participants | Favours intervention |
| Duration of symptoms from the onset of treatment | ||||||
| 7.25 | 12 | 6.33 | 18 | X | ||
| Duration of lesions from the onset of treatment | ||||||
| 8.06 | 16 | 6.52 | 19 | X | ||
| ✓: favours intervention | ||||||
| Intramuscular interferon | Placebo | ||||||
| Outcome | Study | Median (days) | No. participants | Median (days) | No. participants | P value | Favours intervention |
| Duration of lesions from onset of treatment ‐ women | |||||||
| 16 | 34 | 22 | 30 | P < 0.05 for days 18 to 20 only | ✕ | ||
| ✕: does not favour intervention | |||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Duration of symptoms from onset of treatment Show forest plot | 2 | 82 | Mean Difference (IV, Random, 95% CI) | ‐3.22 [‐5.91, ‐0.54] |
| 1.1 Men | 2 | 33 | Mean Difference (IV, Random, 95% CI) | ‐2.10 [‐4.28, 0.09] |
| 1.2 Women | 2 | 49 | Mean Difference (IV, Random, 95% CI) | ‐4.13 [‐10.15, 1.89] |
| 2 Adverse events Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.1 Any adverse event | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.2 Dizziness | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.3 Coryza | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.4 Urticaria | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.5 Tiredness | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.6 Diarrhoea | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.7 Gastrointestinal discomfort | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.8 Renal colic | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.9 Sciatica | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.10 Headache | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.11 Increased serum creatinine | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.12 Decreased red blood cell count | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 Duration of lesions from onset of treatment Show forest plot | 2 | 86 | Mean Difference (IV, Fixed, 95% CI) | ‐3.51 [‐6.19, ‐0.82] |
| 3.1 Men | 2 | 35 | Mean Difference (IV, Fixed, 95% CI) | ‐5.74 [‐9.80, ‐1.69] |
| 3.2 Women | 2 | 51 | Mean Difference (IV, Fixed, 95% CI) | ‐1.74 [‐5.34, 1.85] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Adverse events Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 All adverse effects | 1 | 105 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.70 [0.43, 6.75] |
| 1.2 Phlebitis | 1 | 31 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.19 [0.14, 72.69] |
| 1.3 Maculopapular eruption | 1 | 31 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.21 [0.01, 4.10] |
| 1.4 Nausea | 2 | 135 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.03 [0.49, 18.59] |
| 1.5 Abnormal liver function tests | 1 | 30 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.33 [0.36, 4.97] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Duration of symptoms from onset of treatment Show forest plot | 3 | 195 | Mean Difference (IV, Random, 95% CI) | ‐0.61 [‐2.16, 0.95] |
| 1.1 All participants | 1 | 49 | Mean Difference (IV, Random, 95% CI) | 0.40 [‐1.18, 1.98] |
| 1.2 Primary | 2 | 100 | Mean Difference (IV, Random, 95% CI) | ‐2.04 [‐3.55, ‐0.52] |
| 1.3 Non‐primary | 2 | 46 | Mean Difference (IV, Random, 95% CI) | 0.53 [‐2.79, 3.85] |
| 2 Duration of symptoms from onset of treatment by gender Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.1 Women | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 Duration of lesions from onset of treatment by antibody status Show forest plot | 3 | 195 | Mean Difference (IV, Fixed, 95% CI) | ‐0.86 [‐2.15, 0.42] |
| 3.1 All participants | 1 | 49 | Mean Difference (IV, Fixed, 95% CI) | 0.20 [‐1.33, 1.73] |
| 3.2 Primary | 2 | 100 | Mean Difference (IV, Fixed, 95% CI) | ‐4.09 [‐6.92, ‐1.25] |
| 3.3 Non‐primary | 2 | 46 | Mean Difference (IV, Fixed, 95% CI) | ‐1.91 [‐6.27, 2.46] |
| 4 Duration of lesions from onset of treatment by gender Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.1 Women | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 5 Adverse events Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 5.1 Pain with topical application | 3 | 247 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.74 [0.46, 1.20] |
| 5.2 Rash | 1 | 77 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.03 [0.07, 15.82] |
| 5.3 Itching | 1 | 101 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.62 [0.11, 62.78] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Symptom‐free by end of 5 days Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2 Symptom‐free by end of 7 days Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3 Lesion‐free by end of 7 days Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 4 Lesion‐free by end of 5 days Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Symptom‐free by end of 5 days Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2 Symptom‐free by end of 7 days Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3 Lesion‐free by end of 7 days Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 4 Lesion‐free by end of 5 days Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Symptom and lesion‐free by end of 3 days Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2 Symptom and lesion‐free by end of 6 days Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3 Symptom and lesion‐free by end of 9 days Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 4 Symptom and lesion‐free by end of 12 days Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Duration of symptoms from onset of treatment Show forest plot | 1 | Hazard Ratio (Fixed, 95% CI) | Totals not selected | |
| 1.1 Valacyclovir versus acyclovir | 1 | Hazard Ratio (Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Duration of symptoms from onset of treatment Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.1 Valaciclovir versus acyclovir | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 Adverse events Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.1 Nausea | 2 | 671 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.90 [0.49, 1.65] |
| 3.2 Headache | 2 | 671 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.26 [0.82, 1.93] |
| 4 Duration of lesions from onset of treatment Show forest plot | 1 | Hazard Ratio (Fixed, 95% CI) | Totals not selected | |
| 4.1 Valaciclovir versus acyclovir | 1 | Hazard Ratio (Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Symptom‐free by end of 7 days Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2 Lesion‐free by end of 7 days Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Long versus standard course: adverse events Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.1 Constipation | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 Nausea | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.3 Diarrhoea | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.4 Increase in appetite | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.5 Bells palsy | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.6 Slight white cell count decrease | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.7 Persistent bilirubin elevation | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.8 Slight transient bilirubin elevation | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 HIgh versus low dose: adverse events Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.1 Drug toxicity | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Duration of symptoms from onset of treatment by antibody status Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.1 All participants | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Adverse events Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.1 Visual disturbance | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.2 Dizziness | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.3 Diarrhoea | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.4 Nausea | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.5 Vomiting | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.6 Anorexia | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.7 Sweating | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.8 Fever | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.9 Fatigue | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.10 Chills | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.11 Headache | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.12 Myalgia | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.13 Neutropenia | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 Duration of lesions from onset of treatment by antibody status Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3.1 All participants | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Duration of symptoms from onset of treatment Show forest plot | 1 | 31 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 1.1 Men | 1 | 13 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 1.2 Women | 1 | 18 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 2 Adverse events Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.1 Fever | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.2 Headache | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.3 Chills | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.4 Myalgia | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.5 Nausea | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.6 Vomiting | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.7 Fatigue | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.8 Anorexia | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.9 Diarrhoea | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.10 Neutropenia | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Adverse events Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.1 Transient neutropenia | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 Transient thrombocytopenia | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Participants symptoms resolved at day 5 Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2 Lesions not visible at day 5 Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
