Abstract
Introduction
Genital herpes is an infection with herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2), and is among the most common sexually transmitted diseases.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of different oral antiviral treatments versus each other for a first episode of genital herpes in HIV-negative people? What are the effects of different antiviral treatments for genital herpes in HIV-positive people? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2013 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found eight studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: aciclovir, famciclovir, and valaciclovir.
Key Points
Genital herpes is an infection with herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2). The typical clinical features include painful, shallow anogenital ulceration.
It is among the most common sexually transmitted diseases, with up to 23% of adults in the UK and US having antibodies to HSV-2.
Genital herpes, like other genital ulcer diseases, is a significant risk factor for acquiring HIV for both men and women. People with HIV can have severe herpes outbreaks, and this may help facilitate transmission of both herpes and HIV infections to others.
Oral antiviral treatment of a first episode of genital herpes can decrease symptoms in HIV-negative people.
Data from one RCT indicated that oral valaciclovir and oral aciclovir were equally effective in treating a first episode of genital herpes in HIV-negative people.
We found no RCTs of sufficient quality comparing either oral valaciclovir or oral aciclovir with oral famciclovir in treating a first episode of genital herpes in HIV-negative people.
Daily oral antiviral treatment seems to be effective in preventing recurrence of genital herpes in HIV-positive people.
Data from one RCT indicated that daily oral valaciclovir and daily oral aciclovir seemed equally effective in preventing recurrence of genital herpes in HIV-positive people.
We found no RCTs of sufficient quality comparing either oral valaciclovir or oral aciclovir with oral famciclovir in preventing recurrence of genital herpes in HIV-positive people.
We found no RCTs of sufficient quality to assess whether one oral antiviral is more effective than another in treating first episodes of genital herpes in HIV-positive people.
Clinical context
General background
Genital herpes simplex infection can be caused by either herpes simplex virus (HSV) type 1 (HSV-1) or HSV type 2 (HSV-2) and is one of the most common sexually transmitted diseases. Common symptoms include recurrent painful genital ulcerations. Asymptomatic shedding is frequent, especially in the first year after a primary episode, and probably represents the major source of sexual transmission. The herpes virus has a characteristic protein coat and each of the types has identifiable proteins. Glycoprotein G2 is associated with HSV-2 and glycoprotein G1 is associated with HSV-1 Type-specific antibodies to the viral proteins develop within the first several weeks of infection and persist. Detection of these specific antibodies, in addition to direct detection of the virus, is important in making an accurate diagnosis. There is no cure for HSV infection. In repeated randomised clinical trials, the use of antiviral agents compared to placebo for individuals with a first episode of genital HSV significantly reduces the duration of symptoms and speeds healing. The use of antiviral medications is also shown to reduce the frequency and duration of recurrent outbreaks and to reduce the frequency of asymptomatic shedding. Oral antiviral treatment of someone who is seropositive for HSV is effective in reducing transmission to a previously uninfected sexual partner. Genital herpes, like other genital ulcer diseases, is a significant risk factor for acquiring HIV for both men and women. People with HIV can have severe herpes outbreaks, and this may help facilitate transmission of both herpes and HIV infections to others.
Focus of the review
This update to a previously published review focuses on specific questions for which evidence was insufficient to identify the best treatment. There is now a preponderance of evidence supporting the role of antiviral treatment in treatment of the initial episode of genital herpes. However selecting the most appropriate antiviral treatment remains a challenge and, therefore, this review focuses on the effects of different oral antiviral treatments in two select populations: HIV-negative individuals with a first episode of genital herpes and treatment of both first episode and recurrences for HIV-positive individuals. These populations were selected because evidence from clinical trials was limited at the time of the last systematic review, and an update in these areas could provide clinicians with information on best therapies.
Comments on evidence
We found eight studies that met our inclusion criteria. In regards to the question of the effects of different oral antiviral treatments versus each other for a first episode of genital herpes in the HIV-negative individual, we found high grade evidence from one randomised controlled trial comparing oral valaciclovir and acyclovir. Both treatments were equally effective in treating the first episode by decreasing symptoms with similar rates of adverse effects; however, this evidence is from a single study. For the question regarding treatment of recurrent infections in HIV-positive individuals, we found moderate to very low grade evidence from seven trials. Studies for HIV positive individuals were only included if the majority of subjects in the study were HIV positive. In particular, we found moderate evidence that the recurrence rates of HSV are lower for HIV-positive individuals on valaciclovir compared to placebo, and the recurrence rates are similar between those on acyclovir when compared to valaciclovir. While studies indicated that HIV-positive individuals on acyclovir as compared to placebo had lower recurrence rates and less viral shedding, these studies had several methodological issues.
Search and appraisal summary
The update literature search for this review was carried out from the date of the last search, January 2010, to October 2013. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the review, please see the Methods section. Searching of electronic databases retrieved 62 studies. After deduplication and removal of conference abstracts, 48 records were screened for inclusion in the review. Appraisal of titles and abstracts led to the exclusion of 28 studies and the further review of 20 full publications. Of the 20 full articles evaluated, no systematic reviews and one RCT was added at this update.
Additional information
In this review we found no randomised controlled trials of sufficient quality comparing famiciclovir with other antiviral therapies. Famciclovir is an oral pro-drug of penciclovir with increased bio-availability and a longer half-life than acyclovir and, therefore, is considered a treatment option for primary genital herpes outbreak. There are studies comparing famciclovir with placebo, showing favourable results.
About this condition
Definition
Genital herpes is an infection with herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2). The typical clinical features include painful shallow anogenital ulceration. HSV infections can be confirmed on the basis of virological (e.g., polymerase chain reaction) and serological findings. Using these findings, infections can be categorised as: primary infection, which is defined as HSV confirmed in a person without HSV-1 or HSV-2 antibodies; first episode non-primary infection, which is defined as detection of one viral type in an individual with serological evidence of past infection with the other viral type; and recurrent genital herpes, which is characterised by reactivation of latent HSV-1 or HSV-2 in the presence of antibodies of the same serotype. HSV-1 can also cause gingivostomatitis and orolabial ulcers. HSV-2 can also cause other types of herpes infection, such as ocular herpes. Both virus types can cause infection of the central nervous system (e.g., encephalitis). Genital herpes can be diagnosed using various methods (e.g., clinical diagnosis, culture or PCR of lesions, or serological testing). Clinical diagnosis alone has been shown to be both insensitive and non-specific, therefore, guidelines recommend that evaluation for genital, anal, or perianal ulcers include syphilis serology and darkfield examination, culture for HSV or PCR testing for HSV, and serological testing for type-specific HSV antibody.
Incidence/ Prevalence
Genital herpes infections are among the most common sexually transmitted diseases. Seroprevalence studies showed that 17% of adults in the US, 9% of adults in Poland, and 12% of adults in Australia had HSV-2 antibodies. The studies carried out in Poland and Australia also showed higher seroprevalence in women than in men (HSV-2 seroprevalence in Poland: 10% for women v 9% for men; P = 0.06; HSV-2 seroprevalence in Australia: 16% for women v 9% for men; RR 1.81, 95% CI 1.52 to 2.14). A UK study found that 23% of adults attending sexual health clinics, and 8% of blood donors in London, had antibodies to HSV-2. On the basis of seroprevalence studies, the total number of people who were newly infected with HSV-2 in 2003 has been estimated at 23.6 million, and the total number of people aged 15 to 49 years who were living with HSV-2 infection worldwide in 2003 has been estimated at 536 million.
Aetiology/ Risk factors
Both HSV-1 and HSV-2 can cause genital infection, but HSV-2 is associated with a higher frequency of recurrences. Most individuals with genital HSV infection have only mild symptoms and remain unaware that they have genital herpes. However, these people can still transmit the infection to sexual partners and newborns.
Prognosis
Sequelae of HSV infection include neonatal HSV infection, opportunistic infection in immunocompromised people, recurrent genital ulceration, and psychosocial morbidity. HSV-2 infection is associated with an increased risk of HIV transmission and acquisition. In a large meta-analysis of longitudinal studies in which the relative timing of HSV-2 infection and HIV infection could be established, HSV-2 seropositivity was a significant risk factor for HIV acquisition in general population studies of men (summary adjusted RR 2.7, 95% CI 1.9 to 3.9), women (RR 3.1, 95% CI 1.7 to 5.6), and men who had sex with men (RR 1.7, 95% CI 1.2 to 2.4). Aciclovir suppressive therapy did not seem to reduce the rate of HIV infection in two RCTs that assessed this question. The first RCT (821 HIV-negative, HSV-2-seropositive women) found no significant difference between aciclovir (400 mg twice-daily) and placebo in the incidence of HIV infection (incidence of HIV infection: 4.4 per 100 person-years with aciclovir v 4.1 per 100 person-years with placebo; RR 1.08, 95% CI 0.64 to 1.83). The second RCT (3172 HIV-negative, HSV-2-seropositive people) also found no significant difference between aciclovir (400 mg twice-daily) and placebo in the incidence of HIV infection (3.9 per 100 person-years with aciclovir v 3.3 per 100 person-years with placebo; HR 1.16, 95% CI 0.83 to 1.62). Among the sequelae of HSV infection, the most common neurological complications are aseptic meningitis (reported in about 25% of women during primary infection) and urinary retention (reported in up to 15% of women during primary infection). The absolute risk of neonatal infection is high (41%, 95% CI 26% to 56%) in babies born to women who acquire infection near the time of delivery, and low (<3%) in women with established infection, even in those who have a recurrence at delivery. About 15% of neonatal infections result from postnatal transmission from oral lesions of relatives or hospital personnel.
Aims of intervention
To prevent transmission; to reduce the morbidity of the first episode; to reduce the risk of recurrent disease after a first episode, with minimal adverse effects of treatment.
Outcomes
Transmission of infection (shown clinically, virologically, or serologically, depending on the study); rate of seroconversion; severity of attack (includes symptom severity and duration of lesions); viral shedding (an intermediate outcome that reflects the risk of transmitting the infection, although a direct link between the duration of viral shedding and risk of transmission has not been found); recurrence rates; psychosocial morbidity; quality of life; and adverse effects.
Methods
BMJ Clinical Evidence search and appraisal October 2013. The following databases were used to identify studies for this systematic review: Medline 1966 to October 2013, Embase 1980 to October 2013, and The Cochrane Database of Systematic Reviews 2013, issue 10 (1966 to date of issue). Additional searches were carried out in the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Titles and abstracts of the studies identified by the initial search, run by an information specialist, were first assessed against predefined criteria by an evidence scanner. Full texts for potentially relevant studies were then assessed against predefined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the review were then extracted by an evidence analyst. Study design criteria for inclusion in this review were: published RCTs and systematic reviews of RCTs in the English language that were single-blinded. There was no minimum length of follow-up. We excluded all studies described as 'open', 'open label', or not blinded unless blinding was impossible. RCTs consisted of 20 or more individuals (or at least 10 per arm), of whom at least 80% were followed up. We excluded all studies that recruited people with only a clinical diagnosis of genital herpes (i.e., without serological confirmation). For the question on HIV-positive people, we included studies with a mixed HIV population if the majority of the population was HIV positive. We excluded altogether from the review all studies with a mixed HIV population in which HIV-positive people were a minority. We included RCTs and systematic reviews of RCTs where harms of an included intervention were assessed, applying the same study design criteria for inclusion as we did for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for Genital herpes: oral antiviral treatments.
| Important outcomes | Psychosocial morbidity, Quality of life, Rate of seroconversion, Recurrence rates, Severity of attack, Transmission of infection, Viral shedding | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of different oral antiviral treatments versus each other for a first episode of genital herpes in HIV-negative people? | |||||||||
| 1 (643) | Severity of attack | Oral valaciclovir versus oral aciclovir | 4 | 0 | 0 | 0 | 0 | High | |
| 1 (643) | Viral shedding | Oral valaciclovir versus oral aciclovir | 4 | 0 | 0 | 0 | 0 | High | |
| What are the effects of different oral antiviral treatments for genital herpes in HIV-positive people? | |||||||||
| 3 (865) | Recurrence rates | Daily oral aciclovir versus placebo | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for subgroup analysis in 1 RCT, for 1 RCT being under-powered to detect a clinically important difference between groups, and for incomplete reporting of results in 1 RCT |
| 3 (521) | Viral shedding | Daily oral aciclovir versus placebo | 4 | –3 | 0 | 0 | +1 | Low | Quality points deducted for subgroup analysis in 1 RCT, for 1 RCT being underpowered to detect a clinically important difference between groups, and for incomplete reporting of results in 1 RCT; effect size point added for RR <0.5 |
| 3 (435) | Recurrence rates | Daily oral valaciclovir versus placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results in largest RCT |
| 2 (196) | Viral shedding | Daily oral valaciclovir versus placebo | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for sparse data, and consistency point deducted for conflicting results between studies |
| 1 (1062) | Recurrence rates | Daily oral valaciclovir versus daily oral aciclovir | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
Contributor Information
Lisa M. Hollier, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, US.
Catherine Eppes, Director of Obstetrical Quality and Safety at Ben Taub Maternal Fetal Medicine, Baylor College of Medicine, Houston, TX, US.
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