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BMJ Clin Evid. 2007; 2007: 1603.
Published online 2007 April 1.
PMCID: PMC2943783

Genital herpes

Eva Maria Agnes Jungmann, Consultant Physician HIV/GUM, and Honorary Senior Lecturer

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 interventions to prevent sexual transmission of herpes simplex virus? What are the effects of interventions to prevent transmission of herpes simplex virus from mother to neonate? What are the effects of antiviral treatment in people with a first episode of genital herpes? What are the effects of interventions to reduce the impact of recurrence? What are the effects of treatments in people with genital herpes and HIV? We searched: Medline, Embase, The Cochrane Library and other important databases up to August 2006 (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 35 systematic reviews, RCTs, or observational 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: antivirals, caesarean delivery, condoms, oral acyclovir, psychotherapy, recombinant glycoprotein vaccines, serological screening, and counselling.

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.

Oral antiviral treatment of someone who is seropositive for herpes simplex virus seems to be effective in reducing transmission to a previously uninfected partner.

Despite limited evidence, male condom use is generally believed to reduce sexual transmission of herpes from infected men to uninfected sexual partners.

  • We don't know how effective male condom use is at preventing transmission from infected women to uninfected men.
  • We didn't find any evidence examining the effectiveness of female condoms in preventing transmission.

Recombinant glycoprotein vaccines do not seem any more effective than placebo in preventing transmission to people at high risk from infection.

  • We did not find any evidence about other vaccines.

We found insufficient evidence to draw reliable conclusions on whether antiviral maintenance treatment in late pregnancy, or serological screening and counselling to prevent acquisition of herpes in late pregnancy are effective in preventing transmission of herpes simplex virus from mother to neonate.

  • Caesarean delivery in women with genital lesions at term may reduce the risk of transmission, but is associated with an increased risk of maternal morbidity and mortality.

Oral antiviral treatments effectively decrease symptoms in people with first episodes of genital herpes, although we found insufficient evidence to establish which type of oral antiviral drug was most effective.

If herpes is recurrent, aciclovir, famciclovir, and valaciclovir are all equally beneficial in reducing duration of symptoms, lesion healing time, and viral shedding.

  • Daily maintenance treatment with oral antiviral agents effectively reduces frequency of recurrences, and improves quality of life.
  • We don't know whether psychotherapy is effective in reducing recurrence.

Oral antiviral treatments are generally believed to be useful in treating both first episodes and recurrent episodes of genital herpes in people with HIV, although evidence supporting this is sparse.

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. Herpes simplex virus infections can be confirmed on the basis of virological and serological findings. Types of infection include first episode primary infection, which is defined as herpes simplex virus confirmed in a person without prior findings of HSV-1 or HSV-2 antibodies; first episode non-primary infection, which is HSV-2 confirmed in a person with prior findings of HSV-1 antibodies or vice versa; first recognised recurrence, which is HSV-1 or HSV-2 confirmed in a person with prior findings of HSV-1 or HSV-2 antibodies; and recurrent genital herpes, which is caused by reactivation of latent herpes simplex virus. HSV-1 can also cause gingivostomatitis and orolabial ulcers. HSV-2 can also cause other types of herpes infections, such as ocular herpes. Both virus types can cause infection of the central nervous system (e.g. encephalitis).

Incidence/ Prevalence

Genital herpes infections are among the most common sexually transmitted diseases. Seroprevalence studies showed that 22% of adults in the USA, 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. Seroprevalence of HSV-2 increased by 30.0% (95% CI 15.8% to 45.8%) between the periods 1976-1980 and 1988-1994. However, it should be noted that although antibody levels prove the existence of present or past infections, they do not differentiate between possible manifestations of HSV-2 infections (e.g. genital/ocular). Thus, the figures must be treated with caution when applied to genital herpes only.

Aetiology/ Risk factors

Both HSV-1 and HSV-2 can cause a first episode of genital infection, but HSV-2 is more likely to cause recurrent disease. Most people with HSV-2 infection have only mild symptoms and remain unaware that they have genital herpes. However, these people can still pass on the infection to sexual partners and newborns.

Prognosis

Sequelae of herpes simplex virus infection include neonatal herpes simplex virus 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. 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 labour, and low (< 3%) in women with established infection, even in those who have a recurrence at term. 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

Rates of transmission (shown clinically, virologically, or serologically, depending on the study); seroconversion, severity, and duration of symptoms; healing time; duration of 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; adverse effects of treatment.

Methods

BMJ Clinical Evidence search and appraisal August 2006. The following databases were used to identify studies for this review: Medline 1966 to August 2006, Embase 1980 to August 2006, and The Cochrane Library Issue 3, 2006. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA) — Turning Research into Practice (TRIP), and National Institute for Health and Clinical Excellence (NICE). Abstracts of the studies retrieved were assessed independently by two information specialists using predetermined criteria to identify relevant studies. Study design criteria for evaluation for inclusion in this review were: published systematic reviews and RCTs in any language. RCTs had to be at least single blinded. We excluded all studies described as "open", "open label", or not blinded, unless blinding was impossible. RCTs had to include 20 or more individuals, of whom 80% or more were followed up with no minimum length of follow up. For the condom option, we also carried out a search for prospective and retrospective cohort studies, case-control studies, case series, and population surveillance studies. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the review as required. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).

Table
GRADE evaluation of interventions for genital herpes

Glossary

High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
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.
Serodiscordant couple
A couple in which one partner is infected with herpes simplex virus and the other is not infected.
Very low-quality evidence
Any estimate of effect is very uncertain.

Notes

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.

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2007; 2007: 1603.
Published online 2007 April 1.

Antiviral treatment to prevent sexual transmission

Summary

TRANSMISSION OF INFECTION Compared with placebo: Daily use of valaciclovir reduces the risk of transmission of herpes simplex virus type 2 to a previously uninfected sexual partner at 8 months compared with placebo ( moderate-quality evidence ).

Benefits

We found no systematic review but we found one RCT (1484 serodiscordant couples). It found that valaciclovir (500 mg once daily, taken by the infected partner) significantly reduced the risk of herpes simplex virus type 2 (HSV-2) transmission compared with placebo after 8 months of treatment (overall risk of sexual transmission: 14/743 [2%] with valaciclovir v 27/741 [4%] with placebo; HR 0.52, 95% CI 0.27 to 0.99; risk of symptomatic HSV-2: 0.5% with valaciclovir v 2.2% with placebo; HR: 0.24, 95% CI 0.08 to 0.75). Subgroup analyses found that risks significantly increased if the uninfected partner was female and the duration of the genital HSV-2 infection in the source partner was less than 2 years (HR for female acquisition: 3.30, 95% CI 1.31 to 8.28; HR for transmission from source partner with shorter duration of genital herpes: 2.89, 95% CI 1.12 to 7.49).

Harms

See individual antiviral drugs, and see also harms of daily maintenance antiviral treatment.

Comment

Clinical guide:

RCTs have shown that daily antiviral treatment decreases the frequency of clinical and subclinical viral shedding (see antiviral treatment at the start of recurrence and outcomes section).

Substantive changes

No new evidence

2007; 2007: 1603.
Published online 2007 April 1.

Male condom use to prevent sexual transmission from infected men to uninfected sexual partners

Summary

TRANSMISSION OF INFECTION Compared with no/infrequent condom use: Use of condoms in more than 25% of sexual acts by men infected with genital herpes reduces transmission of herpes simplex virus type 2 to their uninfected sexual partners at 18 months ( moderate-quality evidence ).

Benefits

We found no systematic review or RCTs. In one prospective cohort study (528 couples; [98% heterosexual]; 261 men and 267 women serodiscordant for herpes simplex virus type 2 [HSV-2] infection and followed for 18 months, see comment below), men infected with genital herpes who used condoms in more than 25% of sexual acts were at significantly lower risk of infecting their sexual partners with HSV-2 (502 people; adjusted HR 0.09, 95% CI 0.01 to 0.67).

Harms

The cohort study gave no information on adverse effects.

Comment

Only 61% of couples used condoms during the study, and only 8% [40/502] used them consistently. Controlled trials of condoms for prevention of HSV-2 transmission are not feasible.

Clinical guide:

Even with routine counselling, many couples do not regularly use condoms. Trials of different methods of advising people to use condoms or providing condoms could be performed.

Substantive changes

No new evidence

2007; 2007: 1603.
Published online 2007 April 1.

Female condoms

Summary

We found no clinically important results about the effects of female condoms on prevention of sexual transmission of genital herpes.

Benefits

We found no systematic review or RCTs on the effects of female condoms to prevent sexual transmission.

Harms

We found no RCTs.

Comment

None.

Substantive changes

No new evidence

2007; 2007: 1603.
Published online 2007 April 1.

Male condom use to prevent sexual transmission from infected women to uninfected men

Summary

TRANSMISSION OF INFECTION Compared with no/infrequent condom use: Use of condoms by uninfected men may not reduce their risks at 18 months of acquiring genital herpes from their infected female sexual partners ( very low-quality evidence ).

Benefits

We found no systematic review or RCTs. A subgroup analysis of one prospective cohort study (528 couples; [98% heterosexual]; 261 men and 267 women serodiscordant for herpes simplex virus type 2 [HSV-2] infection and followed for 18 months, see comment below), found no significant difference between male condom use and no male condom use in HSV-2 transmission from infected female partners to uninfected male partners (502 people; adjusted HR 2.02, 95% CI 0.32 to 12.50).

Harms

The study gave no information on adverse effects.

Comment

Only 61% of couples used condoms during the study, and only 8% [40/502] used them consistently. Controlled trials of condoms for prevention of HSV-2 transmission are impractical.

Clinical guide:

Observational studies in sexually transmitted diseases clinics in the USA found that condom use significantly reduced the risk of acquisition of genital herpes in men compared with not using condoms (adjusted OR 0.79, 95% CI 0.71 to 0.89) and significantly reduced the risk of HSV-2 acquisition in men (HR 0.69, 95% CI 0.51 to 0.93).

Substantive changes

No new evidence

2007; 2007: 1603.
Published online 2007 April 1.

Vaccination

Summary

TRANSMISSION OF INFECTION Compared with placebo: Recombinant glycoprotein vaccine (gB2 plus gD2) does not reduce the risk of genital infection with herpes simplex type 2 virus in people at high risk of infection overall, although it may reduce infection in women who are seronegative for herpes simplex virus type 1 and herpes simplex virus type 2 at baseline, and who have regular sexual partners with clinically confirmed genital herpes ( moderate-quality evidence ). NOTE We found no direct information about whether other vaccines are better than no active treatment.

Benefits

Recombinant glycoprotein vaccines versus placebo:

We found no systematic review but we found two RCTs. The first RCT (2393 people seronegative for herpes simplex virus type 2 [HSV-2] and HIV who were at high risk of exposure to genital herpes) compared recombinant glycoprotein vaccine (gB2 plus gD2) versus placebo. It found no significant difference in the proportion of people with herpes simplex virus infection or positive genital herpes simplex virus culture (4.2 cases per 100 person years with glycoprotein vaccine v 4.6 cases per 100 person years with placebo; P = 0.58). Similarly, it found no significant difference in the duration of initial genital herpes (7.1 days with glycoprotein vaccine v 6.5 days with placebo; P = 0.45) or in the frequency of subsequent recurrences in people who acquired genital HSV-2 infection (rate of recurring lesions: 13/24 [54%] with glycoprotein vaccine v 21/33 [64%] with placebo; P = 0.47). The second RCT (2 studies; 847 HSV-1 and HSV-2 seronegative people in study 1 and 1867 HSV-2 seronegative people in study 2 but at risk from a regular sexual partner with clinically confirmed genital herpes) compared recombinant HSV-2 glycoprotein-D-adjuvant vaccine versus placebo. Both study arms found that recombinant HSV-2 glycoprotein vaccine reduced the risk of infection with HSV compared with placebo in women who were previously uninfected with HSV-1 and HSV-2 (infection defined clinically or by virological or serological investigation; RR for infection 0.27, 95% CI 0.09 to 0.81 in study 1; 0.26, 95% CI 0.07 to 0.91 in study 2). However, no significant effect was found in women who were infected with HSV-1 at baseline or in men (in women with HSV-1: RR for infection 2.06, 95% CI 0.51 to 8.03; in men: RR 1.11, 95% CI 0.47 to 2.61 in study 1; RR 1.10, 95% CI 0.53 to 2.27 in study 2).

Other types of vaccine:

We found no systematic review or RCTs on other types of vaccine.

Harms

Recombinant glycoprotein vaccines versus placebo:

The first RCT reported the vaccine to be safe and well tolerated, with frequencies of local and systemic reactions similar to those stated in the literature. In the second RCT, the frequency of soreness at the injection site severe enough to prevent people from engaging in normal actions was higher with vaccine (5%) than with placebo (3% in study 1 and 1% in study 2; significance not reported). The study found no major differences between the two groups in the frequency and type of reported symptoms or withdrawal rates (no statistical values reported).

Other types of vaccine:

We found no RCTs.

Comment

Glycoprotein vaccines differ not only in the choice of recombinant herpes simplex virus molecules but also in the use of adjuvants. The use of different adjuvants may explain the inconsistent efficacy results of otherwise similar glycoprotein vaccines.

Substantive changes

No new evidence

2007; 2007: 1603.
Published online 2007 April 1.

Caesarean delivery to prevent neonatal herpes

Summary

We found no clinically important results about the effects of caesarean delivery on mother-to-baby transmission of genital herpes in mothers with genital lesions at term. ADVERSE EFFECTS Caesarian delivery carries the risk of increased maternal morbidity and mortality.

Benefits

We found no systematic review or RCTs that assessed the effects of caesarean delivery on the risk of mother to child transmission of herpes simplex virus.

Harms

Caesarean delivery is associated with significant maternal morbidity (29% of women having caesarean section) and mortality (excess maternal mortality 15/100 000 deliveries). A study pooling data from different studies estimated that, for every two neonatal deaths from herpes simplex virus prevented, a policy of caesarean delivery might cause one maternal death.

Comment

Clinical guide:

The available evidence suggests that efforts to prevent neonatal herpes simplex virus infection should focus on preventing infection in late pregnancy. The absolute risk of neonatal infection is high (AR 41%, 95% CI 26% to 56%) in babies born to women who acquire infection near the time of labour and low (AR < 3%) in women with established infection, even in those who have recurrence at term. Most women who acquire infection towards the end of pregnancy are undiagnosed, and most cases of neonatal herpes simplex virus infection are acquired from women without a history of genital herpes. Case studies indicate that the transmission of herpes simplex virus type 2 can occur, despite caesarean delivery. Countries vary in their approach to obstetric management of women with recurrent genital herpes at term. In the USA and the UK, these women are advised to have a caesarean delivery, with its attendant risks to the mother. In the Netherlands, women with recurrent genital herpes at delivery have been allowed vaginal birth since 1987. This policy has not resulted in an increase in neonatal herpes (26 cases from 1981–1986 and 19 cases from 1987–1991).

Substantive changes

No new evidence

2007; 2007: 1603.
Published online 2007 April 1.

Antiviral treatment in late pregnancy

Summary

TRANSMISSION OF INFECTION Compared with placebo: Oral antiviral agents given in late pregnancy do not reduce transmission of infection to the neonate ( high-quality evidence ). RECURRENCE OF INFECTION Compared with placebo: Oral antiviral agents reduce the recurrence of infection at term in women with first or recurrent episodes of genital herpes simplex virus during pregnancy ( moderate-quality evidence ). CAESARIAN SECTION RATE Compared with placebo: Oral antiviral agents may reduce rates of caesarian section because of genital herpes compared with placebo ( very low quality evidence ).

Benefits

Rates of neonatal herpes:

We found one systematic review (search date 2003, 5 RCTs, 799 pregnant women at 36 weeks' gestation), which reported no cases of neonatal herpes simplex virus in either the intervention or control groups. One subsequent RCT (112 women with genital herpes simplex virus type 2) comparing oral valaciclovir 500 mg twice daily versus placebo, reported no cases of neonatal herpes simplex virus before discharge or up to 2 weeks after delivery in either the valaciclovir or placebo groups.

Rate of recurrent genital herpes at term:

The review found that aciclovir 800 or 1200 mg daily significantly reduced herpes simplex virus recurrence at delivery compared with placebo (15/424 [4%] with aciclovir v 58/375 [15%] with placebo; OR 0.25, 95% CI 0.15 to 0.40). The subsequent RCT found that valaciclovir 500 mg twice daily significantly reduced herpes simplex virus recurrence in late pregnancy compared with placebo (6/57 [11%] with valaciclovir v 15/55 [27%] with placebo; RR 0.4, 95% CI 0.2 to 0.9). However, there was no significant difference between valaciclovir and placebo in the number of active herpes simplex virus lesions at delivery (3/57 [5%] with valaciclovir v 8/55 [15%] with placebo; RR 0.4, 95% CI 0.1 to 1.3) or in viral shedding by culture or polymerase chain reaction within 7 days of delivery (5/48 [10%] with valaciclovir v 6/50 [12%] with placebo; RR 0.9, 95% CI 0.3 to 2.7).

Rate of caesarean delivery for genital herpes:

The review found that aciclovir 800 or 1200 mg daily significantly reduced the rate of caesarean delivery for herpes simplex virus recurrence compared with placebo (17/424 [4%] with aciclovir v 55/375 [15%] with placebo; OR 0.30, 95% CI 0.13 to 0.67). The trials in the review were heterogeneous in terms of the dose and duration of aciclovir and the populations enrolled. The indication for caesarean delivery for maternal herpes simplex infection was mainly based on clinical diagnosis (presence of prodromal symptoms or genital lesions suspicious for genital herpes) at term. However, in one of the RCTs in the review, delivery by elective caesarean section was performed if a woman experienced a herpes recurrence later than 38 weeks' gestation. In another RCT identified by the review, one woman had a caesarean delivery for genital herpes without a clinical recurrence at term and two women with genital lesions delivered vaginally. In a third RCT identified by the review, three women in the placebo group and one woman in the aciclovir group did not have a caesarean delivery because their lesions were distant from the birth canal. The subsequent RCT found no significant difference between valaciclovir and placebo in the number of women who delivered by caesarean section for active herpes simplex virus infection (3/57 [5%] with valaciclovir v 7/55 [13%] with placebo; RR 0.4, 95%CI 0.1 to 1.5).

Harms

The systematic review gave no information on adverse effects. Two RCTs identified by the review found no short term adverse effects in any neonates exposed to aciclovir prenatally or in neonates treated prophylactically with aciclovir after delivery. A third RCT found no similar neonatal outcomes in the maternal treatment and control groups. A fourth RCT found no evidence of haematological or biochemical toxicity with aciclovir and similar rates of adverse effects between maternal treatment and control groups. However, the RCTs were underpowered to detect rare adverse effects, such as an increase in aciclovir related obstructive uropathy or infection in the newborns. They were also underpowered to detect rare effects in mothers, such as an increase in asymptomatic viral shedding. The subsequent RCT found no significant difference between valaciclovir and placebo in maternal or neonatal outcomes used to evaluate the safety of valaciclovir during pregnancy. However, this RCT was underpowered to detect differences in clinically important outcomes.

Comment

None.

Substantive changes

Oral antiviral maintenance treatment in late pregnancy (≥ 36 weeks' gestation) in women with a history of genital herpes One RCT added; categorisation unchanged (Unknown effectiveness) but benefits and harms data enhanced.

2007; 2007: 1603.
Published online 2007 April 1.

Serological screening and counselling to prevent acquisition of herpes simplex virus in late pregnancy

Summary

We found no clinically important results about the effects of either serological screening or counselling to prevent maternal infection with genital herpes in late pregnancy.

Benefits

We found no systematic review or RCTs that assessed either serological screening with type specific assays to identify women at risk for acquisition of herpes simplex virus infection in late pregnancy, or counselling to avoid genital–genital and oral–genital contact in late pregnancy.

Harms

We found no RCTs.

Comment

None.

Substantive changes

No new evidence

2007; 2007: 1603.
Published online 2007 April 1.

Oral antiviral treatment versus placebo

Summary

SYMPTOMS OF GENITAL HERPES Compared with placebo: Oral aciclovir treatment decreases the duration of lesions, symptoms, and viral shedding compared with placebo in people with a first episode of genital herpes ( moderate-quality evidence ).

Benefits

Oral aciclovir versus placebo:

We found no systematic review but we found three RCTs. The largest RCT (180 people, 119 of whom had a first episode of genital herpes) compared aciclovir (200 mg 5 times daily for 10 days) versus placebo. Analysis in people with a first episode of genital herpes (119 people) found that aciclovir significantly decreased the time to complete healing of lesions (12 days with aciclovir v 14 days with placebo; P = 0.005), reduced the formation of new lesions (percentage of people with new lesions after 48 hours of therapy: 18% with aciclovir v 62% with placebo; P = 0.001), and reduced the duration of pain (median: 5 days with aciclovir v 7 days with placebo; P = 0.05) and viral shedding (median: 2 days with aciclovir v 9 days with placebo; P < 0.001) compared with placebo. The second RCT (31 people with first episode genital herpes) compared aciclovir (200 mg 5 times daily for 5 days) versus placebo. It found that aciclovir significantly reduced the duration of viral shedding (median: 1 day with aciclovir v 13 days with placebo; P < 0.01), and duration of pain (median: 4 days with aciclovir v 8 days with placebo; P < 0.05). Aciclovir also reduced the median time to healing, but this did not reach significance (6 days with aciclovir v 11 days with placebo; P = 0.06). The third RCT (48 people [31 women, 17 men]) compared aciclovir (200 mg 5 times daily for 10 days) versus placebo. It found that aciclovir significantly reduced the duration of viral shedding (mean in women: 4.9 days with aciclovir v 17.7 days with placebo; P = 0.001; mean in men: 6 days with aciclovir v 15 days with placebo; P = 0.02) and time to crusting (mean in women: 8.8 days with aciclovir v 15.0 days with placebo; P = 0.01; mean in men: 5 days with aciclovir v 15 days with placebo; P = 0.01). No precise estimates of effectiveness were available because of the small numbers included. The largest RCT excluded 30/180 (17%) people before analysis: 10 people for not completing the study protocol, 12 because of suspected past infection, and eight because herpes simplex virus was not isolated.

Harms

Adverse effects were rare and similar in the placebo and treatment groups.

Comment

None.

Substantive changes

No new evidence

2007; 2007: 1603.
Published online 2007 April 1.

Different types of oral antiviral treatment

Summary

SYMPTOMS Valaciclovir compared with aciclovir: Oral valaciclovir is as effective as oral aciclovir at reducing symptoms in people with first episodes of genital herpes ( high-quality evidence ).

Benefits

Valaciclovir versus aciclovir:

We found no systematic review but we found one RCT (643 people), comparing oral valaciclovir (1000 mg twice daily for 10 days) versus oral aciclovir (200 mg 5 times daily for 10 days). It found no significant difference between treatments in duration of viral shedding (3 days with valaciclovir v 3 days with aciclovir; HR 1.00, 95% CI 0.84 to 1.18; P = 0.99), time to healing (9 days with valaciclovir v 9 days with aciclovir; HR 1.08, 95% CI 0.92 to 1.27; P = 0.35), and time to resolution of all symptoms (9 days with valaciclovir v 9 days with aciclovir; HR 1.02, 95% CI 0.85 to 1.22; P = 0.85).

Harms

Headache was reported in 12% [74/643] and nausea in 6% [38/643] of people receiving treatment and there was no significant difference between the aciclovir and valaciclovir groups (headache: 41/74 [55%] with valaciclovir v 33/74 [45%] with aciclovir; nausea: 18/38 [47%] with valaciclovir v 20/38 [53%] with aciclovir; significance assessment not reported for either adverse effect, reported as non-significant).

Comment

None.

Substantive changes

No new evidence

2007; 2007: 1603.
Published online 2007 April 1.

Daily oral antiviral treatment

Summary

RECURRENCE Aciclovir compared with placebo: Daily maintenance treatment with oral aciclovir reduces the frequency of recurrences of genital herpes at 1–2 years compared with placebo ( high-quality evidence ). Famciclovir compared with placebo: Daily maintenance treatment with oral famciclovir reduces the frequency of recurrences of genital herpes at 4–12 months compared with placebo ( moderate-quality evidence ). Valaciclovir compared with placebo: Daily maintenance treatment with oral valaciclovir reduces the frequency of recurrences of genital herpes at 1 year compared with placebo (high-quality evidence). QUALITY OF LIFE Oral antiviral agents compared with placebo: Daily treatment with oral aciclovir or valaciclovir improves quality of life at 3 months compared with placebo (high-quality evidence).

Benefits

Aciclovir versus placebo:

We found one non-systematic review (2 RCTs, 107 people) and four subsequent RCTs. The first RCT identified by the non-systematic review (32 people) found that aciclovir 800 mg daily significantly reduced recurrence compared with placebo at 2 years (freedom from recurrence: 5/18 [28%] with aciclovir v 0/14 [0%] with placebo; ARR 28%, 95% CI 1% to 51%). The second RCT identified by the non-systematic review (75 people) found that aciclovir (400 mg twice daily) significantly reduced recurrence compared with placebo at 1 year (freedom from recurrence: 21/48 [44%] with aciclovir v 0/28 [0%] with placebo; ARR 44%, 95% CI 26% to 56%). The first subsequent RCT (1479 people) found that aciclovir 400 mg twice daily significantly reduced recurrence compared with placebo at 1 year (freedom from recurrence: 49% with aciclovir v 5% with placebo; HR 0.21, 95% CI 0.16 to 0.27). The second subsequent RCT (1146 people) also found that aciclovir 400 mg twice daily significantly reduced recurrence compared with placebo at 1 year (recurrence rate: 2% with aciclovir v 13% with placebo; P < 0.0001). Of 210 adults in the trial who completed 5 years of continuous treatment with aciclovir, 53–70% were free of recurrence each year. The third subsequent RCT (34 women with recently acquired genital herpes simplex virus type 2 infection) found that aciclovir (400 mg twice daily for 70 days) reduced viral shedding compared with placebo. It also found that, compared with placebo, aciclovir reduced viral shedding by 95% on days with reported lesions and by 94% on days without lesions. The fourth subsequent RCT (1479 people) compared the effect of oral aciclovir 400 mg twice daily versus placebo on a genital herpes quality of life scale. It found that twice daily aciclovir treatment significantly improved health related quality of life scores compared with placebo after 3 months (mean difference in quality of life score from placebo: 5.1, 95% CI 2.9 to 7.4).

Famciclovir versus placebo:

We found one systematic review (search date not reported, 2 RCTs, 830 people). The first RCT (455 people) identified by the review compared famciclovir (250 mg twice daily, 125 mg 3 times daily, or 250 mg 3 times daily for 1 year) versus placebo. It found that famciclovir significantly increased median time to first recurrence compared with placebo (11 months with famciclovir 250 mg twice daily v 8 months with famciclovir 125 mg 3 times daily v 10 months with famciclovir 250 mg 3 times daily v 1.5 months with placebo; reported as significant; P value not reported). The second RCT identified by the review (375 women) compared famciclovir (125 mg once daily or twice daily; 250 mg once daily or twice daily; or 500 mg once daily, for 4 months) versus placebo. It found that famciclovir 125 mg twice daily, and 250 mg twice daily, significantly prolonged median time to first recurrence compared with placebo (> 120 days with famiciclovir 125 mg twice daily v 82 days with placebo; HR 1.8, 95% CI, 1.0 to 3.0; P = 0.03; > 120 days with famciclovir, 250 mg twice daily v 82 days with placebo; HR 3.6, 95% CI, 1.9 to 6.9; P < 0.001) but not with famciclovir 125 mg once daily, 250 mg once daily, or 500 mg once daily (114 days with famciclovir 125 mg once daily; > 120 days with famciclovir 250 mg once daily, and 500 mg once daily; 82 days with placebo; P > 0.05 for all comparisons with placebo). It also found that famciclovir, 250 mg twice daily significantly increased the proportion of people who remained free of clinically confirmed genital herpes episodes at 120 days compared with placebo (freedom from recurrence: 78% with 250 mg twice daily v 42% with placebo; P < 0.001). Famciclovir 250 mg twice daily was the most effective dosage for reducing recurrence.

Valaciclovir versus placebo:

We found one systematic review (search date not reported, 2 RCTs, 1861 people), which compared valaciclovir versus placebo for frequently recurring genital herpes. We found one additional RCT (1479 people), which compared the effects of oral valaciclovir (1000 mg once daily, 500 mg once daily, and 250 mg once or twice daily) on quality of life versus placebo. The first RCT identified by the review (382 people) found that valaciclovir (500 mg once daily for 16 weeks) significantly increased time to recurrence compared with placebo (HR 0.10, 95% CI 0.11 to 0.21). The second RCT identified by the review (1479 people) compared valaciclovir (1000 mg once daily, 500 mg once daily, and 250 mg once or twice daily; for 1 year), and aciclovir (400 mg twice daily) versus placebo. It found a dose–response effect across the valaciclovir regimens on freedom from recurrence compared with placebo (48–50% with valaciclovir 1000 mg once daily v 40% with valaciclovir 500 mg once daily v 48–50% with valaciclovir 250 mg once daily v 22% with valaciclovir 250 mg once daily v 5% with placebo). Valaciclovir 250 mg twice daily also improved freedom from recurrence by 40% compared with placebo. The additional RCT found that valaciclovir treatment (once or twice daily) significantly improved health related quality of life scores compared with placebo after 3 months (measured using the recurrent genital herpes quality of life questionnaire; P < 0.05).

Harms

Aciclovir, famciclovir, and valaciclovir were well tolerated. People taking aciclovir were followed for up to 7 years, and those taking famciclovir and valaciclovir for up to 1 year. Nausea and headache were infrequent, and participants rarely discontinued treatment because of adverse effects. We found no studies evaluating whether daily maintenance treatment increases high risk sexual behaviour. We found no evidence that daily treatment with aciclovir results in emergence of aciclovir resistant herpes simplex virus during or after stopping treatment in healthy adults.

Comment

None.

Substantive changes

No new evidence

2007; 2007: 1603.
Published online 2007 April 1.

Oral antiviral treatment taken at the start of recurrence

Summary

DURATION OF SYMPTOMS Aciclovir compared with placebo: Oral aciclovir taken at the start of recurrence reduces the duration of lesions and viral shedding in people with recurrent genital herpes compared with placebo ( moderate-quality evidence ). Famciclovir compared with placebo: Oral famciclovir taken at the start of recurrence reduces the duration of lesions and viral shedding compared with placebo in people with recurrent genital herpes (moderate-quality evidence). Valaciclovir compared with placebo: Oral valaciclovir taken at the start of recurrence reduces the duration of lesions and viral shedding compared with placebo in people with recurrent genital herpes ( high-quality evidence ). Oral antiviral drugs compared with each other: Aciclovir is as effective as famciclovir or valaciclovir at reducing the duration of symptoms when taken at the start of recurrence (high-quality evidence). Valaciclovir for 3 days compared with 5 days: Oral valaciclovir for 3 days is as effective at reducing the duration of symptoms compared with oral valaciclovir for 5 days (moderate-quality evidence).

Benefits

Aciclovir versus placebo:

We found no systematic review but we found one non-systematic review (number of RCTs not reported, 650 people) and one subsequent RCT. The RCTs in the review compared oral aciclovir started at the first sign of recurrence (200 mg 5 times daily or 800 mg twice daily, for 5 days) versus placebo. The review found that aciclovir reduced the period of viral shedding (1 day with aciclovir v 2 days with placebo) and duration of lesions (5 days with aciclovir v 6 days with placebo; significance not assessed) compared with placebo. The subsequent RCT (131 people with ≥ 3 recurrences in the previous 12 months, observed for ≥ 1 recurrence) found that aciclovir (800 mg 3 times daily for 2 days) significantly reduced the duration of lesions (median: 4 days with aciclovir v 6 days with placebo; P = 0.001), episodes (median: 4 days with aciclovir v 6 days with placebo; P < 0.001), and viral shedding (median: 25.0 hours with aciclovir v 58.5 hours with placebo; P = 0.04) compared with placebo.

Famciclovir versus placebo:

We found one systematic review (search date not reported; 1 RCT, 467 people). The included RCT found that oral famciclovir (125–500 mg twice daily for 5 days) significantly reduced the duration of lesions (median: 4 days with famciclovir v 5 days with placebo; P value not reported) and viral shedding (2 days with famciclovir v 3 days with placebo; P value not reported) compared with placebo. One subsequent RCT (308 people presenting within 6.5 hours of recurrence of symptoms) of clinic initiated treatment compared oral famciclovir (125, 250, or 500 mg twice daily for 5 days) versus placebo. The RCT found that, compared with placebo, all doses of famciclovir significantly reduced the time to cessation of viral shedding (125 mg: HR 3.29, 95% CI 2.19 to 4.95; 250 mg: HR 3.26, 95% CI 2.16 to 4.92; 500 mg: HR, 3.56, 95% CI, 2.29 to 5.53) and to complete healing (125 mg: HR 1.48, 95% CI 1.06 to 2.08; 250 mg: HR 1.74, 95% CI 1.23 to 2.46; 500 mg: HR 1.79, 95% CI 1.26 to 2.53). One subsequent RCT (329 people with recurrent herpes simplex virus type 2 [HSV-2] and ≥ 4 recurrences in the previous 12 months) compared famciclovir (1000 mg twice daily for 1 day) versus placebo. The RCT found that self initiated oral famciclovir significantly decreased the time to healing of aborted and non-aborted genital lesions compared with placebo (3.5 days with famciclovir v 5.0 days with placebo; P < 0.001).

Valaciclovir versus placebo:

We found one systematic review (search date not reported, 1 RCT, 987 people). The RCT identified by the review compared oral valaciclovir (500 or 1000 mg twice daily for 5 days) versus placebo. The RCT found that self initiated oral valaciclovir significantly decreased episode duration (median: 4 days with valaciclovir v 6 days with placebo; HR 1.9, 95% CI 1.6 to 2.3) and viral shedding (median: 2 days with valaciclovir v 4 days with placebo; HR 2.9, 95% CI 2.1 to 3.9), and increased the rate of aborted recurrences (31% with valaciclovir v 21% with placebo; RR 1.5, 95% CI 1.1 to 1.9) compared with placebo.

Famciclovir versus aciclovir:

We found one RCT (204 people), which found no significant difference in time to lesion healing between oral famciclovir and aciclovir (mean: 5.1 days with famciclovir v 5.4 days with aciclovir; mean difference +0.3 days, 95% CI –0.3 days to +0.8 days).

Valaciclovir versus aciclovir:

We found one systematic review (search date not reported, 1 RCT, 739 people). The included RCT compared oral valaciclovir (500 mg twice daily for 5 days) versus aciclovir (200 mg 5 times daily for 5 days). It found no significant difference in healing time (HR: 0.96, 95% CI 0.80 to 1.14), symptom duration (HR: 0.93, 95% CI 0.79 to 1.08), or viral shedding (HR: 0.98, 95% CI 0.75 to 1.27) between the two antiviral drugs.

Valaciclovir for 3 days versus 5 days:

We found two RCTs. The first RCT (531 people with ≥ 6 recurrences of genital herpes a year) found no difference between 3 and 5 days of treatment with valaciclovir 500 mg twice daily in episode duration (median: 4.7 days with 3 days of valaciclovir v 4.6 days with 5 days of valaciclovir; significance not reported) or aborted recurrences (27% with 3 days of valaciclovir v 21% with 5 days of valaciclovir; RR 1.23, 95% CI 0.92 to 1.65). People initiating treatment within 6 hours of first symptoms or signs were significantly more likely to have an aborted episode than those starting treatment after 6 hours (OR 1.93, 95% CI 1.28 to 2.9). The second RCT (800 people with ≥ 4 outbreaks of genital herpes a year) found no significant difference between 3 and 5 days of treatment with valaciclovir (500 mg twice daily) in lesion healing time (median: 4.4 days with 3 days of valaciclovir v 4.7 days with 5 days of valaciclovir, HR 0.95, 95% CI 0.81 to 1.13) or aborted lesions (25% with 3 days of valaciclovir v 27% with 5 days of valaciclovir; RR 1.04, 95% CI 0.83 to 1.32).

Harms

Adverse effects (mostly headache and nausea) were rare, and the frequency was similar for aciclovir, valaciclovir, famciclovir, and placebo (figures not reported in the review). One subsequent RCT reported adverse effects of mild to moderate severity associated with famciclovir (mostly headache, nausea, diarrhoea, abdominal pain, and dizziness).

Comment

Clinical guide:

The benefit was found to be greater if the person with recurrent herpes initiated treatment at the first symptom or sign of a recurrence, ideally within 6 hours of onset of symptoms.

Substantive changes

Oral antiviral treatment taken at the start of recurrence Two RCTs added; categorisation unchanged (Beneficial) but benefits and harms data enhanced.

2007; 2007: 1603.
Published online 2007 April 1.

Psychotherapy

Summary

RECURRENCE Compared with control: Psychotherapy may reduce recurrence rates of genital herpes ( very low-quality evidence ).

Benefits

We found one systematic review (search date 1991), which identified six poor quality studies of psychotherapeutic interventions in 69 people (4 studies had < 10 people). Interventions varied from hypnotherapy and progressive muscle relaxation to cognitive therapy and multifaceted intervention. The largest RCT (31 people with > 4 recurrences a year) compared psychosocial intervention versus social support or waiting list. Psychosocial intervention involved information on herpes simplex virus, relaxation training, stress management instructions, and an imagery technique. People receiving social support discussed their feelings and experiences relating to herpes simplex virus infection. People receiving psychosocial intervention had significantly lower recurrence rates compared with pretreatment frequency, social support, or waiting list (recurrences per year: 6 with psychosocial intervention v 11 [in total] with pretreatment, social support, and waiting list; P < 0.001). However, small numbers of people, inadequate controls, and subjective and retrospective assessment of recurrence frequency at baseline limit the usefulness of these studies.

Harms

The review and the RCT gave no information on adverse effects.

Comment

Controlled studies that include prospective clinical evaluation of disease activity are needed.

Substantive changes

No new evidence

2007; 2007: 1603.
Published online 2007 April 1.

Daily oral antiviral treatment for preventing recurrence of genital herpes

Summary

RECURRENCE Compared with placebo: Valaciclovir is more effective than placebo in preventing recurrence of herpes simplex virus infection in people with HIV ( high-quality evidence ). Compared with aciclovir: Valaciclovir is no more effective than aciclovir at preventing recurrence of herpes simplex virus infection at 48 weeks in people with HIV (high-quality evidence).

Benefits

Valaciclovir versus placebo:

We found one RCT (239 people with HIV and a history of recurrent herpes simplex virus). The RCT found that valaciclovir (500 mg twice daily) significantly reduced recurrence (AR for freedom from recurrence: 65% with valaciclovir v 26% with placebo; RR 2.5, 95% CI 1.8 to 3.5) and increased the median time to first recurrence (> 180 days with valaciclovir v 59 days with placebo; HR 16.7, 95% CI 7.3 to 33.3) compared with placebo at 6 months.

Valaciclovir versus aciclovir:

We found one RCT (1062 people), which compared three treatments: valaciclovir 500 mg twice daily, valaciclovir 1000 mg once daily, and aciclovir 400 mg twice daily for 48 weeks. It found no significant difference between either dose of valaciclovir and aciclovir in time to recurrence (HR for valaciclovir 500 mg twice daily v aciclovir: 0.73, 95% CI 0.50 to 1.06; HR for valaciclovir 1000 mg once daily v aciclovir: 1.31, 95% CI 0.94 to 1.82).

Harms

Valaciclovir versus placebo:

The RCT found that valaciclovir increased the risk of headache (13% with valaciclovir v 8% with placebo), fatigue (8% with valaciclovir v 5% with placebo), influenza (8% with valaciclovir v 3% with placebo), nasopharyngitis (8% with valaciclovir v 2% with placebo), and rash (8% with valaciclovir v 1% with placebo) compared with placebo, although rates of diarrhoea (12% with both treatments) and nausea (8% with both treatments) were similar between treatments. The RCT gave no information on adverse effects in people taking valaciclovir beyond 6 months.

Valaciclovir versus aciclovir:

The RCT found that the rate of withdrawal because of adverse effects was similar with aciclovir and valaciclovir (AR adverse effects leading to withdrawal, including nausea and headache: 11% with valaciclovir v 9% with aciclovir; significance not assessed).

Comment

Valaciclovir significantly reduced the rate of recurrences of genital herpes. However, 35% of people being treated had a recurrence within 6 months. One RCT found that recurrence was significantly more likely with valaciclovir 1000 mg taken once daily than with valaciclovir 500 mg taken twice daily (people remaining recurrence free at 48 weeks: 71% with valaciclovir 1000 mg once daily v 82% with valaciclovir 500 mg twice daily; HR 1.80, 95% CI 1.26 to 2.57; P < 0.05).

Substantive changes

No new evidence

2007; 2007: 1603.
Published online 2007 April 1.

Oral antiviral treatment versus no treatment for an acute recurrent episode of genital herpes

Summary

We found no clinically important results about the effects of oral antiviral treatment in people with HIV. Consensus regards antiviral treatment as effective for treating recurrences in people with HIV, based on evidence in people who are not immunocompromised, and in immunocompromised people without HIV.

Benefits

We found no systematic review or RCTs comparing oral antiviral treatment versus no treatment for a recurrent episode of genital herpes in peole with HIV (see comment below).

Harms

We found no RCTs.

Comment

One prospective study found an increased rate of herpes simplex virus shedding in people infected with HIV. HIV has also been detected in genital herpes lesions, suggesting that herpes simplex virus infection may increase the risk of sexual transmission of HIV.

Clinical guide:

Although we found no placebo controlled RCTs in people with HIV, consensus regards antiviral treatment as effective for treating recurrences in people with HIV, based on evidence in people who are not immunocompromised (see Oral antiviral treatment taken at the start of recurrence) and in immunocompromised people without HIV.

Substantive changes

No new evidence

2007; 2007: 1603.
Published online 2007 April 1.

Oral antiviral treatment for first episode genital herpes

Summary

We found no clinically important results about the effects of treatment of first-episode genital herpes in people with HIV. Current consensus is that oral antiviral treatment is effective for the treatment of first-episode genital herpes in people with HIV.

Benefits

We found no systematic review or RCTs examining effects of treatments for first episode genital herpes in people with HIV.

Harms

We found no RCTs.

Comment

Current consensus is that oral antiviral treatment is effective for the treatment of first episode genital herpes in people with HIV.

Substantive changes

No new evidence

2007; 2007: 1603.
Published online 2007 April 1.

Different types of oral antiviral treatment for an acute recurrent episode of genital herpes

Summary

DURATION OF SYMPTOMS Antiviral drugs compared with each other: Aciclovir is as effective as famciclovir or valaciclovir at reducing the duration of symptoms in people with HIV who have acute recurrent episodes of genital herpes ( high-quality evidence ).

Benefits

Famciclovir versus aciclovir:

We found one RCT (193 people on stable antiretroviral treatment), which compared famciclovir (500 mg twice daily) versus aciclovir (400 mg 5 times daily) for 1 week. It found no significant difference between treatments in time to healing (median: 7 days with both treatments; HR 1.01, 95% CI 0.79 to 1.29), duration of viral shedding (median: 2 days with both treatments; HR 0.93, 95% CI 0.68 to 1.27), or time to loss of symptoms (median: 4 days with both treatments; HR 0.99, 95% CI 0.75 to 1.30). It also found no significant difference between the two treatments in the risk of developing new lesions during treatment (17% with famciclovir v 13% with aciclovir; ARI +3.4%, 95% CI –4.8% to +11.5%).

Valaciclovir versus aciclovir:

We found one RCT (467 people), which compared valaciclovir (1000 mg twice daily) versus aciclovir (200 mg 5 times daily) for 5 days. It found no significant difference between treatments in time to lesion healing (HR: 0.98, 95% CI 0.79 to 1.22) or episode duration (HR: 0.93, 95% CI 0.75 to 1.14).

Harms

Famciclovir versus aciclovir:

The RCT reported that adverse effects, mostly headache (17% with famciclovir v 15% with aciclovir), nausea (11% with famciclovir v 13% with aciclovir), diarrhoea (7% with famciclovir v 11% with aciclovir), and abdominal pain (3% with famciclovir v 6% with aciclovir; significance not assessed), were experienced by more than 3% of people taking either famciclovir or aciclovir. There were no reports of either haemolytic uraemic syndrome or thrombotic thrombocytopenic purpura.

Valaciclovir versus aciclovir:

The RCT reported that adverse effects, mostly headache, nausea, and diarrhoea, were experienced by fewer than 10% of people taking either valaciclovir or aciclovir.

Comment

None.

Substantive changes

No new evidence


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