4RECOMMENDATIONS FOR TREATMENT OF GENITAL HERPES SIMPLEX VIRUS

RECOMMENDATION 1

For adults and adolescents with a first clinical episode of genital HSV infection, the WHO STI guideline recommends treatment over no treatment.

Strong recommendation, moderate quality evidence

Remarks: This recommendation also applies to people living with HIV, people who are immunocompromised, people with a severe episode and pregnant women.

RECOMMENDATION 2

For adults and adolescents with a first clinical episode of genital HSV infection, the WHO STI guideline suggests a standard dose of aciclovir over valaciclovir or famciclovir.

Conditional recommendation, moderate quality evidence

Dosages:

• aciclovir 400 mg orally thrice daily for 10 days (standard dose)
• aciclovir 200 mg orally five times daily for 10 days
• valaciclovir 500 mg orally twice daily for 10 days
• famciclovir 250 mg orally thrice daily for 10 days

Remarks: Given that follow-up visits may not be possible during the course of treatment and symptoms of the first clinical episode may be prolonged, therapy is provided for 10 days. Although the benefits of the medicines are probably similar, the costs of valaciclovir and famciclovir are higher than aciclovir, and therefore aciclovir is preferred. The choice of medicine may also depend on compliance considerations. This recommendation also applies to people living with HIV, people who are immunocompromised, people with a severe episode and pregnant women.

SUMMARY OF THE EVIDENCE

The evidence for treatment of a first clinical episode of genital HSV infection compared to no treatment was of moderate quality. Data from eight randomized controlled trials were reported in six articles comparing aciclovir to no treatment or placebo. In these trials, various oral dosages of aciclovir were used over periods of 5–10 days. One study assessed intravenous administration. The findings indicate that the duration of symptoms and lesions is probably reduced (2–4 days fewer) with aciclovir compared to placebo. Pain may be reduced by two more days (mean difference [MD]: 2.1 days fewer; 95% confidence interval (CI): 2.95–1.25). The duration of viral shedding may be reduced by nine more days (MD: 9.2 days fewer; 95% CI: 11.1–7.29). Adverse events may also be reduced with treatment compared to placebo. No studies were found comparing valaciclovir or famciclovir to no treatment. The Guideline Development Group (GDG) agreed that the magnitude of the benefits of treatment was moderate and the adverse events trivial.

The overall quality of the evidence for the comparisons between aciclovir, valaciclovir and famciclovir was moderate to low. Two studies compared aciclovir (200 mg five times daily for 7 or 10 days) to valaciclovir (300 mg or 1000 mg twice daily for 7 or 10 days). The findings indicate that the duration of symptoms, viral shedding and pain, and levels of compliance and risk of adverse events are probably similar with either medicine. Different dosages of famciclovir (125, 250, 500 or 750 mg thrice daily for 5 or 10 days) were compared to aciclovir (200 mg five times daily for 5 or 10 days) in three studies. Findings indicate that the duration of lesions, symptoms and viral shedding and risk of adverse events are probably similar with either medicine, and probably similar between 5- or 10-day treatment duration with 250 mg and 500 mg famciclovir. One other small study compared a standard dose of aciclovir at 1000 mg daily to 4000 mg daily for 10 days. Although the evidence is uncertain (i.e. very low quality for this comparison), the findings indicate that the higher daily dose (4000 mg) may reduce the duration of pain by two days, but may increase the duration of lesions by one day and may increase the risk of adverse events; the duration of viral shedding was shown to be similar with either dose.

Overall, the GDG agreed that there were trivial differences between medicines in terms of the benefits or adverse events, and trivial increases in the benefits gained from higher doses of aciclovir. The GDG also agreed that pharmacokinetic data for the different medicine regimens supported those using fewer tablets and shorter treatment durations (e.g. for 5 days). However, follow-up visits may not be possible during the course of treatment in some settings and symptoms of the first clinical episode may be prolonged, in addition to the fact that neurologic complications, such as meningitis and urinary retention, tend to occur towards the end of the episode. Therefore, although these complications are rare, the GDG agreed that therapy should be provided for a longer duration than 5 days, given the safety of the medicine, the potential benefits of the medicine and lack of concern about resistance. As there is a high probability of patients not returning for follow-up, and to facilitate procurement, packaging and dispensing, the GDG recommended a 10-day regimen rather than a range (for 7–10 days). For all medicines in the studies reviewed, quality of life and transmission of HSV or HIV were not measured. Viral shedding was measured in some studies, but the GDG agreed that this measure was not a useful surrogate for HSV transmission.

The GDG agreed that there would be little variability in patient values and preferences relating to the different medicines and treatment regimens. However, higher value is likely to be placed on reducing the number and frequency of tablets taken. Research relating to other conditions indicates that adherence to treatment regimens may be improved with simpler regimens, although when compliance was measured in the studies included for HSV treatments, compliance was similar between medicines and regimens. Overall, it was agreed that the different regimens and medicines are probably acceptable to most people. Both valaciclovir and famciclovir are more expensive than aciclovir, and famciclovir is more expensive than valaciclovir. Where the medicines are a direct cost to people with HSV, the more expensive medicines would probably reduce equity if recommended.

In summary, there are probably moderate benefits of treatment over no treatment, and trivial differences between medicines in terms of the benefits and adverse events. There is probably no important uncertainty or variability in patients values and preferences relating to the different medicines and treatment regimens, but acceptability may vary depending on the medicine dosages. All medicines are feasible to provide, but aciclovir costs less than famciclovir or valaciclovir.

RECOMMENDATION 3

For adults and adolescents with a recurrent clinical episode of genital HSV infection, the WHO STI guideline suggests treatment over no treatment.

Conditional recommendation, moderate quality evidence

Remarks: Treatment should be given within the first 24 hours of the onset of symptoms or during the prodromal phase. This recommendation also applies to people living with HIV, people who are immunocompromised and pregnant women.

RECOMMENDATION 4

For adults and adolescents with a recurrent clinical episode of genital HSV infection, the WHO STI guideline suggests the use of aciclovir over valaciclovir or famciclovir.

Conditional recommendation, moderate quality evidence

Dosages for adults, adolescents and pregnant women:

• aciclovir 400 mg orally thrice daily for 5 days, 800 mg twice daily for 5 days, or 800 mg thrice daily for 2 days
• valaciclovir 500 mg orally twice daily for 3 days
• famciclovir 250 mg twice daily for 5 days

Dosages for people living with HIV and people who are immunocompromised:

• aciclovir 400 mg orally thrice daily for 5 days
• valaciclovir 500 mg orally twice daily for 5 days
• famciclovir 500 mg orally twice daily for 5 days

Remarks: Although the benefits of the medicines are probably similar, the costs of valaciclovir and famciclovir are higher than aciclovir, and therefore aciclovir is preferred. The choice of dosage may depend on compliance considerations. Treatment should be given within the first 24 hours of the onset of symptoms or during the prodromal phase.

SUMMARY OF THE EVIDENCE

The evidence for treatment of recurrent clinical episodes of genital HSV infection that are not frequent compared to no treatment is of moderate quality, due to unclear randomization methods and/or unclear loss to follow-up in the trials. Data from 16 randomized controlled trials were reported in 13 articles, relating to the use of aciclovir (9 trials), valaciclovir (3 trials) and famciclovir (5 trials). The findings indicate that aciclovir in various dosages for 2–5 days probably reduces the duration of viral shedding (MD: 1.32 fewer days; 95% CI: 1.36–1.27), symptoms (MD: 2.02 fewer days; 95% CI: 3.27–0.77) and lesions (MD: 1.07 fewer days; 95% CI: 1.3–1.0) when compared to placebo. Valaciclovir in various dosages probably reduces the duration of viral shedding by a median of 2 days, and lesions and symptoms by 1–2 days when compared to placebo. Famciclovir in various dosages probably reduces the duration of viral shedding, lesions and symptoms by a median of 1–2 days when compared to placebo. The GDG agreed that the differences in benefits were small and the differences in harms were trivial between the medicines and no treatment. In most trials, quality of life, compliance, pain, genital HSV transmission, and HIV transmission and acquisition were not measured.

Aciclovir, valaciclovir and famciclovir were compared. Two trials compared aciclovir and valaciclovir and found that there is probably little to no difference between the two medicines in terms of duration of viral shedding, lesions and symptoms, and risk of adverse events (moderate quality evidence). One trial compared aciclovir to famciclovir and found that there may be little to no difference in the same outcomes (low quality evidence). Another trial compared famciclovir to valaciclovir and found that there is probably little to no difference in outcomes (moderate quality evidence). The GDG agreed that there were only trivial differences in benefits and harms between the medicines.

Different dosages of aciclovir were compared in two trials (200 mg five times daily for 5 days versus alternatives). The findings indicate that there may be little to no difference between the various doses in terms of duration of symptoms, lesions and viral shedding, and adverse events. Different dosages of valaciclovir were compared in four trials (500 mg twice daily for 5 days versus the same for 3 days, and versus 1000 mg twice daily for 5 days). Again findings indicate there is probably little to no difference in outcomes between the doses. Famciclovir at doses of 125, 250 or 500 mg twice daily for 5 days were compared and there may be little to no difference in outcomes across these different dosages.

There were data providing moderate to low quality evidence from three studies that compared aciclovir to placebo in people living with HIV, and two studies that compared different doses of aciclovir, valaciclovir and famciclovir. The effects were inconsistent across different doses, but most doses were provided for 5 days and generally resulted in benefits and few harms.

The GDG agreed that there would be little variability in patient values and preferences relating to the different medicines and treatment regimens. However, higher value is likely to be placed on reducing the number and frequency of tablets taken. Research relating to other conditions indicates that adherence to treatment regimens may be improved with simpler regimens, although when compliance was measured in the studies included for HSV treatments, compliance was similar between different medicines and treatment regimens. Overall, it was agreed that the different regimens and medicines are probably acceptable to most people. Since the comparisons of different dosages of medicines compared to placebo and to each other showed few differences, the GDG agreed to recommend the dosages and regimens requiring fewer days of treatment and fewer tablets per day. Both valaciclovir and famciclovir are more expensive than aciclovir, and famciclovir is more expensive than valaciclovir. Where the medicines are a direct cost to people with HSV, the more expensive medicines would probably reduce equity if recommended.

In summary, there are probably small benefits and trivial side-effects of episodic therapy over no treatment, and moderate additional costs of providing episodic treatment versus no treatment. There may be trivial differences in benefits and side-effects between the different medicines and dosages. Although there is probably no important uncertainty or variability in the values patients place on reducing the duration of lesions and other symptoms, acceptability of episodic therapy may depend on the individual. All medicines are feasible to provide, but aciclovir costs less than famciclovir or valaciclovir.

RECOMMENDATION 5

For adults and adolescents with recurrent clinical episodes of genital HSV infection that are frequent, severe or cause distress, the WHO STI guideline suggests suppressive therapy over episodic therapy, and reassessment after one year.

Conditional recommendation, moderate quality evidence

Remarks: Individuals who have frequent recurrences (e.g. 4–6 times a year or more), severe symptoms or episodes which cause distress will likely choose suppressive therapy over episodic therapy. To determine frequency or severity, episodes can be monitored for the first few months. This recommendation also applies to people living with HIV, people who are immunocompromised and pregnant women.

RECOMMENDATION 6

For adults and adolescents with recurrent clinical episodes of genital HSV infection that are frequent, severe or cause distress, the WHO STI guideline suggests aciclovir over valaciclovir or famciclovir for suppressive therapy.

Conditional recommendation, low quality evidence

Dosages for adults, adolescents and pregnant women:

• aciclovir 400 mg orally twice daily
• valaciclovir 500 mg orally once daily
• famciclovir 250 mg orally twice daily

Dosages for people living with HIV and people who are immunocompromised:

• aciclovir 400 mg orally twice daily
• valaciclovir 500 mg orally twice daily
• famciclovir 500 mg orally twice daily

Remarks: Individuals who have frequent recurrences (e.g. 4–6 times a year or more), severe symptoms or episodes which cause distress will likely choose suppressive therapy over episodic therapy. To determine frequency or severity, episodes can be monitored for the first few months. Although the benefits of the medicines may be similar, the costs of valaciclovir and famciclovir are higher than aciclovir, and therefore aciclovir is preferred. The choice of medicine may also depend on compliance considerations.

SUMMARY OF THE EVIDENCE

The evidence for suppressive therapy compared to episodic therapy of recurrent and frequent clinical episodes of genital HSV infection is of moderate quality for aciclovir therapies and valaciclovir therapies, but low quality for famciclovir therapies. Most studies included people with four or more recurrences per year and provided therapy for 6–12 months. The GDG agreed that there were large benefits with suppressive over episodic therapy and trivial differences in harms for people with frequently recurrent episodes of genital HSV infection. The GDG also agreed that treatment regimens including lower doses and fewer tablets should be recommended.

Six studies compared suppressive therapy with aciclovir (200 mg or 400 mg twice daily and 800 mg once daily) to episodic therapy with aciclovir (usually 200 mg five times daily for 5 days) and found that clinical recurrence is probably delayed and experienced by fewer people with suppressive therapy, with probably little difference in side-effects or compliance. The number of lesions with viral shedding is also probably reduced. Seven studies compared suppressive therapy with valaciclovir (250–1000 mg per day) to episodic therapy with valaciclovir (500 mg twice daily for 5 days). Clinical recurrence is probably delayed and experienced by fewer people with suppressive therapy, with probably little difference in side-effects or compliance. There may also be fewer days of pain and fewer genital HSV transmissions to partners. The number of lesions with viral shedding is also probably reduced. One study compared suppressive therapy with famciclovir (250 mg twice daily for 6 months) to episodic therapy with famciclovir (125 mg twice daily for 5 days) and found that clinical recurrence may be delayed and experienced by fewer people with suppressive therapy, and there may be little difference in quality of life, satisfaction with therapy, or side-effects.

Few studies directly compared different dosages of a specific suppressive therapy. One study compared aciclovir at 200 mg twice daily to 200 mg five times daily. The quality of evidence was low; the findings indicated little to no difference in recurrence, compliance or side-effects. Two studies compared valaciclovir 500 mg daily with 1000–3000 mg daily. There was very low quality evidence for little to no difference in the duration of episodes, genital HSV shedding and side-effects; and moderate quality evidence for little to no difference in the number of people who experienced a recurrence (risk ratio: 1.04; 95% CI: 0.94–1.16). Three studies compared famciclovir at doses greater than 250 mg twice daily to doses of 250 mg or less twice daily. The time to first recurrence is probably similar across doses with little to no difference in side-effects. There may be fewer episodes per month with the higher dose regimen, as well as fewer days of genital HSV shedding. One study compared suppressive therapy with valaciclovir to aciclovir and found that there may be little to no difference in outcomes. Another study compared famciclovir to valaciclovir and found that there is probably little to no difference in recurrences and there may also be little to no difference in side-effects and compliance, but there may be more days of genital HSV shedding with famciclovir (risk ratio: 2.23; 95% CI: 1.18–4.89).

For people living with HIV, there is moderate to low quality evidence from 13 studies reporting various outcome measures. There may be more benefits with treatment versus no treatment and the results were similar across different medicines and dosages. Medicines and dosages evaluated were aciclovir 400 mg orally twice daily, valaciclovir 500 mg orally twice daily (or 1000 mg once daily), and famciclovir 500 mg orally twice daily. The GDG agreed to recommend these doses as there is experience with them.

The GDG agreed that there is probably no variability in patient values and preferences relating to the different medicines and treatment regimens. However, higher value is likely placed on avoiding genital HSV transmission (but there were few data) and reducing the number and frequency of tablets taken. Research relating to other conditions indicates that adherence may be improved with simpler medicine regimens, although when compliance was measured in the studies included for HSV treatments, compliance was similar between medicines. Overall, it was agreed that the different regimens and medicines are probably acceptable to most people. Since the comparisons of different dosages of medicines to placebo and to each other showed only small differences, the GDG agreed to recommend the dosages and regimens requiring fewer days of treatment and fewer tablets per day. There were no included studies for cost–effectiveness, but the GDG agreed that the costs would likely be high for any of the medicines and that costs depend on the setting. Although the cost may be high for an individual, there is a small population with frequent clinical episodes of genital HSV infection requiring suppressive therapy. There may also be a potential for cost savings in terms of work productivity and health care use. The impact on equity was unclear as genital HSV infection occurs most in disadvantaged populations who may not have access to suppressive therapy. However, equity could be increased with improved access. Both valaciclovir and famciclovir are more expensive than aciclovir, and famciclovir is more expensive than valaciclovir. Where the medicines are a direct cost to people with HSV, the more expensive medicines would probably reduce equity if recommended.

In summary, the benefits of suppressive therapy over episodic therapy are probably large and the side-effects trivial. The medicines and treatment regimens are probably feasible and acceptable to individuals, but there are large costs with suppressive therapy, which may reduce equity between some populations. Less expensive medicines, such as aciclovir, may reduce the potential for this inequity.