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WHO Guidelines for the Treatment of Genital Herpes Simplex Virus. Geneva: World Health Organization; 2016.

Cover of WHO Guidelines for the Treatment of Genital Herpes Simplex Virus

WHO Guidelines for the Treatment of Genital Herpes Simplex Virus.

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ANNEX DEVIDENCE TABLES AND EVIDENCE-TO-DECISION FRAMEWORKS

RECOMMENDATION 1

Should treatment versus no treatment be provided for first clinical episodes of herpes simplex virus?
Population:First clinical episodes of herpes simplex virus
Intervention:Treatment
Comparison:No treatment
Main outcomes:Critical: Duration of clinical episode, HSV-2 severity/pain, quality of life
Important: Ulcer healing, side-effects, HSV-2 transmission, duration of shedding, compliance
Setting:Outpatient
Perspective:Population
Background:The herpes simplex virus (HSV), or herpes, is categorized into two types: herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2). Both HSV-1 and HSV-2 are highly infectious. HSV-1 is transmitted by oral-to-oral contact and mainly causes herpes labialis, or “cold sores”, but can also cause genital herpes. HSV-2 is a sexually transmitted infection (STI) that can cause genital herpes. Most infections are transmitted via asymptomatic viral shedding.
Oral antiviral medications are available for initial, episodic, and suppressive therapy; however, there is no cure for the infection. The medications can vary: aciclovir, famciclovir and valaciclovir.
In 2003, World Health Organization (WHO) guidelines recommended dosages are: aciclovir, 200 mg orally, 5 times daily for 7 days; aciclovir, 400 mg orally, 3 times daily for 7 days; valaciclovir, 1 g orally, twice daily for 7 days; or famciclovir, 250 mg orally, 3 times daily for 7 days.
The Guideline Development Group (GDG) identified the above treatments for review.

ASSESSMENT

JudgementResearch evidence
ProblemIs the problem a priority?
  • No
  • Probably no
  • Probably yes
  • Yes
  • Varies
  • Don’t know
Research evidence:
Globally in 2012, it was estimated that over 417 million people were currently infected with HSV-2. For new infections, in people 15–49 years old (2012), it was estimated at 19.2 million, of whom 11.8 million were women and 7.4 million were men. Estimates are heterogeneous across regions, but typically greater in low-and middle-income countries (with the exception of the USA). When symptoms of genital herpes occur, there are generally one or more genital or anal blisters called ulcers. First-episode infections of genital herpes are more extensive, and primary lesions last two to six weeks versus approximately one week for lesions in recurrent disease. First clinical episodes can also be associated with central nervous system, fever and flu-like symptoms. Social stigma and other social sequelae can occur. Infection with HSV-2 also may increase the risk of acquiring HIV infection. Moreover, HSV-2 can be transmitted to neonates from an infected pregnant mother.
Desirable EffectsHow substantial are the desirable anticipated effects?
  • Trivial
  • Small
  • Moderate
  • Large
  • Varies
  • Don’t know
Research evidence:
We found a Cochrane protocol by Heslop (2013), and data was provided from this review. We included 5 randomized controlled trials (RCTs) comparing aciclovir in different doses compared to placebo: Nilsen (1982), Bryson (1983), Corey (1983), Mertz (1984) and Kinghorn (1986). In addition, data from 3 RCTs pooled in Weiss (2011) were used.
We did not find studies that evaluated valaciclovir or famciclovir compared to no treatment/placebo. Data for other subgroups were not available (e.g. people with positive HIV status, people who are immunocompromised and pregnant women).
A summary of the findings from these studies is provided in the Evidence Table.
Additional considerations:
Various oral dosages of aciclovir were used and were provided for 5–10 days; 1 study assessed intravenous administration.
Differences in duration of symptoms and lesions is probably reduced with aciclovir and ranged from 2–4 days. Pain may be reduced by 2 days (mean difference [MD]: 2.1 days fewer; 95% CI: 2.95–1.25). The duration of viral shedding may be reduced by 9 days (MD: 9.2 days fewer; 95% CI: 11.1–7.29).
The GDG agreed that the effects of treatment would likely be similar in other populations (e.g. people with positive HIV status, people who are immunocompromised and pregnant women).
This data were used to also inform recommendations for people with “severe infections”. Severe infections have traditionally not been well defined, although first clinical episodes can often be severe. Therefore, the benefits would likely apply to people with “severe infections”.
Undesirable EffectsHow substantial are the undesirable anticipated effects?
  • Large
  • Moderate
  • Small
  • Trivial
  • Varies
  • Don’t know
Certainty of evidenceWhat is the overall certainty of the evidence of effects?
  • Very low
  • Low
  • Moderate
  • High
  • No included studies
Additional considerations:
Most studies did not report on randomization methods or allocation concealment. However, the GDG agreed that the omission is likely due to reporting issues in journals and likely performed in the studies. Imprecision was a factor for some outcomes due to few events but was considered with risk of bias of the studies and the evidence downgraded to moderate. The GDG agreed that it was unlikely that any negative studies were not captured. The group conceded that it was unlikely that new trials would be done, given that it might be unethical to not provide treatment.
ValuesIs there important uncertainty about or variability in how much people value the main outcomes?
  • Important uncertainty or variability
  • Possibly important uncertainty or variability
  • Probably no important uncertainty or variability
  • No important uncertainty or variability
Research evidence:
A discrete choice exercise suggested subjects’ preferences were influenced by both the treatment they follow and attributes of treatment including cost. Of all the attributes, patients place high value in unit change in chance of recurrence (1%), followed by unit change in number of tablets taken daily (1 tablet), unit change in chance of becoming infected with HIV, unit change in number of tablets taken in addition during each recurrence.
In addition, qualitative studies also suggested stigma related is also an attribute.
Balance of effectsDoes the balance between desirable and undesirable effects favour the intervention or the comparison?
  • Favours the comparison
  • Probably favours the comparison
  • Does not favour either the intervention or the comparison
  • Probably favours the intervention
  • Favours the intervention
  • Varies
  • Don’t know
Resources requiredHow large are the resource requirements (costs)?
  • Large costs
  • Moderate costs
  • Negligible costs and savings
  • Moderate savings
  • Large savings
  • Varies
  • Don’t know
ABCD*EF
Aciclovir 200 mg po55–10 days$0.05$1.25 to $2.50$1.56 to $3.12
Aciclovir 400 mg po35–10 days$0.04$0.60 to $1.20$0.75 to $1.50
Valaciclovir 500 mg – 1 g po25–10 days$0.625$6.25 to $12.50$7.81 to $15.60
Famciclovir 250 mg po35–10 days$4.38$13.14 to $26.28$16.42 to $32.85
*Sources: International drug price indicator guide (MSH, 2015) and www​.drugs.com
A: treatment; B: doses per day; C: treatment duration; D: drug cost per dose; E: drug cost per full-course treatment; F: 25% procurement as defined by International drug price indicator guide (MSH, 2015).
po: orally
Additional considerations:
The GDG wondered why the higher dose was less expensive than the smaller one and assumed this was due to economies of scale. The group concluded that across several settings, the cost was probably considered moderate, although valaciclovir was more expensive than aciclovir, and famciclovir was known to be the most expensive.
Certainty of evidence of required resourcesWhat is the certainty of the evidence of resource requirements (costs)?
  • Very low
  • Low
  • Moderate
  • High
  • No included studies
Research evidence:
Data for cost not based on research studies.
Additional considerations:
None
Cost effectivenessDoes the cost-effectiveness of the intervention favour the intervention or the comparison?
  • Favours the comparison
  • Probably favours the comparison
  • Does not favour either the intervention or the comparison
  • Probably favours the intervention
  • Favours the intervention
  • Varies
  • No included studies
Research evidence:
No research evidence available.
Additional considerations:
The GDG agreed that there were moderate costs for moderate benefits. Therefore, the treatment is favoured over the placebo.
EquityWhat would be the impact on health equity?
  • Reduced
  • Probably reduced
  • Probably no impact
  • Probably increased
  • Increased
  • Varies
  • Don’t know
Research evidence:
No research evidence available.
Additional considerations:
Out of pocket expenses may affect people differently in countries. If covered, then it would not lead to out-of-pocket payments and not lead to inequity.
The GDG agreed that equity effects were unclear. If the drugs are too expensive, equity would only increase for those who can pay for it in out-of-pocket payments. However, a recommendation could lead to better coverage.
AcceptabilityIs the intervention acceptable to key stakeholders?
  • No
  • Probably no
  • Probably yes
  • Yes
  • Varies
  • Don’t know
Research evidence:
We searched for reviews and studies specific to herpes treatment acceptability. A systematic review of the literature for treatment utilization in sexually transmitted diseases (in India) reported that utilization ranged from 16% to 55% in the community-based studies and was higher (~70%) in research trials.
Treatment may not be acceptable to patients due to the resources and availability of services, social factors and distance. Non-utilization was also due to ignorance, illiteracy and lack of awareness; and women reported a lack of female doctors, being afraid of results and judgement of doctors, stigma, shyness and embarrassment. Cost of care and less faith in clinical care were also factors. Compliance data from some RCTs (see Evidence tables) indicated little or no difference in compliance between different regimens. An overview of reviews of medication adherence (Ryan, 2014) reported that adherence may be improved with simpler drug regimens. However, when compliance was measured in the studies included for HSV treatments, compliance was similar between drugs.
Additional considerations:
The GDG agreed that if personal payment was required for drugs, it may not be acceptable. The GDG did not believe that the drugs would be unacceptable to key stakeholders, other than by availability and cost.
FeasibilityIs the intervention feasible to implement?
  • No
  • Probably no
  • Probably yes
  • Yes
Research evidence:
No research evidence available.
Additional considerations:
The treatment was considered widely available, but cost was still a concern. Additionally, there was concern that the drug might not be paid for by health systems or donors as the infection was considered recurrent, ignoring the more detrimental effects of the first infection.

SUMMARY OF JUDGEMENTS

Judgement
ProblemNoProbably noProbably yesYesVariesDon’t know
Desirable EffectsTrivialSmallModerateLargeVariesDon’t know
Undesirable EffectsLargeModerateSmallTrivialVariesDon’t know
Certainty of evidenceVery lowLowModerateHighNo included studies
ValuesImportant uncertainty or variabilityPossibly important uncertainty or variabilityProbably no important uncertainty or variabilityNo important uncertainty or variability
Balance of effectsFavours the comparisonProbably favours the comparisonDoes not favour either the intervention or the comparisonProbably favours the interventionFavours the interventionVariesDon’t know
Resources requiredLarge costsModerate costsNegligible costs and savingsModerate savingsLarge savingsVariesDon’t know
Certainty of evidence of required resourcesVery lowLowModerateHighNo included studies
Cost effectivenessFavours the comparisonProbably favours the comparisonDoes not favour either the intervention or the comparisonProbably favours the interventionFavours the interventionVariesNo included studies
EquityReducedProbably reducedProbably no impactProbably increasedIncreasedVariesDon’t know
AcceptabilityNoProbably noProbably yesYesVariesDon’t know
FeasibilityNoProbably noProbably yesYesVariesDon’t know

CONCLUSIONS

Should treatment versus no treatment be provided for first clinical episodes of herpes simplex virus type 2?
Type of recommendationStrong recommendation against the interventionConditional recommendation against the interventionConditional recommendation for either the intervention or the comparisonConditional recommendation for the interventionStrong recommendation for the intervention
RecommendationFor 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.
JustificationThe 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 GDG agreed that the magnitude of the benefits of treatment was moderate and the adverse events trivial.
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.
Subgroup considerationsThis recommendation also applies to people living with HIV, people who are immunocompromised, people with a severe episode and pregnant women.
Implementation considerations
Monitoring and evaluation
Research prioritiesLittle evidence was found for outcomes critical to making decisions about drugs to treat first or recurrent episodes of genital HSV infections. Important patient outcomes should be measured in clinical trials, such as genital HSV acquisition and transmission, HIV acquisition and transmission, quality of life and pain. There were few available data for direct comparisons of different drugs, in particular, for comparisons with famciclovir. There were also few studies comparing the different dosages of the drugs. Future research could use the dosages recommended in these guidelines as comparators. Equity issues, acceptance of and compliance with different drugs and regimens should also be explored in people with genital HSV infections. Although this search was not limited to different populations, there were few data for key populations, such as people with HIV infection, people who were immunocompromised and pregnant women. More information can also be provided to allow for the critical appraisal of clinical trials by following the standards of reporting of RCTs, in particular for the methods of randomization and allocation concealment and blinding.

EVIDENCE TABLE

Aciclovir versus placebo

Bryson 1983Aciclovir: 200 mg capsule po) 5 × a day × 10 days
Placebo: placebo capsule po 5 × a day × 10 days
Kinghorn 1986Aciclovir: 200 mg tablets po 5 × a day × 7 days
Placebo: placebo tablets po 5 × a day × 7 days
Nilsen 1982Aciclovir: 2 × 100 mg capsules po 5 × a day × 5 days
Placebo: 2 placebo capsules po 5 × a day × 5 days
Mertz 1984Aciclovir: 200 mg capsule po 5 × a day × 10 days
Placebo: placebo capsule po 5 × a day × 10 days
Corey 1983Aciclovir intravenous (IV): 5 mg/kg IV over 1 hour × 5 days (15 doses) every 8 hours
Placebo: normal saline IV over 1 hour 5 days (15 doses), every 8 hours
Weiss 2011 (Maynaud 2009, Phiri 2010, Paz-Bailey 2009)Aciclovir 400 mg 3 × a day × 5 days OR aciclovir 800 mg 2 × a day × 5 days
Placebo 3 × a day × 5 days OR placebo 2 × a day × 5 days

IV: intravenous; po: orally

Quality assessmentNo. of patientsEffectQualityImportance
No. of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsAciclovirPlaceboRelative (95% CI)Absolute (95% CI)
Duration of symptoms from onset of treatment (assessed with: time to resolution)
5Randomized trialsNot serious1Not seriousNot seriousSerious1None119119_MD 3.2 days fewer (4.94–1.46 fewer)2⊕⊕⊕○
MODERATE
CRITICAL
Pain
3Randomized trialsSerious3Not seriousNot seriousSerious3None6960_MD 2.1 days fewer (2.95–1.25 fewer)4⊕⊕○○
LOW
CRITICAL
Quality of life – not measuredCRITICAL
Duration of lesions from onset of treatment
5Randomized trialsNot serious1Not seriousNot seriousSerious1None197193_MD 3.51 days fewer (6.19–0.82 fewer)1⊕⊕⊕○
MODERATE
IMPORTANT
Duration of viral shedding
3Randomized trialsSerious3Not seriousNot seriousSerious3None6960_MD 9.2 days fewer (11.1–7.29 fewer)5⊕⊕○○
LOW
IMPORTANT
Adverse Events – any adverse event
2Randomized trialsSerious3Not seriousNot seriousSerious3None11/130 (8.5%)15/133 (11.3%)RR 0.74 (0.36– 1.53)29 fewer per 1000 (from 60 more to 72 fewer)⊕⊕○○
LOW
IMPORTANT
HSV-2 transmission – not measured

CI: confidence interval; MD: mean difference

1

Randomization and blinding process were unclear in most studies but not downgraded and instead considered with imprecision due to few participants.

2

Two of the five studies were used in the meta-analysis, with similar results in the other three. Weiss (2011) also reported slightly faster healing with aciclovir (P = 0.04) but in people with HSV-2 or other ulcers.

3

Randomization and blinding process were unclear, and there was imprecision due to few participants.

4

Kinghorn (1986) reported MD. Two other studies (Corey 1983 and Nilsen 1982) reported median values that were consistent.

5

MD from one study and the two other studies showed consistent results. The 95% CI did not exclude no difference between the interventions.

REFERENCES
    Systematic review
    1.
    Heslop R, Roberts H, Flower D, Jordan V. Interventions for men and women with their first episode of genital herpes. Cochrane Database Syst Rev. 2016;(8):CD010684. [PMC free article: PMC8502075] [PubMed: 27575957]
    Included studies
    1.
    Bryson YJ, Dillon M, Lovett M. Treatment of first episodes of genital herpes simplex virus infection with oral acyclovir. A randomized double-blind controlled trial in normal subjects. N Engl J Med. 1983;308(16):916–21. [PubMed: 6339923]
    2.
    Kinghorn GR, Abeywickreme I, Jeavons M. Efficacy of combined treatment with oral and topical acyclovir in first episode genital herpes. Genitourin Med. 1986;62(3):186–8. [PMC free article: PMC1011934] [PubMed: 3525386]
    3.
    Nilsen AE, Aasen T, Halsos AM. Efficacy of oral acyclovir in the treatment of initial and recurrent genital herpes. Lancet. 1982;2(8298):571–3. [PubMed: 6125728]
    4.
    Mertz GJ, Critchlow CW, Benedetti J. Double-blind placebo-controlled trial or oral acyclovir in first-episode genital herpes simplex virus infection. JAMA. 1984;252(9):1147–51. [PubMed: 6088819]
    5.
    Corey L, Fife KH, Benedetti JK. Intravenous acyclovir for the treatment of primary genital herpes. Ann Int Med. 1983;98(6):914–20. [PubMed: 6305244]
    6.
    Weiss HA, Paz Bailey G, Phiri S, Gresenguet G, LeGoff J, Pepin J, et al. Episodic therapy for genital herpes in sub-Saharan Africa: a pooled analysis from three randomized controlled trials. PLoS One. 2011;6(7):e22601. [PMC free article: PMC3143155] [PubMed: 21799914] [CrossRef]
    a. Mayaud P, Legoff J, Weiss HA, Gresenguet G, Nzambi K, Bouhlal H, et al. ANRS 1212 Study Group. Impact of acyclovir on genital and plasma HIV-1 RNA, genital herpes simplex virus type 2 DNA, and ulcer healing among HIV-1-infected African women with herpes ulcers: a randomized placebo-controlled trial. J Infect Dis. 2009;200(2):216–26. [PubMed: 19530940] [CrossRef]
    b. Phiri S, Hoffman IF, Weiss HA, Martinson F, Nyirenda N, Kamwendo D, et al. Impact of aciclovir on ulcer healing, lesional, genital and plasma HIV-1 RNA among patients with genital ulcer disease in Malawi. Sex Transm Infect. 2010;86(5):345–52. [PubMed: 20444742] [CrossRef]
    c. Paz-Bailey G, Sternberg M, Puren AJ, Markowitz LE, Ballard R, Delany S, et al. Improvement in healing and reduction in HIV shedding with episodic acyclovir therapy as part of syndromic management among men: a randomized, controlled trial. J Infect Dis. 2009;200(7):1039–49. [PubMed: 19715417] [CrossRef]
    Patient values and preferences, acceptability and cost: specific to herpes simplex virus infections
    1.
    Scalone L, Ryan M, Kotsopoulos N, Patel R. Evaluation of patients’ preferences for genital herpes treatment. Sex Transm Dis. 2011;38(9):802–7. [PubMed: 21844733] [CrossRef]
    2.
    International drug price indicator guide, 2014 edition (updated annually). Medford (MA): Management Sciences for Health; 2015. [accessed 6 June 2016]. http://erc​.msh.org/dmpguide​/pdf/DrugPriceGuide_2014.pdf.
    Patient values and preferences, acceptability and cost: other sexually transmitted infections and conditions
    1.
    Nagarkar A, Mhaskar P. A systematic review on the prevalence and utilization of health care services for reproductive tract infections/sexually transmitted infections: evidence from India. Indian J Sex Transm Dis. 2015;36(1):18–25. [PMC free article: PMC4555893] [PubMed: 26392649] [CrossRef]
    2.
    Ryan R, Santesso N, Lowe D, Hill S, Grimshaw J, Prictor M, et al. Interventions to improve safe and effective medicines use by consumers: an overview of systematic reviews. Cochrane Database Syst Rev. 2014;(4):CD007768. [PMC free article: PMC6491214] [PubMed: 24777444]
    Additional references
    1.
    Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386(9995):743–800. [PMC free article: PMC4561509] [PubMed: 26063472] [CrossRef]
    2.
    Newman L, Rowley J, Vander Hoorn S, Wijesooriya NS, Unemo M, Low N, et al. Global estimates of the prevalence and incidence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting. PLoS One. 2015;10(12):e0143304. [PMC free article: PMC4672879] [PubMed: 26646541] [CrossRef]

RECOMMENDATION 2

Should aciclovir, valaciclovir or famciclovir be used for the treatment of first clinical episodes of herpes simplex virus type 2 infections?
Population:First clinical episodes of HSV-2
Intervention or Comparison:Aciclovir, Valaciclovir, Famciclovir
Main outcomes:Critical: Duration of clinical episode, HSV-2 severity/pain, quality of life
Important: Ulcer healing, side-effects, HSV-2 transmission, duration of shedding, compliance For pregnant women critical outcomes: Maternal outcomes (caesarean section), fetal outcomes (neonatal herpes – meningo-encephalitis, fever, hepatitis), teratogenicity, fetal loss, toxicity, neonatal death)
Setting:Outpatient
Perspective:Population
Background:The herpes simplex virus (HSV), or herpes, is categorized into two types: herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2). Both HSV-1 and HSV-2 are highly infectious. HSV-1 is transmitted by oral-to-oral contact and mainly causes herpes labialis, or “cold sores”, but can also cause genital herpes. HSV-2 is a sexually transmitted infection that can cause genital herpes. Most infections are transmitted via asymptomatic viral shedding.
Oral antiviral medications are available for initial, episodic and suppressive therapy; however, there is no cure for the infection. The medications can vary: aciclovir, famciclovir and valaciclovir.
In 2003, WHO guidelines recommended aciclovir, 200 mg orally, 5 times daily for 7 days; aciclovir, 400 mg orally, 3 times daily for 7 days; valaciclovir, 1 g orally, twice daily for 7 days; or famciclovir, 250 mg orally, 3 times daily for 7 days. The Guideline Development Group (GDG) identified these treatments for review.

ASSESSMENT

JudgementResearch evidence
ProblemIs the problem a priority?
  • No
  • Probably no
  • Probably yes
  • Yes
  • Varies
  • Don’t know
Research evidence:
Globally, in 2012, it was estimated that over 417 million people were currently infected with HSV-2. For new infections in people 15–49 years old (2012), it was estimated at 19.2 million, of whom 11.8 million were women and 7.4 million were men. Estimates are heterogeneous across regions, but typically greater in low and middle–income countries (with the exception of US). When symptoms of genital herpes occur, there are generally one or more genital or anal blisters called ulcers. First-episode genital herpes infections are more extensive, and primary lesions last two to six weeks versus approximately one week for lesions in recurrent disease. First clinical episodes can also be associated with central nervous system, fever and flu-like symptoms. Social stigma and other social sequelae can occur. Infection with HSV-2 also may increase the risk of acquiring HIV infection. Moreover, HSV-2 can be transmitted to neonates from an infected pregnant mother.
Desirable EffectsHow substantial are the desirable anticipated effects?
  • Trivial
  • Small
  • Moderate
  • Large
  • Varies
  • Don’t know
Research evidence:
We found a Cochrane protocol by Heslop (2013), and data was provided from this review.
We included 3 RCTs comparing valaciclovir to aciclovir, famciclovir to aciclovir, and aciclovir at different doses. We also added Loveless (1997) from our search, which was an analysis of three RCTs comparing famciclovir to aciclovir.
Data for other subgroups was not available (e.g. people with positive HIV status, people who are immunocompromised, and pregnant women).
A summary of the findings from these studies is provided in the evidence tables.
Additional considerations:
No data was available for certain dosages.
Different dosages of aciclovir, valaciclovir and famciclovir were compared with each other. Two trials compared aciclovir and valaciclovir and found that there were probably little-to-no differences for duration of viral shedding, lesions, symptoms and adverse events (moderate quality evidence). One trial compared aciclovir to famciclovir and found that there may be little-to-no differences for outcomes (low quality evidence). Another trial compared famciclovir to valaciclovir and found that there were probably little-to-no differences for outcomes (moderate quality evidence). The GDG agreed that there are trivial differences in benefits and harms between treatments.
Different dosages of aciclovir were compared in two trials (200 mg 5 times daily for 5 days versus alternatives). There may be little-to-no difference between the doses for outcomes. Different dosages of valaciclovir were compared in 4 trials (500 mg twice daily for 5 days versus alternatives). There are probably little-to-no differences between the doses for outcomes. Famciclovir at 125, 250 or 500 mg twice daily for 5 days were compared, and there may be little-to-no differences in outcomes across the different dosages.
For all drugs, quality of life and HSV or HIV transmission 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.
Undesirable EffectsHow substantial are the undesirable anticipated effects?
  • Large
  • Moderate
  • Small
  • Trivial
  • Varies
  • Don’t know
Certainty of evidenceWhat is the overall certainty of the evidence of effects?
  • Very low
  • Low
  • Moderate
  • High
  • No included studies
Additional considerations:
The quality of the evidence was moderate for some comparisons, but low quality for other comparisons and very low quality for comparisons (e.g. high- and low-dose aciclovir).
Most studies did not report on randomization methods or allocation concealment. However, the GDG agreed that the omission is likely due to reporting issues in journals and likely performed in the studies. Imprecision was a factor for some outcomes due to few events but was considered with risk of bias of the studies and the evidence downgraded to moderate. The GDG agreed that it is unlikely that negative studies were not captured.
ValuesIs there important uncertainty about or variability in how much people value the main outcomes?
  • Important uncertainty or variability
  • Possibly important uncertainty or variability
  • Probably no important uncertainty or variability
  • No important uncertainty or variability
  • No known undesirable outcomes
Research evidence:
A discrete choice exercise suggested subjects’ preferences were influenced by both the treatment they follow and attributes of treatment including cost. Of all the attributes, patients place high value in unit change in chance of recurrence (1%), followed by unit change in number of tablets taken daily (1 tablet), unit change in chance of becoming infected with HIV, unit change in number of tablets taken in addition during each recurrence.
Qualitative studies also suggested stigma related was important.
Balance of effectsDoes the balance between desirable and undesirable effects favour the intervention or the comparison?
  • Favours the comparison
  • Probably favours the comparison
  • Does not favour either the intervention or the comparison
  • Probably favours the intervention
  • Favours the intervention
  • Varies
  • Don’t know
Research evidence:
No research evidence was identified.
Additional considerations:
The GDG agreed that the differences between drugs were trivial for benefits and harms and therefore did not favour one over another. Other factors such as cost, feasibility, acceptability, may decide use.
Resources requiredHow large are the resource requirements (costs)?
  • Large costs
  • Moderate costs
  • Negligible costs and savings
  • Moderate savings
  • Large savings
  • Varies
  • Don’t know
Research evidence:
ABCD*EF
aciclovir 200 mg po55–10 days$0.05$1.25 to $2.50$1.56 to $3.12
aciclovir 400 mg po35–10 days$0.04$0.60 to $1.20$0.75 to $1.50
valaciclovir 500 mg – 1 g po25–10 days$0.625$6.25 to $12.50$7.81 to $15.60
famciclovir 250 mg po35–10 days$4.38$13.14 to $26.28$16.42 to $32.80
*Sources: International drug price indicator guide (MSH, 2015) and www​.drugs.com
A: treatment; B: dose per day; C: treatment duration; D: drug cost, per dose; E: drug cost per full-course treatment; F: 25% procurement as defined by International drug price indicator guide (MSH, 2015)
po: orally
Additional considerations:
The GDG wondered why the higher dose was less expensive than the smaller one and assumed this was due to economies of scale. The group concluded that across several settings, the cost was probably considered moderate, although valaciclovir was more expensive than aciclovir, and famciclovir was known to be the most expensive. Valaciclovir is approximately 10 times more expensive than aciclovir.
Certainty of evidence of required resourcesWhat is the certainty of the evidence of resource requirements (costs)?
  • Very low
  • Low
  • Moderate
  • High
  • No included studies
Research evidence:
No research evidence available.
Cost effectivenessDoes the cost-effectiveness of the intervention favour the intervention or the comparison?
  • Favours the comparison
  • Probably favours the comparison
  • Does not favour either the intervention or the comparison
  • Probably favours the intervention
  • Favours the intervention
  • Varies
  • No included studies
Research evidence:
No research evidence available.
Additional considerations:
The GDG agreed that there were moderate costs for moderate benefits. However, cost effectiveness would vary with aciclovir versus famciclovir or valaciclovir.
EquityWhat would be the impact on health equity?
  • Reduced
  • Probably reduced
  • Probably no impact
  • Probably increased
  • Increased
  • Varies
  • Don’t know
Research evidence:
No research evidence was identified.
Additional considerations:
Out of pocket expenses may affect people differently in countries.
If coverage, then would not lead to out of pocket payments and not lead to inequity.
The GDG agreed that equity effects were unclear. If the drugs were too expensive, equity would only increase for those who can pay for it in out of pocket payments. However, a recommendation could lead to better coverage. Overall, the GDG was concerned that higher costs of valaciclovir and famciclovir could contribute to decreasing equity if recommended.
AcceptabilityIs the intervention acceptable to key stakeholders?
  • No
  • Probably no
  • Probably yes
  • Yes
  • Varies
  • Don’t know
Research evidence:
We searched for reviews and studies specific to herpes treatment acceptability. A systematic review of the literature for use of treatments in sexually transmitted diseases (in India) reported that utilization ranged from 16% to 55% in the community-based studies and was higher (~70%) in research trials.
Treatment might not be acceptable to patients due to the resources and availability of services, social factors, and distance. Non-utilization was also due to ignorance, illiteracy and lack of awareness; and women reported a lack of female doctors, being afraid of results and judgement of doctors, stigma, shyness, and embarrassment. Cost of care and less faith in clinical care were also factors.
An overview of reviews of medication adherence (Ryan, 2014) reported that adherence might be improved with simpler drug regimens. However, when compliance was measured in the studies included for HSV treatments, compliance was similar between drugs.
Additional considerations:
The GDG suggested that the easier regimen of valaciclovir could be beneficial in settings that could afford it and where compliance was an issue. However, there was little-to-no difference in compliance when measured in trials, and compliance is likely dependent on the presence of symptoms.
The GDG agreed that if personal payment was required for drugs, it might not be acceptable.
The GDG did not believe that the drugs would be unacceptable to key stakeholders, other than by availability and cost.
FeasibilityIs the intervention feasible to implement?
  • No
  • Probably no
  • Probably yes
  • Yes
  • Varies
  • Don’t know
Research evidence:
No research evidence was identified.
Additional considerations:
The treatment was considered widely available, but cost was still a concern. Additionally, there was concern that the drug might not be paid for by health systems or donors as the infection was considered recurrent, ignoring the more detrimental effects of the first infection.
The GDG agreed that follow-up during the course of treatment might not be possible in some settings, and symptoms of the first clinical episode might be prolonged. For these reasons, the GDG agreed that therapy for a longer duration should be provided (e.g. for 10 days).

SUMMARY OF JUDGEMENTS

Judgement
ProblemNoProbably noProbably yesYesVariesDon’t know
Desirable EffectsTrivialSmallModerateLargeVariesDon’t know
Undesirable EffectsLargeModerateSmallTrivialVariesDon’t know
Certainty of evidenceVery lowLowModerateHighNo included studies
ValuesImportant uncertainty or variabilityPossibly important uncertainty or variabilityProbably no important uncertainty or variabilityNo important uncertainty or variabilityNo known undesirable outcomes
Balance of effectsFavours the comparisonProbably favours the comparisonDoes not favour either the intervention or the comparisonProbably favours the interventionFavours the interventionVariesDon’t know
Resources requiredLarge costsModerate costsNegligible costs and savingsModerate savingsLarge savingsVariesDon’t know
Certainty of evidence of required resourcesVery lowLowModerateHighNo included studies
Cost effectivenessFavours the comparisonProbably favours the comparisonDoes not favour either the intervention or the comparisonProbably favours the interventionFavours the interventionVariesNo included studies
EquityReducedProbably reducedProbably no impactProbably increasedIncreasedVariesDon’t know
AcceptabilityNoProbably noProbably yesYesVariesDon’t know
FeasibilityNoProbably noProbably yesYesVariesDon’t know

CONCLUSIONS

Should aciclovir, valaciclovir or famciclovir be used for the treatment of first clinical episodes of herpes simplex virus type 2 infections?
Type of recommendationStrong recommendation against the interventionConditional recommendation against the interventionConditional recommendation for either the intervention or the comparisonConditional recommendation for the interventionStrong recommendation for the intervention
RecommendationFor 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 5 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.
JustificationThe 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.
Subgroup considerationsThis recommendation also applies to people living with HIV, people who are immunocompromised, people with a severe episode and pregnant women.
Implementation considerations
Monitoring and evaluation
Research prioritiesLittle evidence was found for outcomes critical to making decisions about drugs to treat first or recurrent episodes of genital HSV infections. Important patient outcomes should be measured in clinical trials, such as genital HSV acquisition and transmission, HIV acquisition and transmission, quality of life and pain. There were few available data for direct comparisons of different drugs, in particular for comparisons with famciclovir. There were also few studies comparing the different dosages of the drugs. Future research could use the dosages recommended in these guidelines as comparators. Equity issues, acceptance of and compliance with different drugs and regimens should also be explored in people with genital HSV infections. Although this search was not limited to different populations, there were few data for key populations, such as people with HIV infection, people who are immunocompromised and pregnant women. More information can also be provided to allow for the critical appraisal of clinical trials by following the standards of reporting of RCTs, in particular for the methods of randomization and allocation concealment and blinding.

EVIDENCE TABLES

Aciclovir versus valaciclovir

Fife 1997valaciclovir 1000 mg 2 × a day × 10 days
aciclovir 200 mg 5 × a day × 10 days
Lai 2000aciclovir 200 mg 5 × a day × 7–10 days
valaciclovir 300 mg 2 × a day × 7–10 days
Quality assessmentNo. of patientsEffectQualityImportance
No. of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOtherValaciclovirAciclovirRelative (95% CI)Absolute (95% CI)
Duration of symptoms from onset of treatment
2Randomized trialsSerious1Not seriousNot seriousNot serious1None336335MD 0.3 days more (0.81 fewer to 1.41 more)2⊕⊕⊕○
MODERATE
CRITICAL
Quality of life – not measured
Pain
1Randomized trialsSerious1Not seriousNot seriousNot serious1None323320Median 5 days in each group3⊕⊕⊕○
MODERATE
CRITICAL
Duration of viral shedding
1Randomized trialsSerious1Not seriousNot seriousNot serious1None323320Median 3 days in each group4⊕⊕⊕○
MODERATE
IMPORTANT
HSV-2 transmission – not measured
Adverse events – any adverse event
2Randomized trialsSerious1Not seriousNot seriousNot serious1None61/336 (18.2%)54/335 (16.1%)RR 1.12 (0.81– 1.57)19 more per 1000 (from 31 fewer to 92 more)⊕⊕⊕○
MODERATE
IMPORTANT
Compliance
1Randomized trialsSerious1Not seriousNot seriousNot serious1NoneThe patients were generally compliant: only 46 patients (25 receiving valaciclovir and 21 receiving aciclovir) failed to take at least 80% of their study medication.⊕⊕⊕○
MODERATE
IMPORTANT

MD: mean difference; HR: hazard ratio; RR: relative risk

1

Unclear randomization, blinding and loss to follow-up in some trials but considered with some imprecision around the effect.

2

MD reported from one study, and the larger study (n = 643) reported HR 1.02 (0.85–1.22).

3

HR 1.0 (0.85–1.18) also reported

4

HR also reported 1.01 (0.85–1.20).

FAMCICLOVIR VERSUS ACICLOVIR

Loveless 1997 (data from 3 RCTs)famciclovir tid 250 mg, 500 mg or 750 mg × 5 days
aciclovir 200 mg 5 × daily × 5 days
famciclovir tid 125 mg, 250 mg or 500 mg × 10 days
aciclovir 200 mg 5 × daily × 10 days
Quality assessmentNo. of patientsEffectQualityImportance
No. of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOtherFamciclovirAciclovir
Duration of lesions from onset of treatment (assessed with: median time to complete healing)
3Randomized trialsSerious1Not seriousNot seriousNot seriousNone712238Median 7–8 days with famciclovir and 6–7 days with aciclovir (similar)⊕⊕⊕○
MODERATE
IMPORTANT
Pain – not measured
Quality of life – not measured
Adverse events – Drug toxicity (assessed with: number of events)
3Randomized trialsSerious1Not seriousNot seriousNot seriousNone712238Mild nausea and dizziness reported events with famciclovir⊕⊕⊕○
MODERATE
CRITICAL
Duration of symptoms from onset of treatment
3Randomized trialsSerious1Not seriousNot seriousNot seriousNone375123Median 6–8 days for 5-day famciclovir, 8–12 days for 10-day famciclovir and 7–13 days with aciclovir (similar)⊕⊕⊕○
MODERATE
IMPORTANT
HSV-2 transmission – not measured
Compliance – not measured
Duration of viral shedding (median time to cessation viral shedding)
3Randomized trialsSerious1Not seriousNot seriousNot seriousNone555190Median 2–3 days with famciclovir and 3 days with aciclovir (similar)⊕⊕⊕○
MODERATE
IMPORTANT

CI: confidence intervals; MD: mean difference; RR: relative risk

1

Unclear randomization process, and some imprecision of results and CI.

FAMCICLOVIR (5 DAYS) VERSUS FAMCICLOVIR (10 DAYS)

Quality assessmentNo. of patientsEffectQualityImportance
No. of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOtherFamciclovir 5 daysFamciclovir 10 days
Duration of lesions from onset of treatment (assessed with: median time complete healing)
3Randomized trialsSerious1Not seriousNot seriousNot seriousNone285427Median 7–8 days (similar)⊕⊕⊕○
MODERATE
IMPORTANT
Pain – not measured
Quality of life – not measured
Adverse events – drug toxicity (assessed with: number of events)
3Randomized trialsSerious1Not seriousNot seriousNot seriousNone285427Mild nausea and dizziness reported events with famciclovir⊕⊕⊕○
MODERATE
CRITICAL
Duration of symptoms from onset of treatment (assessed with: time to loss of symptoms)
3Randomized trialsSerious1Not seriousNot seriousNot seriousNone150225Median 6–8 days for 5 days and 8–12 days for 10 days (similar)⊕⊕⊕○
MODERATE
IMPORTANT
HSV-2 transmission – not measured
Compliance – not measured
Duration of viral shedding (median time to cessation viral shedding)
3Randomized trialsSerious1Not seriousNot seriousNot seriousNone207348Median 2–3 days (similar)⊕⊕⊕○
MODERATE1
IMPORTANT

CI: confidence intervals; MD: mean difference; RR: relative risk

1

Unclear randomisation process, and some imprecision of results and CI.

ACICLOVIR HIGH DOSE VERSUS ACICLOVIR LOW DOSE

Wald 1994High dose aciclovir (4 g daily × 10 days)Standard dose aciclovir (1 g daily × 10 days)
Quality assessmentNo. of patientsEffectQualityImportance
No. of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsAciclovir high doseAciclovir low doseRelative (95% CI)Absolute (95% CI)
Duration of lesions from onset of treatment (assessed with: median time to resolution of all lesions)
1Randomized trialsVery serious1Not seriousNot seriousSerious2None5928Median 1 day more⊕○○○
VERY LOW
IMPORTANT
Pain
1Randomized trialsVery serious1Not seriousNot seriousSerious2None5928Median 2 days fewer⊕○○○
VERY LOW
CRITICAL
Quality of life – not measured
Adverse events – drug toxicity (assessed with: number of events)
1Randomized trialsVery serious1Not seriousNot seriousSerious2None7/88 (8.0%)0/41 (0.0%)RR 7.08 (0.41– 121.05)517 more per 1000 (from 50 fewer to 1000 more)⊕○○○
VERY LOW
CRITICAL
8.5%
Time to first recurrence
1Randomized trialsVery serious1Not seriousNot seriousSerious2None5928Median 8 days fewer (11–196 fewer)⊕○○○
VERY LOW
IMPORTANT
HSV-2 transmission – not measured
Compliance – not measured
Duration of viral shedding
1Randomized trialsSerious1Not seriousNot seriousSerious2None5928Median 3 days for each dose⊕⊕○○
LOW
IMPORTANT

CI: confidence intervals; MD: mean difference; RR: relative risk

1

Unclear randomization process, incomplete outcome data, difference in baseline characteristics, and considering imprecision

2

Few participants and results not precise

REFERENCES
    Systematic review
    1.
    Heslop R, Roberts H, Flower D, Jordan V. Interventions for men and women with their first episode of genital herpes. Cochrane Database Syst Rev. 2016;(8):CD010684. [PMC free article: PMC8502075] [PubMed: 27575957]
    Included studies
    1.
    Lai WH. Valaciclovir hydrochloride versus aciclovir in the treatment of first-episode genital herpes: a controlled, randomized open trial. Chinese J Dermatovenereol. 2000;14(1):34–6. (in Chinese)
    2.
    Wald A, Benedetti J, Davis G, Remington M, Winter C, Corey L. A randomized, double-blind, comparative trial comparing high-and standard-dose oral acyclovir for first-episode genital herpes infections. Antimicrob Agents Chemother. 1994;38(2):174–6. [PMC free article: PMC284421] [PubMed: 8192438]
    3.
    Fife KH, Barbarash RA, Rudolph T, Degregorio B, Roth R, Cameron WB, et al. Valaciclovir versus acyclovir in the treatment of first-episode genital herpes infection: results of an international, multicenter, double-blind, randomized clinical trial. Sex Transm Dis. 1997;24(8):481–6. [PubMed: 9293612]
    4.
    Loveless M, Sacks SI, Harris JRW. Famciclovir in the management of first-episodic genital herpes. Infect Dis Clin Pract. 1997;691(suppl):S12–S16.
    Patient values and preferences, acceptability and cost: specific to herpes simplex virus infections
    1.
    Scalone L, Ryan M, Kotsopoulos N, Patel R. Evaluation of patients’ preferences for genital herpes treatment. Sex Transm Dis. 2011;38(9):802–7. [PubMed: 21844733]
    2.
    International drug price indicator guide, 2014 edition (updated annually). Medford (MA): Management Sciences for Health; 2015. [accessed 6 June 2016]. http://erc​.msh.org/dmpguide​/pdf/DrugPriceGuide_2014.pdf.
    Patient values and preferences, acceptability and cost: other sexually transmitted infections and conditions
    1.
    Nagarkar A, Mhaskar P. A systematic review on the prevalence and utilization of health care services for reproductive tract infections/sexually transmitted infections: evidence from India. Indian J Sex Transm Dis. 2015;36(1):18–25. [PMC free article: PMC4555893] [PubMed: 26392649] [CrossRef]
    2.
    Ryan R, Santesso N, Lowe D, Hill S, Grimshaw J, Prictor M, et al. Interventions to improve safe and effective medicines use by consumers: an overview of systematic reviews. Cochrane Database Syst Rev. 2014;(4):CD007768. [PMC free article: PMC6491214] [PubMed: 24777444]
    Additional references
    1.
    Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386(9995):743–800. [PMC free article: PMC4561509] [PubMed: 26063472] [CrossRef]
    2.
    Newman L, Rowley J, Vander Hoorn S, Wijesooriya NS, Unemo M, Low N, et al. Global estimates of the prevalence and incidence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting. PLoS One. 2015;10(12):e0143304. [PMC free article: PMC4672879] [PubMed: 26646541] [CrossRef]

RECOMMENDATION 3 AND 4

Should episodic therapy be used for the treatment of recurrent episodes of herpes simplex virus infections?
Population:Recurrent episodes of herpes simplex infections
Intervention:Episodic therapy
Comparison:No therapy and different dosages
Main outcomes:Critical: HSV-2 transmission, HSV-2 shedding
Important: HSV-2 severity/pain, quality of life, side-effects, compliance, ulcer healing, duration of clinical episode
Setting:Outpatients
Perspective:Patients
Background:The herpes simplex virus (HSV), or herpes, is categorized into two types: herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2). Both HSV-1 and HSV-2 are highly infectious. HSV-1 is transmitted by oral-to-oral contact and mainly causes herpes labialis, or cold sores, but can also cause genital herpes. HSV-2 is an STI that can cause genital herpes. Most infections are transmitted via asymptomatic viral shedding.
Oral antiviral medications are available for initial, episodic and suppressive therapy; however, there is no cure for the infection. The medications vary: aciclovir, famciclovir and valaciclovir.
In 2003, WHO guidelines recommended dosages for: aciclovir, 200 mg orally, 5 times daily for 5 days; aciclovir, 400 mg orally, 3 thrice daily for 5 days; aciclovir, 800 mg orally, twice daily for 5 days; valaciclovir, 500 mg orally, twice daily for 5 days; valaciclovir, 1000 mg orally, once daily for 5 days; OR famciclovir, 125 mg orally, twice daily for 5 days.
The Guideline Development Group (GDG) identified the above treatments for review.

ASSESSMENT

JudgementResearch evidence
ProblemIs the problem a priority?
  • No
  • Probably no
  • Probably yes
  • Yes
  • Varies
  • Don’t know
Research evidence:
Globally in 2012, it was estimated that over 417 million people were currently infected with HSV-2. For new infections in people 15–49 years old (2012), it was estimated at 19.2 million, of whom 11.8 million were women and 7.4 million were men. Estimates are heterogeneous across regions, but typically greater in low- and middle-income countries (with the exception of the USA). Recurrent episodes are caused by HSV reactivation. Recurrent episodes can occur in 20% to 50% of people, and the median recurrence rate is four in the first year. The rate of recurrence usually decreases over time but increases in about one quarter of patients. Immunosuppressed patients have more severe and frequent recurrences. Infection with HSV-2 also may increase the risk of acquiring an HIV infection. Moreover, HSV-2 can be transmitted to neonates from an infected pregnant mother.
Desirable EffectsHow substantial are the desirable anticipated effects?
  • Trivial
  • Small
  • Moderate
  • Large
  • Varies
  • Don’t know
Research evidence:
We included thirteen reports of 16 RCTs that compared treatment with no treatment and compared different drugs and different dosages: Reichman 1982, Reichman 1984, Goldberg 1986, Sacks 1996, Spruance 1996, Tyring 1998, Wald 2002, Aoki 2006, Fife 2008, Paz-Bailey 2009, Leone Abudalu 2010, Phiri 2010, and Baeten 2012.
Of the studies comparing to placebo, there were aciclovir (9 trials), valaciclovir (3 trials) and famciclovir (5 trials).
We found 1 systematic review and used it to verify the included studies (Le Cleach et al., 2014).
The summary of the findings for treatment to no treatment and different drugs and different dosages are in the evidence tables.
Additional considerations:
Aciclovir in various dosages for 2 to 5 days probably reduces the duration of viral shedding (MD: 1.32 fewer days; 95% CI: 1.36 to 1.27 fewer), symptoms (MD: 2.02 fewer days; 95% CI: 3.27 to 0.77 fewer) and lesions (MD: 1.07 fewer days; 95% CI: 1.3 to 1.0 fewer) when compared to placebo.
Valaciclovir 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 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 benefits were small and the harms trivial between drugs and no treatment. In most trials, quality of life, compliance, pain, HSV-2 transmission, and HIV acquisition and transmission were not measured.
Different dosages of aciclovir, valaciclovir and famciclovir were compared with each other. Two trials compared aciclovir and valaciclovir and found that there were probably little-to-no differences for duration of viral shedding, lesions, symptoms and adverse events (moderate quality evidence). One trial compared aciclovir to famciclovir and found that there was little-to-no difference for outcomes (low quality evidence). Another trial compared famciclovir to valaciclovir and found that there were probably little-to-no differences for outcomes (moderate quality evidence). The GDG agreed that there were trivial differences in benefits and harms among treatments.
Different dosages of aciclovir were compared in two trials (200 mg 5 × a day for 5 days versus alternatives).
There may be little-to-no difference between the doses for outcomes. Different dosages of valaciclovir were compared in 4 trials (500 mg twice a day × 5 days versus alternatives). There were probably little-to-no differences between the doses for outcomes. Famciclovir at 125, 250 or 500 mg twice daily × 5 days were compared, and there may be little-to-no differences in outcomes across the different dosages.
Three studies compared aciclovir to placebo in people living with HIV, and two studies compared different doses of aciclovir, valaciclovir and famciclovir. The effects were inconsistent across different doses, but most doses were provided for 5 days resulting in benefits and few harms.
Undesirable EffectsHow substantial are the undesirable anticipated effects?
  • Large
  • Moderate
  • Small
  • Trivial
  • Varies
  • Don’t know
Certainty of evidenceWhat is the overall certainty of the evidence of effects?
  • Very low
  • Low
  • Moderate
  • High
  • No included studies
Research evidence:
No research evidence was identified.
Additional considerations:
The quality of the evidence for treatment of infrequent recurrent HSV-2 infection compared to no treatment was of moderate quality due to unclear randomization methods and/or unclear loss to follow-up in the trials.
For comparisons of different drugs and dosages, the quality of the evidence was also moderate.
ValuesIs there important uncertainty about or variability in how much people value the main outcomes?
  • Important uncertainty or variability
  • Possibly important uncertainty or variability
  • Probably no important uncertainty or variability
  • No important uncertainty or variability
Research evidence:
A discrete choice exercise suggested subjects’ preferences were influenced by both the treatment they follow and attributes of treatment including cost. Of all the attributes, patients place high value in unit change in chance of recurrence (1%), followed by unit change in number of tablets taken daily (1 tablet), unit change in chance of becoming infected with HIV, unit change in number of tablets taken in addition during each recurrence. In addition, qualitative studies suggested stigma related was also important.
Additional considerations:
None
Balance of effectsDoes the balance between desirable and undesirable effects favour the intervention or the comparison?
  • Favours the comparison
  • Probably favours the comparison
  • Does not favour either the intervention or the comparison
  • Probably favours the intervention
  • Favours the intervention
  • Varies
  • Don’t know
Research evidence:
No research evidence was identified.
Additional considerations:
The GDG agreed that there would be little variability. However, it may be dependent on the severity of the recurrent episodes (this would be covered in recommendations for recurrent episodes that are frequent or severe).
Resources requiredHow large are the resource requirements (costs)?
  • Large costs
  • Moderate costs
  • Negligible costs and savings
  • Moderate savings
  • Large savings
  • Varies
  • Don’t know
ABCDEF
Aciclovir 200 mg po55 days$0.05$1.25$1.56
Aciclovir 400 mg po33–5 days$0.04$0.36 to $1.00$0.45 to $1.25
Aciclovir 800 mg po25 daysn.a.n.a.n.a.
Aciclovir 800 mg po32 daysn.a.n.a.n.a.
Valaciclovir 500 mg23–5 days$0.625$3.75 to $6.25$4.68 to $7.80
Valaciclovir 1 g po23–5 daysn.an.an.a
Famciclovir 125 mg po25 daysn.a.n.a.n.a
Famciclovir 1 g po21 daysn.a.n.a.n.a.
Sources: International drug price indicator guide (MSH, 2015) and www​.drugs.com
A: treatment; B: dose per day; C: treatment duration; D: drug cost, per dose; E: drug cost per full-course treatment; F: 25% procurement as defined by International drug price indicator guide (MSH, 2015). po: orally
Additional considerations:
The GDG agreed that the costs were cost of treatment per episode, not the absolute cost of treatment. The costs were moderate for aciclovir but increase due to recurrence, were greater for valaciclovir and greater for famciclovir.
Certainty of evidence of required resourcesWhat is the certainty of the evidence of resource requirements (costs)?
  • Very low
  • Low
  • Moderate
  • High
  • No included studies
Research evidence:
No research evidence was identified.
Additional considerations:
None
Cost effectivenessDoes the cost-effectiveness of the intervention favour the intervention or the comparison?
  • Favours the comparison
  • Probably favours the comparison
  • Does not favour either the intervention or the comparison
  • Probably favours the intervention
  • Favours the intervention
  • Varies
  • No included studies
Research evidence:
No research evidence was identified.
Additional considerations:
The GDG agreed that there are small benefits with the drugs and moderate costs; less cost effectiveness with valaciclovir and famciclovir. Overall, the GDG agreed that cost effectiveness did not favour either of the drugs.
EquityWhat would be the impact on health equity?
  • Reduced
  • Probably reduced
  • Probably no impact
  • Probably increased
  • Increased
  • Varies
  • Don’t know
Research evidence:
No research evidence was identified.
Additional considerations:
The GDG discussed the proposition that a recommendation would reduce equity as it might decrease the amount of the drug available for primary infections, which has been highlighted as a priority due to more severe symptoms and sequelae. Overall, the GDG decided that there was probably no impact on equity.
However, equity may be reduced when using the more costly valaciclovir and famciclovir.
AcceptabilityIs the intervention acceptable to key stakeholders?
  • No
  • Probably no
  • Probably yes
  • Yes
  • Varies
  • Don’t knows
Research evidence:
We searched for reviews and studies specific to herpes treatment acceptability. A systematic review of the literature for treatment utilization in STIs (in India) reported that utilization ranged from 16% to 55% in the community-based studies, and was higher (~70%) in research trials.
Treatment might not be acceptable to patients due to the resources and availability of services, social factors and distance. Non-utilization was also due to ignorance, illiteracy and lack of awareness; and women reported a lack of female doctors, being afraid of results and judgement of doctors, stigma, shyness and embarrassment. Cost of care and less faith in clinical care were also factors.
An overview of reviews of medication adherence (Ryan, 2014) reported that adherence might be improved with simpler drug regimens. However, when compliance was measured in the studies included for HSV treatments, compliance was similar among drugs.
Additional considerations:
Given the nature of the course of treatment, the GDG discussed that aciclovir might be more acceptable. Valaciclovir might be more acceptable to patients who can afford it, but it may be unacceptable to those who cannot afford it.
Therefore, the acceptability varies across settings. The same conclusions were reached for famciclovir.
FeasibilityIs the intervention feasible to implement?
  • No
  • Probably no
  • Probably yes
  • Yes
  • Varies
  • Don’t know
Research evidence:
No research evidence was identified.
Additional considerations:
The treatment was considered widely available, but cost was still a concern. Additionally, there was concern that the drug might not be paid for by health systems or donors as the infection was considered recurrent.
The GDG also discussed that treatment could be more effective if it were available for administration to a patient at the earliest stages of symptoms, rather than having to wait until they could see a clinician for their treatment. Thus, group members suggested that the recommendation recognize that benefits could be maximized if this opportunity to operationalize pharmacy workers to provide drugs is taken.

SUMMARY OF JUDGEMENTS

Judgement
ProblemNoProbably noProbably yesYesVariesDon’t know
Desirable EffectsTrivialSmallModerateLargeVariesDon’t know
Undesirable EffectsLargeModerateSmallTrivialVariesDon’t know
Certainty of evidenceVery lowLowModerateHighNo included studies
ValuesImportant uncertainty or variabilityPossibly important uncertainty or variabilityProbably no important uncertainty or variabilityNo important uncertainty or variability
Balance of effectsFavours the comparisonProbably favours the comparisonDoes not favour either the intervention or the comparisonProbably favours the interventionFavours the interventionVariesDon’t know
Resources requiredLarge costsModerate costsNegligible costs and savingsModerate savingsLarge savingsVariesDon’t know
Certainty of evidence of required resourcesVery lowLowModerateHighNo included studies
Cost effectivenessFavours the comparisonProbably favours the comparisonDoes not favour either the intervention or the comparisonProbably favours the interventionFavours the interventionVariesNo included studies
EquityReducedProbably reducedProbably no impactProbably increasedIncreasedVariesDon’t know
AcceptabilityNoProbably noProbably yesYesVariesDon’t know
FeasibilityNoProbably noProbably yesYesVariesDon’t know

CONCLUSIONS

Should episodic therapy be used for the treatment of recurrent episodes of herpes simplex virus type 2 infections?
Type of recommendationStrong recommendation against the interventionConditional recommendation against the interventionConditional recommendation for either the intervention or the comparisonConditional recommendation for the interventionStrong recommendation for the intervention
RecommendationThe GDG had a vote, which resulted (14 for; 6 against) in favouring a conditional recommendation of using aciclovir for treatment of recurrent infections over no treatment.
There was a GDG vote (12 for; 9 against) that there would be a conditional recommendation for the use of valaciclovir, the primary condition being that of cost.
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.
JustificationThe 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.
Subgroup considerationsThis recommendation also applies to people living with HIV, people who are immunocompromised and pregnant women.
Implementation considerationsTreatment should be started at the onset of symptoms and choice of dosage may depend on individual compliance.
Monitoring and evaluation
Research prioritiesLittle evidence was found for outcomes critical to making decisions about drugs to treat first or recurrent episodes of genital HSV infections. Important patient outcomes should be measured in clinical trials, such as genital HSV acquisition and transmission, HIV acquisition and transmission, quality of life and pain. There were few available data for direct comparisons of different drugs, in particular for comparisons with famciclovir. There were also few studies comparing the different dosages of the drugs. Future research could use the dosages recommended in these guidelines as comparators. Equity issues, acceptance of and compliance with different drugs and regimens should also be explored in people with genital HSV infections. Although this search was not limited to different populations, there were few data for key populations, such as people with HIV infection, people who are immunocompromised and pregnant women. More information can also be provided to allow for the critical appraisal of clinical trials by following the standards of reporting of RCTs, in particular for the methods of randomization and allocation concealment and blinding.

EVIDENCE TABLES

Aciclovir versus placebo

StudyDosage
Baeten 2012aciclovir 400 mg orally 3 × daily × 5 days
Goldberg 1986 group Aaciclovir 800 mg 2 × daily × 5 days
Goldberg 1986 group Baciclovir 200 mg 5 × daily × 5 days
Paz Bailey 2009aciclovir 400 mg 3 × daily × 5 days
Phiri 2010aciclovir 800 mg 2 × daily for 5 days
Reichman 1982 study Aaciclovir 200 mg 5 × daily × 5 days
Reichman 1982 study Baciclovir 200 mg 5 × daily × 5 days
Tyring 1998aciclovir 200 mg 5 × daily × 5 days
Wald 2002aciclovir 800 mg 3 × daily × 2 days
Quality assessmentNo. of patientsEffectQualityImportance
No. of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOtherEpisodic aciclovirPlaceboRelative (95% CI)Absolute (95% CI)
Duration of viral shedding (assessed with: days)
5Randomized trialsSerious1Not seriousNot seriousNot seriousNone792440MD 1.32 days fewer (1.36–1.27 fewer)2⊕⊕⊕○
MODERATE
CRITICAL
Duration of symptoms from onset of treatment (assessed with: days)
4Randomized trialsSerious1Not seriousNot seriousNot seriousNone657262MD 2.02 days fewer (3.27–0.77 fewer)2⊕⊕⊕○
MODERATE
IMPORTANT
Duration of lesions from onset of treatment
9Randomized trialsSerious1Not seriousNot seriousNot seriousNone991551MD 1.07 days fewer (1.13–1.00 fewer)3⊕⊕⊕○
MODERATE
IMPORTANT
Quality of life – not measured
Compliance – not measured
HSV-2 severity/pain – not measured
HSV-2 transmission – not measured
HIV transmission and acquisition – not measured
Adverse event – any adverse event
5Randomized trialsSerious1Not seriousNot seriousNot seriousNone65/555 (12.1%)34/445 (7.6%)RR 1.20 (0.61–2.35)15 more per 1000 (from 30 fewer to 103 more)⊕⊕⊕○
MODERATE
IMPORTANT

CI: confidence intervals; MD: mean difference; RR: relative risk

1

Most studies had unclear randomization or unclear loss to follow-up.

2

Two of the studies (Tyring 1998 and Wald 2002) reported median values consistent with the pooled mean difference.

3

Four of the studies reported median values and results are consistent.

VALACICLOVIR VERSUS PLACEBO

StudyDosage
Spruance 1996 group Avalaciclovir 1 g 2 × daily × 5 days
Spruance 1996 group Bvalaciclovir 500 mg 2 × daily × 5 days
Tyring 1998valaciclovir 1000 mg 2 × daily × 5 days
Quality assessmentImpactQualityImportance
No. of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerations
Duration of viral shedding
3Randomized trialsSerious1Not seriousNot seriousNot seriousNoneMedian values for people (1040) receiving valaciclovir was 2 days and receiving placebo (441) was 4 days. 1 study (694 people) also reported HR 2.55 (1.91–3.40) with placebo.⊕⊕⊕○
MODERATE
CRITICAL
HSV-2 transmission – not measured
Duration of lesions from onset of treatment (assessed with: days)
3Randomized trialsSerious1Not seriousNot seriousNot seriousNoneMedian values for people (1040) receiving valaciclovir ranged from 4–5 days and with placebo (441) was 6 days.⊕⊕⊕○
MODERATE
IMPORTANT
Duration of symptoms from onset of treatment (assessed with: days)
3Randomized trialsSerious1Not seriousNot seriousNot seriousNoneMedian values for people (1040) receiving valaciclovir ranged from 4–5 days and with placebo (441) was 5.9 days.⊕⊕⊕○
MODERATE
IMPORTANT
Quality of life – not measured
Compliance – not measured
Adverse events
2Randomized trialsSerious1Not seriousNot seriousNot seriousNone1 study (787) reported similar adverse events across groups. Another study reported 4/512 with a serious adverse events with valaciclovir and 1/182 with placebo.⊕⊕⊕○
MODERATE
IMPORTANT
Specific adverse events - see forest plots

CI: confidence intervals; MD: mean difference; RR: relative risk

1

Unclear blinding or randomization in most studies, or lost to follow-up.

FAMCICLOVIR VERSUS PLACEBO

StudyDosage
Sacks 1996 group Afamciclovir 125 mg 2 × daily × 5 days
Sacks 1996 group Bfamciclovir 250 mg 2 × daily × 5 days
Sacks 1996 group Cfamciclovir 500 mg 2 × daily × 5 days
Aoki 2006famciclovir 1000 mg 2 × daily × 1 day
Leone 2010famciclovir 1000 mg 2 × daily × 1 day
Quality assessmentNo. of patientsEffectQualityImportance
No. of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOtherepisodic famciclovirPlaceboRelative (95% CI)Absolute (95% CI)
Duration of viral shedding
3Randomized trialsSerious1Not seriousNot seriousNot seriousNone1 article reported 3 separate analyses (669 participants): median number of days 1.3–1.7 days with famciclovir and 3.4 days with placebo.⊕⊕⊕○
MODERATE
CRITICAL
HSV-2 transmission – not measured
Duration of lesions from onset of treatment
5Randomized trialsSerious1Not seriousNot seriousNot seriousNoneMedian duration was reported and ranged from 3.5–5.38 with famciclovir (730 participants); and 4.8–5 days with placebo (567 participants).⊕⊕⊕○
MODERATE
IMPORTANT
Duration of symptoms from onset of treatment
5Randomized trialsSerious1Not seriousNot seriousNot seriousNoneMedian duration was reported and ranged from 3.1–4.5 days with famciclovir (730 participants); and 3.7–5.7 days with placebo (567 participants).⊕⊕⊕○
MODERATE
IMPORTANT
Compliance – not measured
Quality of life – not measured
HSV-2 severity/pain – not measured
Adverse events (serious and non-serious)
3Randomized trialsSerious1Not seriousNot seriousNot seriousNone269/572 (47.0%)71/199 (35.7%)RR 1.14 (0.95–1.36)250 more per 1000 (from 18 fewer to 128 more)⊕⊕⊕○
MODERATE
IMPORTANT

CI: confidence intervals; MD: mean difference; RR: relative risk

1

Unclear blinding or randomization in most studies, or lost to follow-up.

2

1 study (n=329) reported similar non-serious adverse events in both groups and no serious adverse events.

REFERENCES
    Systematic review
    1.
    Le Cleach L, Trinquart L, Do G, Maruani A, Lebrun-Vignes B, Ravaud P, Chosidow O. Oral antiviral therapy for prevention of genital herpes outbreaks in immunocompetent and nonpregnant patients. Cochrane Database Syst Rev. 2014;(8):CD009036. [PubMed: 25086573]
    References of included studies
    1.
    Aoki FY, Tyring S, Diaz-Mitoma F, Gross G, Gao J, Hamed K. Single-day, patient-initiated famciclovir therapy for recurrent genital herpes: a randomized, double-blind, placebo-controlled trial. Clin Infect Dis. 2006;42(1):8–13. [PubMed: 16323085] [CrossRef]
    2.
    Baeten JM, Reid SE, Delany-Moretlwe S, Hughes JP, Wang RS, Wilcox E, et al. Clinical and virologic response to episodic acyclovir for genital ulcers among HIV-1 seronegative, herpes simplex virus type 2 seropositive African women: a randomized, placebo-controlled trial. Sex Transm Dis. 2012;39(1):21–4. [PMC free article: PMC3244838] [PubMed: 22183840] [CrossRef]
    3.
    Fife KH, Warren TJ, Justus SE, Heitman CK. HS2100275 Study Team. An international, randomized, double-blind, placebo-controlled, study of valacyclovir for the suppression of herpes simplex virus type 2 genital herpes in newly diagnosed patients. Sex Transm Dis. 2008;35(7):666–73. [PubMed: 18461016] [CrossRef]
    4.
    Goldberg LH, Kaufman R, Conant MA, Sperber J, Allen ML, Illeman M, Chapman S. Oral acyclovir for episodic treatment of recurrent genital herpes: efficacy and safety. J Am Acad Dermatol. 1986;15(2 Pt.I):256–64. [PubMed: 3745529]
    5.
    Leone P, Abudalu M, Mitha E, Gani M, Zhou W, Hamed K. One-day famciclovir vs. placebo in patient-initiated episodic treatment of recurrent genital herpes in immunocompetent Black patients. Curr Med Res Opin. 2010;26(3):653–61. [PubMed: 20070143] [CrossRef]
    6.
    Paz-Bailey G, Sternberg M, Puren AJ, Markowitz LE, Ballard R, Delany S, et al. Improvement in healing and reduction in HIV shedding with episodic acyclovir therapy as part of syndromic management among men: a randomized, controlled trial. J Infect Dis. 2009;200(7):1039–49. [PubMed: 19715417] [CrossRef]
    7.
    Phiri S, Hoffman IF, Weiss HA, Martinson F, Nyirenda N, Kamwendo D, et al. Impact of aciclovir on ulcer healing, lesional, genital and plasma HIV-1 RNA among patients with genital ulcer disease in Malawi. Sex Transm Infect. 2010;86(5):345–52. [PubMed: 20444742] [CrossRef]
    8.
    Reichman RC, Ginsberg M, Barrett-Connor E, Wyborny C, Connor JD, Redfield D, et al. Controlled trial of oral acyclovir in the therapy of recurrent herpes simplex genitalis. A preliminary report. Am J Med. 1982;73(1 A):338–41. [PubMed: 7048921]
    9.
    Reichman RC, Badger GJ, Mertz GJ, Corey L, Richman DD, Connor JD, et al. Treatment of recurrent genital herpes simplex infections with oral acyclovir. A controlled trial. JAMA. 1984;251(16):2103–7. [PubMed: 6368877]
    10.
    Spruance SL, Tyring SK, DeGregorio B, Miller C, Beutner K. Valaciclovir HSV Study Group. A large-scale, placebo-controlled, dose-ranging trial of peroral valaciclovir for episodic treatment of recurrent herpes genitalis. Arch Intern Med. 1996;156(15):1729–35. [PubMed: 8694673]
    11.
    Sacks SL, Aoki FY, Diaz-Mitoma F, Sellors J, Shafran SD. Patient-initiated, twice-daily oral famciclovir for early recurrent genital herpes: a randomized, double-blind multicenter trial. JAMA. 1996;276(1):44–9. [PubMed: 8667538]
    12.
    Tyring SK, Douglas JM Jr, Corey L, Spruance SL, Esmann J. A randomized, placebo-controlled comparison of oral valacyclovir and acyclovir in immunocompetent patients with recurrent genital herpes infections. Arch Dermatol. 1998;134(2):185–91. [PubMed: 9487210]
    13.
    Wald A, Carrell D, Remington M, Kexel E, Zeh J, Corey L. Two-day regimen of acyclovir for treatment of recurrent genital herpes simplex virus type 2 infection. Clin Infect Dis. 2002;34(7):944–8. [PubMed: 11880960] [CrossRef]

EPISODIC ACICLOVIR VERSUS NO TREATMENT FOR PEOPLE LIVING WITH HIV

Efficacy of aciclovir for episodic therapy versus no treatment for people living with HIV
Quality assessmentSummary of findings
No. of participants (studies) Follow-upRisk of biasInconsistencyIndirectnessImprecisionPublication biasOverall quality of evidenceStudy event rates (%)Relative effect (95% CI)Anticipated absolute effects
With no treatmentWith aciclovirRisk with no treatmentRisk difference with episodic drug
Aciclovir 800 mg twice daily × 5 days vs placebo: number of people healed (ulcer healing)
215 (1 RCT)Not seriousNot seriousNot seriousVery serious1None⊕⊕○○
LOW
87/107 (81.3%)91/108 (84.3%)RR 1.04 (0.92–1.17)813 per 100033 more per 1000 (65 fewer to 138 more)
Aciclovir 800 mg twice daily × 5 days vs placebo: side-effects
371 (1 RCT)Not seriousNot seriousNot seriousVery serious1None⊕⊕○○
LOW
11/187 (5.9%)19/184 (10.3%)RR 1.76 (0.86–3.59)59 per 100045 more per 1000 (8 fewer to 152 more)
Aciclovir 400 mg 3 times daily × 5 days vs placebo: number of people healed (ulcer healing)
721 (2 RCTs)Not seriousNot seriousNot seriousVery serious1None⊕⊕○○
LOW
165/365 (45.2%)158/356 (44.4%)RR 0.99 (0.84–1.16)452 per 10005 fewer per 1000 (72 fewer to 72 more)
Aciclovir 400 mg 3 × daily × 5 days vs placebo: HIV viral load
193 (1 RCT)Not seriousNot seriousNot seriousVery serious1None⊕⊕○○
LOW
39/105 (37.1%)21/88 (23.9%)RR 0.64 (0.41–1.01)371 per 1000134 fewer per 1000 (219 fewer to 4 more)
Aciclovir 800 mg twice daily × 5 days vs placebo: HIV viral load
1500 (3 RCTs)Not seriousNot seriousNot seriousNot seriousNone⊕⊕⊕○
MODERATE
Three studies reported that Plasma HIV-1 RNA among patients with detectable plasma HIV-1 RNA (measured at day 0 to day 28), mean (95% CI), log10 copies/ml: for aciclovir 4.85 (4.73–5.40) to 4.71 (5.10–5.50); for placebo 4.84 (4.71–5.50) to 4.85 (4.71–5.50)

CI: confidence interval; RR: risk ratio

1

Considered with imprecise results since 95% CI includes potential for fewer or greater cures or adverse events and few events across studies

REFERENCES
1.
Weiss HA, Paz Bailey G, Phiri S, Gresenguet G, LeGoff J, Pepin J, et al. Episodic therapy for genital herpes in sub-Saharan Africa: a pooled analysis from three randomized controlled trials. PLoS One. 2011;6(7):e22601. [PMC free article: PMC3143155] [PubMed: 21799914] [CrossRef]
a. Mayaud P, Legoff J, Weiss HA, Gresenguet G, Nzambi K, Bouhlal H, et al. ANRS 1212 Study Group. Impact of acyclovir on genital and plasma HIV-1 RNA, genital herpes simplex virus type 2 DNA, and ulcer healing among HIV-1-infected African women with herpes ulcers: a randomized placebo-controlled trial. J Infect Dis. 2009;200(2):216–26. [PubMed: 19530940] [CrossRef]
b. Phiri S, Hoffman IF, Weiss HA, Martinson F, Nyirenda N, Kamwendo D, et al. Impact of aciclovir on ulcer healing, lesional, genital and plasma HIV-1 RNA among patients with genital ulcer disease in Malawi. Sex Transm Infect. 2010;86(5):345–52. [PubMed: 20444742] [CrossRef]
c. Paz-Bailey G, Sternberg M, Puren AJ, Markowitz LE, Ballard R, Delany S, et al. Improvement in healing and reduction in HIV shedding with episodic acyclovir therapy as part of syndromic management among men: a randomized, controlled trial. J Infect Dis. 2009;200(7):1039–49. [PubMed: 19715417] [CrossRef]

EPISODIC ACICLOVIR VERSUS EPISODIC VALACICLOVIR

Bodsworth 1997valaciclovir 500 mg 2 × daily × 5 days
aciclovir 200 mg 5 × daily × 5 days
Tyring 1998valaciclovir 1000 mg 2 × daily × 5 days
aciclovir 200 mg 5 × daily × 5 days
Quality assessmentNo. of patientsEffectQualityImportance
No. of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOtherEpisodic valaciclovirEpisodic aciclovirRelative (95% CI)Absolute (95% CI)
Duration of viral shedding
1Randomized trialsSerious1Not seriousNot seriousNot seriousNone1 study (1018 participants) reported median of 2 days of viral shedding across the 2 groups. Another study reported HR 0.97 (0.75–1.26) in favour of valaciclovir.⊕⊕⊕○
MODERATE
IMPORTANT
Viral shedding (number of people with at least one positive culture of lesion)
2Randomized trialsSerious1Not seriousNot seriousNot seriousNone330/890 (37%)332/867 (38%)RR 0.97 (0.86–1.09)11 per 1000 fewer (from 52 fewer to 33 more)⊕⊕⊕○
MODERATE
IMPORTANT
HSV-2 transmission – not measured
Duration of lesions from onset of treatment (assessed with: days)
2Randomized trialsSerious1Not seriousNot seriousNot seriousNone2 studies (1757 participants) reported median values across groups of 4.4–4.8 days.⊕⊕⊕○
MODERATE
CRITICAL
Duration of symptoms from onset of treatment (assessed with: days)
2Randomized trialsSerious1Not seriousNot seriousNot seriousNone2 studies (1757 participants) reported median values across all groups of 4.6–4.8 days.⊕⊕⊕○
MODERATE
CRITICAL
HSV-2 severity/pain – not measured
Quality of life – not measured
Compliance – not measured
Adverse events (serious)
2Randomized trialsSerious1Not seriousNot seriousSerious3None1/890 (0.1%)2/867 (0.2%)RR 0.32 (0.03–3.11)1 fewer per 1000 (from 1 fewer to 2 more⊕⊕⊕○
MODERATE
IMPORTANT

MD: mean difference; HR: hazard ratio; RR: relative risk.

1

Unclear randomization methods or incomplete data from studies

EPISODIC ACICLOVIR VERSUS EPISODIC FAMCICLOVIR

Chodisow 2001aciclovir 200 mg 5 × daily × 5 days
famciclovir 125 mg twice daily × 5 days
Quality assessmentEffectNo. of patientsQualityImportance
No. of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOtherEpisodic aciclovirEpisodic famciclovirRelative (95% CI)Absolute (95% CI)
Duration of viral shedding – not measured
HSV-2 transmission – not measured
Duration of lesions from onset of treatment (assessed with: days)
1Randomized trialsSerious1Not seriousNot seriousSerious1None97107MD 0.25 days more (0.3 more to 0.8 fewer)⊕⊕○○
LOW
CRITICAL
Duration of symptoms from onset of treatment – not measured
HSV-2 severity/pain – not measured
Quality of life – not measured
Compliance
1Randomized trialsSerious1Not seriousNot seriousSerious1None1 study with 204 participants reported comparable compliance with only 5 people in each group with less than 80% compliance⊕⊕○○
LOW
IMPORTANT
Adverse events (non-serious and serious)
1Randomized trialsSerious1Not seriousNot seriousSerious1None1 study with 204 participants reported that non-serious adverse events did not differ between groups and included headache, nausea and gastrointestinal events. 4/107 participants receiving aciclovir reported serious adverse events, while none were reported with famciclovir.⊕⊕○○
LOW
IMPORTANT

CI: confidence interval; MD: mean difference

1

Method of randomization and allocation unclear, and approximately 10% of participants lost to follow-up – downgraded with imprecision due to few participants.

EPISODIC VALACICLOVIR VERSUS EPISODIC FAMCICLOVIR

Abudalu 2008famciclovir 1000 mg 2 × daily × 1 day
valaciclovir 500 mg 2 × daily × 3 days
Quality assessmentNo. of patientsEffectQualityImportance
No. of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsEpisodic valaciclovirEpisodic famciclovirRelative (95% CI)Absolute (95% CI)
HSV-2 transmission – not measured
Duration of viral shedding – not measured
Duration of lesions from onset of treatment (assessed with: days)
1Randomized trialsSerious1Not seriousNot seriousNot seriousNone1 study (651 participants) reported median of 3.01 for valaciclovir and 3.07 for famciclovir.⊕⊕⊕○
MODERATE
CRITICAL
Duration of symptoms from onset of treatment
1Randomized trialsSerious1Not seriousNot seriousNot seriousNone1 study (651 participants) reported median of 3.0 for valaciclovir and 3.03 for famciclovir.⊕⊕⊕○
MODERATE
CRITICAL
HSV-2 severity/pain – not measured
Quality of life – not measured
Compliance
1Randomized trialsSerious1Not seriousNot seriousNot seriousNoneAdherence to study medication as prescribed was excellent, with 97.6% of famciclovir-treated patients (362 of 371 patients) receiving 2 doses on day 1 and 92.2% of valaciclovir-treated patients (355 of 385 patients) receiving all 6 doses over 3 days.⊕⊕⊕○
MODERATE
IMPORTANT
Adverse events – not serious
1Randomized trialsSerious1Not seriousNot seriousNot seriousNone86/385 (22.3%)86/371 (23.2%)RR 0.96 (0.74–1.25)⊕⊕⊕○
MODERATE
IMPORTANT

MD: mean difference; RR: relative risk

1

Method of randomization and allocation unclear, and approximately 10% did not complete study.

EPISODIC ACICLOVIR VERSUS EPISODIC ACICLOVIR

Goldberg 1986aciclovir oral 800 mg (4 capsules) 2 × daily × 5 days
aciclovir 200 mg (1 capsule) 5 × daily × 5 days
Straus 1986aciclovir 200 mg capsules 1 capsule 5 × daily × 5 days (daily group)
aciclovir 400 mg capsules 1 capsule 3 × daily on weekend days only (weekend group)
Quality assessmentNo. of patientsEffectQualityImportance
No. of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOtherEpisodic aciclovir 800 mgEpisodic aciclovir 200 mgRelative (95% CI)Absolute (95% CI)
Duration of viral shedding – not measured
Viral shedding (number of people with at least one positive culture of lesion) – not measured
HSV-2 transmission – not measured
Duration of lesions from onset of treatment (assessed with: days)
1Randomized trialsSerious1Not seriousNot seriousSerious2None8140MD 0.9 fewer (1.72 fewer to 0.08 fewer)⊕⊕○○
LOW
CRITICAL
Duration of symptoms from onset of treatment (assessed with: days)
1Randomized trialsSerious1Not seriousNot seriousSerious2None7737MD 0.6 fewer (1.54 fewer to 0.34 more)⊕⊕○○
LOW
CRITICAL
Proportion of patients with recurrent herpes while therapy
1Randomized trialsSerious1Not seriousNot seriousSerious2None3/18 (16.7%)13/17 (76.5%)RR 0.22 (0.08–0.63)596 fewer per 1000 (from 285–704 fewer)⊕⊕○○
LOW
IMPORTANT
HSV-2 severity/pain – not measured
Quality of life – not measured
Compliance
1Randomized trialsSerious1Not seriousNot seriousSerious2None1 study (121 participants) reported that with daily treatment compliance was excellent⊕⊕○○
LOW
IMPORTANT
Adverse events (diarrhoea) - see forest plots for other side-effects
1Randomized trialsSerious1Not seriousNot seriousSerious2None3/18 (16.7%)7/17 (41.2%)RR 0.40 (0.12–1.32)247 fewer per 1000 (from 132 more to 362 fewer)⊕⊕○○
LOW
IMPORTANT

MD: mean difference; RR: relative risk

1

Unclear randomization process, and some imprecision of results and confidence intervals.

2

Few events to determine effect.

EPISODIC VALACICLOVIR VERSUS EPISODIC VALACICLOVIR

Leone 2002valaciclovir 500 mg bid 5-day regimen
valaciclovir 500 mg bid 3-day regimen
Strand 2002valaciclovir 500 mg bid × 5-day regimen
valaciclovir 500 mg bid × 3-day regimen
Saiag 1999valaciclovir 1000 mg 1 × daily × 5-day regimen
valaciclovir 500 mg bid × 5-day regimen
Spruance 1996valaciclovir 1000 mg once daily × 5-day regimen
valaciclovir 500 mg bid × 5-day regimen
Quality assessmentNo. of patientsEffectQualityImportance
No. of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOtherEpisodic valaciclovirEpisodic valaciclovirRelative (95% CI)Absolute (95% CI)
Duration of viral shedding
2Randomized trialsSerious1Not seriousNot seriousNot seriousNone2 studies (1259 participants) reported median values across groups of 1.7–2.0 days.⊕⊕⊕○
MODERATE
CRITICAL
Viral shedding (number of people with at least one positive culture of lesion) – not measured
HSV-2 transmission – not measured
Duration of lesions from onset of treatment (assessed with: days)
4Randomized trialsSerious1Not seriousNot seriousNot seriousNone4 studies (2630 participants) reported median values across groups of 3.4–4.9 days.⊕⊕⊕○
MODERATE
CRITICAL
Numbers of complete lesion healed
1Randomized trialsSerious1Not seriousNot seriousNot seriousNone359/444 (80.9%)77.8%RR 1.04 (0.97–1.11)31 more per 1000 (from 23 fewer to 86 more)⊕⊕⊕○
MODERATE
CRITICAL
Duration of symptoms from onset of treatment (assessed with: days)
3Randomized trialsSerious1Not seriousNot seriousNot seriousNone3 studies (1980 participants) reported median values across groups of 4.0–4.7 days.⊕⊕⊕○
MODERATE
CRITICAL
HSV-2 severity/pain (assessed with: days)
4Randomized trialsSerious1Not seriousNot seriousNot seriousNone4 studies (2902 participants) reported median values across groups of 2.5–3.0 days.⊕⊕⊕○
MODERATE
IMPORTANT
Quality of life – not measured
Compliance – not measured
Adverse events (general) – see forest plots for individual side-effects
1Randomized trialsSerious1Not seriousNot seriousNot seriousNone72/444 (16.2%)83/478 (17.4%)RR 0.93 (0.70–1.25)12 fewer per 1000 (from 43 more to 52 fewer)⊕⊕⊕○
MODERATE
IMPORTANT

CI: confidence interval; RR: relative risk

1

Approximately 10% did not complete study; patients not likely blinded to length of regimen

EPISODIC FAMCICLOVIR VERSES EPISODIC FAMCICLOVIR

Sacks 1996famciclovir 125 mg, 250 mg, 500 mg 2 × daily × 5 days
Sacks 2005famciclovir 125 mg, 250 mg, 500 mg 2 × daily × 5 days
Quality assessmentNo. of patientsEffectQualityImportance
No. of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsEpisodic famciclovirEpisodic famciclovirRelative (95% CI)Absolute (95% CI)
Duration of viral shedding
2Randomized trialsSerious1Not seriousNot seriousSerious2None2 studies (350 participants) reported median of 1.3–1.7 days of viral shedding across the 3 groups.⊕⊕○○
LOW
CRITICAL
Viral shedding (number of people with at least one positive culture of lesion) – not measured
HSV-2 transmission – not measured
Duration of lesions from onset of treatment (assessed with: days)
2Randomized trialsSerious1Not seriousNot seriousSerious2None2 studies (350 participants) reported median of 3.7–4.4 days of lesion healed across the 3 groups.⊕⊕○○
LOW
CRITICAL
Duration of symptoms from onset of treatment (assessed with: days)
2Randomized trialsSerious1Not seriousNot seriousSerious2None2 studies (184 participants) reported median of 3.8–4.4 days of duration of symptoms across the 3 groups.⊕⊕○○
LOW
CRITICAL
HSV-2 severity/pain – not measured
Quality of life – not measured
Compliance – not measured
Adverse events (not serious)
1Randomized trialsSerious1Not seriousNot seriousSerious2None1 study (229 participants) reported that number of patients with adverse events between 47–55 across the 3 groups.⊕⊕○○
LOW
IMPORTANT

CI: confidence interval; MD: mean difference; RR: relative risk

1

Unclear randomization process, and some imprecision of results and CIs.

2

Few events to determine effect.

REFERENCES
    Systematic review
    1.
    Le Cleach L, Trinquart L, Do G, Maruani A, Lebrun-Vignes B, Ravaud P, Chosidow O. Oral antiviral therapy for prevention of genital herpes outbreaks in immunocompetent and nonpregnant patients. Cochrane Database Syst Rev. 2014;(8):CD009036. [PubMed: 25086573]
    Included studies
    1.
    Abudalu M, Tyring S, Koltun W, Bodsworth N, Hamed K. Single-day, patient-initiated famciclovir therapy versus 3-day valacyclovir regimen for recurrent genital herpes: a randomized, double-blind, comparative trial. Clin Infect Dis. 2008;47(5):651–8. [PubMed: 18637755] [CrossRef]
    2.
    Bodsworth NJ, Crooks RJ, Borelli S, Vejlsgaard G, Paavonen J, Worm AM, et al. Valaciclovir versus aciclovir in patient initiated treatment of recurrent genital herpes: a randomised, double blind clinical trial. Genitourin Med. 1997;73(2):110–6. [PMC free article: PMC1195783] [PubMed: 9215092]
    3.
    Chosidow O, Drouault Y, Leconte-Veyriac F, Aymard M, Ortonne JP, Pouget F, et al. Famciclovir vs. aciclovir in immunocompetent patients with recurrent genital herpes infections: a parallel-groups, randomized, double-blind clinical trial. Br J Dermatol. 2001;144(4):818–24. [PubMed: 11298543]
    4.
    Goldberg LH, Kaufman R, Conant MA. Oral acyclovir for episodic treatment of recurrent genital herpes: efficacy and safety. J Am Acad Dermatol. 1986;15(2 I):256–64. [PubMed: 3745529]
    5.
    Leone PA, Trottier S, Miller JM. Valacyclovir for episodic treatment of genital herpes: a shorter 3-day treatment course compared with 5-day treatment. Clin Infect Dis. 2002;34(7):958–62. [PubMed: 11880962]
    6.
    Saiag P, Praindhui D, Chastang C. A double-blind, randomized study assessing the equivalence of valacyclovir 1000 mg once daily versus 500 mg twice daily in the episodic treatment of recurrent genital herpes. J Antimicrob Chemother. 1999;44(4):525–31. [PubMed: 10588314]
    7.
    Spruance SL, Tyring SK, DeGregorio B, Miller C, Beutner K. A large-scale, placebo-controlled, dose-ranging trial of peroral valaciclovir for episodic treatment of recurrent herpes genitalis. Valaciclovir HSV Study Group. Arch Intern Med. 1996;156(15):1729–35. [PubMed: 8694673]
    8.
    Strand A, Patel R, Wulf HC, Coates KM, Andersen B, Andersen P, et al. Aborted genital herpes simplex virus lesions: findings from a randomised controlled trial with valaciclovir. Sex Transm Infect. 2002;78(6):435–9. [PMC free article: PMC1758363] [PubMed: 12473805]
    9.
    Sacks SL, Aoki FY, Diaz-Mitoma F, Sellors J, Shafran SD. Patient-initiated, twice-daily oral famciclovir for early recurrent genital herpes: a randomized, double-blind multicenter trial. JAMA. 1996;276(1):44–9. [PubMed: 8667538]
    10.
    Straus SE, Seidlin M, Takiff HE, Rooney JF, Lehrman SN, Bachrach S, et al. Double-blind comparison of weekend and daily regimens of oral acyclovir for suppression of recurrent genital herpes. Antiviral Res. 1986;6(3):151–9. [PubMed: 3015019]
    11.
    Sacks SL, Aoki FY, Martel AY, Shafran SD, Lassonde M. Clinic-initiated, twice-daily oral famciclovir for treatment of recurrent genital herpes: a randomized, double-blind, controlled trial. Clin Infect Dis. 2005;41(8):1097–104. [PubMed: 16163627]
    12.
    Tyring SK, Douglas JM Jr, Corey L, Spruance SL, Esmann J. A randomized, placebo-controlled comparison of oral valacyclovir and acyclovir in immunocompetent patients with recurrent genital herpes infections. Arch Dermatol. 1998;134(2):185–91. [PubMed: 9487210]

EPISODIC THERAPY FOR PEOPLE LIVING WITH HIV

Efficacy of different treatments for episodic drugs for people living with HIV
Quality assessmentSummary of findings
No. of participants (studies) Follow-upRisk of biasInconsistencyIndirectnessImprecisionPublication biasOverall quality of evidenceStudy event rates (%)Relative effect (95% CI)Anticipated absolute effects
With aciclovirWith comparisonRisk with aciclovirRisk difference with comparison
Valaciclovir at 1000 mg twice daily or aciclovir at 200 mg 5 × daily × 5 days: healing
467 (1 RCT)Not seriousNot seriousNot seriousVery serious1None⊕⊕○○
LOW
No differences were detected between the valaciclovir 1000 mg twice daily and aciclovir 200 mg 5 × daily regimens on episode duration or lesion healing. Lesions were observed to progress through all stages to healing in 394 of the 467 treated patients. The hazard ratio [CI] for valaciclovir vs aciclovir on lesion healing was 0.98 [0.79, 1.22], P = 0.89, and the median healing time was 5 days.
Valaciclovir at 1000 mg twice daily or aciclovir at 200 mg 5 × daily × 5 days: side-effects
467 (1 RCT)Not seriousNot seriousNot seriousVery serious1None⊕⊕○○
LOW
92/237 (38.8%)86/230 (37.4%)RR 0.96 (0.76–1.21)Moderate
388 per 100016 fewer per 1000 (93 fewer to 82 more)
Famciclovir 500 mg twice daily, or aciclovir 400 mg 5 × daily × 7 days: median time to complete healing of all lesions
293 (1 RCT)Not seriousNot seriousNot seriousVery serious1None⊕⊕○○
LOW
The median time to complete healing of all lesions was 7 days in both treatment groups with a hazard ratio of 1.01 (95% CI, 0.79±1.29; P = 0.95).
Famciclovir 500 mg twice daily, or aciclovir 400 mg five times daily for 7 days: median time to cessation of viral shedding
293 (1 RCT)Not seriousNot seriousNot seriousVery serious1None⊕⊕○○
LOW
The median time to cessation of viral shedding from all lesions was 2 days for both famciclovir and aciclovir (hazard ratio, 0.93; 95% CI, 0.68±1.27; P = 0.64).
Famciclovir 500 mg twice daily, or aciclovir 400 mg five times daily for 7 days: median time to loss of symptoms
293 (1 RCT)Not seriousNot seriousNot seriousVery serious1None⊕⊕○○
LOW
The median time to loss of all lesion associated symptoms was 4 days in both groups (hazard ratio, 0.99; 95% CI, 0.75±1.30; P = 0.93).
Famciclovir 500 mg twice daily, or aciclovir 400 mg five times daily for 7 days: side-effects
293 (1 RCT)Not seriousNot seriousNot seriousVery serious1None⊕⊕○○
LOW
82/143 (57.3%)81/150 (54.0%)RR 0.94 (0.77–1.16)Moderate
573 per 100034 fewer per 1000 (132 fewer to 92 more)

CI: confidence interval; RR: risk ratio

1

Considered with imprecise results since 95% CI includes potential for fewer or greater cures or adverse events and few events across studies

REFERENCES
1.
Warren T, Harris J, Brennan CA. Efficacy and safety of valaciclovir for the suppression and episodic treatment of herpes simplex virus in patients with HIV. Clin Infect Dis. 2004;39(Suppl 5):S258–S266. [PubMed: 15494897]
2.
Conant MA, Schacker TW, Murphy RL, Gold J, Crutchfield LT, Crooks RJ. International Valaciclovir HSV Study Group. Valaciclovir versus aciclovir for herpes simplex virus infection in HIV-infected individuals: two randomized trials. Int J STD AIDS. 2002;13(1):12–21. [PubMed: 11802924]
3.
Romanowski B, Aoki FY, Martel AY, Lavender EA, Parsons JE, Saltzman RL. Collaborative Famciclovir HIV Study Group. Efficacy and safety of famciclovir for treating mucocutaneous herpes simplex infection in HIV-infected individuals. AIDS. 2000;14(9):1211–7. [PubMed: 10894286]
Patient values and preferences, acceptability and cost: specific to herpes simplex virus infections
1.
Scalone L, Ryan M, Kotsopoulos N, Patel R. Evaluation of patients’ preferences for genital herpes treatment. Sex Transm Dis. 2011;38(9):802–7. [PubMed: 21844733] [CrossRef]
2.
International drug price indicator guide, 2014 edition (updated annually). Medford (MA): Management Sciences for Health; 2015. [accessed 6 June 2016]. http://erc​.msh.org/dmpguide​/pdf/DrugPriceGuide_2014.pdf.
Patient values and preferences, acceptability and cost: other sexually transmitted infections and conditions
1.
Nagarkar A, Mhaskar P. A systematic review on the prevalence and utilization of health care services for reproductive tract infections/sexually transmitted infections: evidence from India. Indian J Sex Transm Dis. 2015;36(1):18–25. [PMC free article: PMC4555893] [PubMed: 26392649] [CrossRef]
2.
Ryan R, Santesso N, Lowe D, Hill S, Grimshaw J, Prictor M, et al. Interventions to improve safe and effective medicines use by consumers: an overview of systematic reviews. Cochrane Database Syst Rev. 2014;(4):CD007768. [PMC free article: PMC6491214] [PubMed: 24777444]
Additional references
1.
Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386(9995):743–800. [PMC free article: PMC4561509] [PubMed: 26063472] [CrossRef]
2.
Newman L, Rowley J, Vander Hoorn S, Wijesooriya NS, Unemo M, Low N, et al. Global estimates of the prevalence and incidence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting. PLoS One. 2015;10(12):e0143304. [PMC free article: PMC4672879] [PubMed: 26646541] [CrossRef]

RECOMMENDATION 5 AND 6

Should suppressive antiviral versus episodic antiviral be used for the treatment of frequent recurrent episodes of herpes simplex virus?
Population:Frequent recurrent episodes of herpes simplex virus
Intervention:Suppressive antiviral
Comparison:Episodic antiviral
Main outcomes:Critical: Recurrent clinical episodes, HSV-2 severity/pain, quality of life, HSV-2 transmission, HSV-2 shedding
Important: Side-effects, HIV acquisition and transmission, HIV viral load, compliance
Add for pregnant women critical outcomes: Maternal outcomes (caesarean section), fetal outcomes (neonatal herpes, teratogenicity, fetal loss, toxicity, neonatal death)
Setting:Outpatients
Perspective:Population
Background:The herpes simplex virus (HSV), or herpes, is categorized into two types: HSV-1 and HSV-2. Both HSV-1 and HSV-2 are highly infectious. HSV-1 is transmitted by oral-to-oral contact and mainly causes herpes labialis, or “cold sores”, but can also cause genital herpes. HSV-2 is a sexually transmitted infection that can cause genital herpes. Most infections are transmitted via asymptomatic viral shedding.
Oral antiviral medications are available for initial, episodic, and suppressive therapy; however, there is no cure for the infection. The medications vary: aciclovir, famciclovir and valaciclovir.
In 2003, WHO guidelines recommended the following dosage regimens for episodic treatment of recurrent infection: aciclovir, 200 mg orally, 5 times daily for 5 days; aciclovir, 400 mg orally, 3 times daily for 5 days; aciclovir, 800 mg orally, twice daily for 5 days; valaciclovir, 500 mg orally, twice daily for 5 days; valaciclovir, 1000 mg orally, once daily for 5 days; OR famciclovir, 125 mg orally, twice daily for 5 days.
For suppressive therapy, the recommended dosage regimens were: aciclovir, 400 mg, orally, twice daily, continuously; valaciclovir 500 mg, orally, once daily; valaciclovir 1000 mg orally, once daily; famciclovir, 250 mg orally, twice daily.
The Guideline Development Group (GDG) identified the following treatments for review:
Episodic therapy:
Aciclovir 200 mg po 5×/d × 5 days
Aciclovir 400 mg po tid × 3–5 days
Aciclovir 800 mg po bid × 5 days
Aciclovir 800 mg po tid × 2 days
Valaciclovir 500 mg po bid × 3–5 days
Valaciclovir 1 g po bid × 3–5 days
Famciclovir 125 mg po bid × 5 days
Famciclovir 1 g po bid × 1 day
Suppressive therapy:
Aciclovir 200 mg po qid
Aciclovir 400 mg po bid
Valaciclovir 500 mg po qd
Valaciclovir 1 g po qd
Famciclovir 250 mg po bid

bid: twice daily; po: orally; qd: once daily; qid: four times daily; tid: thrice daily

ASSESSMENT

JudgementResearch evidence
ProblemIs the problem a priority?
  • No
  • Probably no
  • Probably yes
  • Yes
  • Varies
  • Don’t know
Research evidence:
Recurrent episodes of genital HSV-2 occur a median of 4 (women) to 5 (men) times during the first year. However, there is great variability in the frequency of recurrences, even during the first year. In a study of 457 persons with newly acquired HSV-2 infection, 38% had 6 or more recurrences and 20% had more than 10 recurrences during the first year. 14% of women and 26% of men had more than 10 recurrences and only 26% of women and 8% of men had no or 1 recurrence in the first year of infection. Subsequently, the frequency of episodes slowly decreases, with an average decrease of 2 recurrences between years 1 and 5 of infection. Benedetti J, Corey L, Ashley R. Recurrence rates in genital herpes after symptomatic first-episode infection. Ann Intern Med. 1994;121(11):847–54.
Desirable EffectsHow substantial are the desirable anticipated effects?
  • Trivial
  • Small
  • Moderate
  • Large
  • Varies
  • Don’t know
Research evidence:
Data from one Cochrane systematic review was used: Le Cleach 2014. We included 14 RCTs: Straus 1984, Mattison 1988, Mertz 1988, Mostow 1988, Baker 1989, Patel 1997, Reitano 1998, Corey 2004, Sekhin 2004, Fife 2006, Fife 2007, Fife 2008, Bartlett 2008, and Celum 2008. In these studies, all groups received treatment for their recurrences, but between episodes, some received a placebo while others received an intervention.
Additional considerations:
Most studies included people with 4 or more recurrences per year for 6–12 months. The GDG agreed that there are large benefits with suppressive over episodic therapy.
Six studies compared suppressive aciclovir (from 200 to 400 mg twice daily and 800 mg once daily) to episodic therapy (usually 200 mg 5 times daily for 5 days) and found clinical recurrence was probably delayed and experienced by fewer people with suppressive therapy, and probably few differences in side-effects or compliance. The number of lesions with viral shedding was also probably reduced. Seven studies compared suppressive therapy with valaciclovir (from 250 to 1000 mg per day) to episodic therapy with valaciclovir (500 mg twice daily for 5 days). Clinical recurrence was probably delayed and experienced by fewer people with suppressive therapy, and probably few differences in side-effects or compliance. There may also be fewer days of pain and fewer HSV-2 transmissions to partners. The number of lesions with viral shedding was also probably reduced. One study compared suppressive famciclovir (250 mg twice daily for 6 months) to episodic therapy and found 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.
There were few studies that 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 quality for little-to-no differences in recurrence, compliance and side-effects. Two studies compared valaciclovir 500 mg daily to 1000–3000 mg daily. There was very low quality evidence for little-to-no difference in duration of episodes, HSV-2 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 250 mg twice daily or less. The time to first recurrence was probably similar across doses with little-to-no difference in side-effects. There may be fewer episodes per month with greater than 250 mg twice daily and fewer days of HSV-2 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 may be little-to-no differences in side-effects and compliance, but there may be more days of HSV-2 shedding with famciclovir (risk ratio: 2.23; 95% CI: 1.18–4.89).
Undesirable EffectsHow substantial are the undesirable anticipated effects?
  • Large
  • Moderate
  • Small
  • Trivial
  • Varies
  • Don’t know
Certainty of evidenceWhat is the overall certainty of the evidence of effects?
  • Very low
  • Low
  • Moderate
  • High
  • No included studies
Research evidence:
No research evidence was identified.
Additional considerations:
Overall, when comparing suppressive to episodic therapy, the quality of the evidence was moderate.
When comparing the different drugs and dosages of suppressive therapy, the quality of the evidence was low.
ValuesIs there important uncertainty about or variability in how much people value the main outcomes?
  • Important uncertainty or variability
  • Possibly important uncertainty or variability
  • Probably no important uncertainty or variability
  • No important uncertainty or variability
Research evidence:
A discrete choice exercise suggested subjects’ preferences were influenced by both the treatment they follow and attributes of treatment including cost. Of all the attributes, patients place high value in unit change in chance of recurrence (1%), followed by unit change in number of tablets taken daily (1 tablet), unit change in chance of becoming infected with HIV, unit change in number of tablets taken in addition during each recurrence.
In addition, qualitative studies suggested stigma related is also important.
Additional considerations:
The GDG agreed that, clinically, people value non-transmission as the priority, followed by non-recurrence. They agreed that these priorities probably did not significantly vary.
Balance of effectsDoes the balance between desirable and undesirable effects favour the intervention or the comparison?
  • Favours the comparison
  • Probably favours the comparison
  • Does not favour either the intervention or the comparison
  • Probably favours the intervention
  • Favours the intervention
  • Varies
  • Don’t know
Research evidence:
No research evidence was identified.
Additional considerations:
The GDG agreed that suppressive therapy with any of the drugs was favoured over episodic therapy.
Resources requiredHow large are the resource requirements (costs)?
  • Large costs
  • Moderate costs
  • Negligible costs and savings
  • Moderate savings
  • Large savings
  • Varies
  • Don’t know
Research evidence:
Cost for episodic therapy
ABCDEF
Aciclovir 200 mg po55 days$0.05$1.25$1.56
Aciclovir 400 mg po33–5 days$0.04$0.36–$1.00$0.45–$1.25
Aciclovir 800 mg po25 daysn.a.n.a.n.a.
Aciclovir 800 mg po32 daysn.a.n.a.n.a.
Valaciclovir 500 mg23–5 days$0.625$3.75–$6.25$4.68–$7.80
Valaciclovir 1 g po23–5 daysn.an.an.a
Famciclovir 125 mg po25 daysn.a.n.a.n.a
Famciclovir 1 g po21 dayn.a.n.a.n.a.
Cost for suppressive therapy per day
ABDEF
Aciclovir 200 mg po4$ 0.05$0.20$0.25
Aciclovir 400 mg po2$ 0.04$0.08$0.10
Valaciclovir 500 mg1$ 0.625$0.625$0.78
Valaciclovir 1 g po1n.a.n.a.n.a.
Famciclovir 250 mg po2$ 4.38$8.76$10.95
*Sources: International drug price indicator guide (MSH, 2015) and www​.drugs.com
A: treatment; B: dose per day; C: treatment duration; D: drug cost, per dose; E: drug per full-course treatment; F: 25% procurement as defined by International drug price indicator guide (MSH, 2015).
po: orally
Additional considerations:
The GDG was unable to determine the costs of suppressive therapy since costs were of individual dosages. The GDG agreed that the costs would be large.
Certainty of evidence of required resourcesWhat is the certainty of the evidence of resource requirements (costs)?
  • Very low
  • Low
  • Moderate
  • High
  • No included studies
Research evidence:
No research evidence was available.
Additional considerations:
None
Cost effectivenessDoes the cost-effectiveness of the intervention favour the intervention or the comparison?
  • Favours the comparison
  • Probably favours the comparison
  • Does not favour either the intervention or the comparison
  • Probably favours the intervention
  • Favours the intervention
  • Varies
  • No included studies
Research evidence:
No research evidence available.
Additional considerations:
The GDG agreed that the costs would likely be high for any of the drugs and depend on the setting. Although the cost may be high for an individual, there is a small population that would have frequent HSV-2 infections requiring suppressive therapy. There may also be a potential for cost savings in work productivity and health care use.
EquityWhat would be the impact on health equity?
  • Reduced
  • Probably reduced
  • Probably no impact
  • Probably increased
  • Increased
  • Varies
  • Don’t know
Research evidence:
No research evidence available.
Additional considerations:
The impact on equity was unclear as HSV-2 occurs most in disadvantaged populations who may not have access to suppressive therapy; but with increasing access, equity could be increased. However, valaciclovir and famciclovir are more expensive than aciclovir and would probably reduce equity if recommended.
AcceptabilityIs the intervention acceptable to key stakeholders?
  • No
  • Probably no
  • Probably yes
  • Yes
  • Varies
  • Don’t know
Research evidence:
An overview of reviews of medication adherence (Ryan, 2014) reported that adherence may be improved with simpler drug regimens. However, when compliance was measured in the studies included for HSV treatments, compliance was similar among drugs.
Additional considerations:
Many thought that some patients would be quite unwilling to take 2 pills per day for an extended time on suppressive therapy. Indeed, some physicians might be unwilling to administer this to many patients if compliance is going to be low. Additionally, the intervention may be unacceptable in terms of cost to whoever is paying for the drugs. Overall, it was agreed that the different regimens and drugs are probably acceptable to most people.
FeasibilityIs the intervention feasible to implement?
  • No
  • Probably no
  • Probably yes
  • Yes
  • Varies
  • Don’t know
Research evidence:
No research evidence was identified.
Additional considerations:
Although the cost may be high for an individual, there is a small population that would have frequent HSV-2 infections requiring suppressive therapy. This would make it feasible to provide it to a small number of people.
Follow-up may be difficult in some countries.
It will also be important to define “frequent”, and it was suggested that this varies by patient, and the recommendation should be flexible to take into consideration individual patient preferences.

SUMMARY OF JUDGEMENTS

Judgement
ProblemNoProbably noProbably yesYesVariesDon’t know
Desirable EffectsTrivialSmallModerateLargeVariesDon’t know
Undesirable EffectsLargeModerateSmallTrivialVariesDon’t know
Certainty of evidenceVery lowLowModerateHighNo included studies
ValuesImportant uncertainty or variabilityPossibly important uncertainty or variabilityProbably no important uncertainty or variabilityNo important uncertainty or variability
Balance of effectsFavours the comparisonProbably favours the comparisonDoes not favour either the intervention or the comparisonProbably favours the interventionFavours the interventionVariesDon’t know
Resources requiredLarge costsModerate costsNegligible costs and savingsModerate savingsLarge savingsVariesDon’t know
Certainty of evidence of required resourcesVery lowLowModerateHighNo included studies
Cost effectivenessFavours the comparisonProbably favours the comparisonDoes not favour either the intervention or the comparisonProbably favours the interventionFavours the interventionVariesNo included studies
EquityReducedProbably reducedProbably no impactProbably increasedIncreasedVariesDon’t know
AcceptabilityNoProbably noProbably yesYesVariesDon’t know
FeasibilityNoProbably noProbably yesYesVariesDon’t know

CONCLUSIONS

Should suppressive antiviral versus episodic antiviral be used for the treatment of recurrent episodes of herpes simplex virus?
Type of recommendationStrong recommendation against the interventionConditional recommendation against the interventionConditional recommendation for either the intervention or the comparisonConditional recommendation for the interventionStrong recommendation for the intervention
RecommendationRecommendation 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.
JustificationThe 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.
Subgroup considerations
Implementation considerations
Monitoring and evaluation
Research prioritiesLittle evidence was found for some outcomes critical to making decisions in trials comparing drugs to placebo or comparing different drugs to treat first or recurrent episodes of genital HSV infections. Important patient outcomes should be measured in clinical trials, such as genital HSV acquisition and transmission, HIV acquisition and transmission, quality of life and pain. There were few available data for direct comparisons of different drugs, in particular for comparisons with famciclovir. There were also few studies comparing the different dosages of the drugs. Future research could use the dosages recommended in these guidelines as comparators. Equity issues, acceptance of and compliance with different drugs and regimens should also be explored in people with genital HSV infections. Although this search was not limited to different populations, there were few data for key populations, such as people with HIV infection, people who are immunocompromised and pregnant women. More information can also be provided to allow for the critical appraisal of clinical trials by following the standards of reporting of RCTs, in particular for the methods of randomization and allocation concealment and blinding.

EVIDENCE TABLES

Suppressive aciclovir versus episodic aciclovir

SuppressiveEpisodic
Baker 1989aciclovir 800 mg 1 × dailyaciclovir 200 mg 5 × daily × 5 days
Mattison 1988aciclovir 200 mg 2 × dailyaciclovir 200 mg 5 × daily × 5 days
Mertz 1988aciclovir 400 mg 2 × daily × 1 yearaciclovir 200 mg 5 × daily × 5 days
Straus 1984aciclovir 200 mg 3 × daily × 35 daysaciclovir 200 mg 5 × daily × 5 days
Sacks 1988aciclovir 200 mg 3 × daily × 6 monthsaciclovir 200 mg 5 × daily × 5 days
Celum 2008aciclovir 400 mg 2 × daily × 12–18 monthsaciclovir 400 mg 3 × daily × 5 days
Quality assessmentNo. of patientsEffectQualityImportance
No. of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOtherSuppressive antiviralEpisodic antiviralRelative (95% CI)Absolute (95% CI)
Time to first recurrent episode
5Randomized trialsSerious1Not seriousNot seriousNot seriousNoneNo. of people: Suppressive 737, episodic: 449. In 2 trials with suppressive 400 mg × 2 or 800 mg daily, mean or median time was ~250 days, and 18 days with episodic. 3 trials with < 800 mg daily, time ranged from 72–250 days.⊕⊕⊕○
MODERATE
CRITICAL
Mean number of recurrence/month
6Randomized trialsSerious1Not seriousSerious2Not seriousNoneNo. of people: Suppressive 2380, episodic 2277. In 2 trials with suppressive 400 mg × 2 or 800 mg daily, mean number per month was 0.18, and 0.72–0.95 with episodic. 3 trials with < 800 mg daily ranged from 0.02–0.37⊕⊕⊕○
MODERATE
CRITICAL
Number of participants with at least one clinical recurrence
5Randomized trialsSerious1Not seriousNot seriousNot seriousNone363/650 (55.8%)547/561 (97.5%)RR 0.57 (0.53–0.61)3419 fewer per 1000 (from 380–458 fewer)⊕⊕⊕○
MODERATE
CRITICAL
Number of lesions with viral shedding (assessed with viral cultures and PCR – HSV DNA)
2Randomized trialsSerious1,2Not seriousNot seriousNot seriousNoneLargest study (1664 lesions analysed) found RR 0.70 (0.62–0.78) meaning 173 fewer per 1000 (from 127–219 fewer). Small study with 133 lesions analysed found RR 0.28 (0.04–1.87).⊕⊕⊕○
MODERATE
IMPORTANT
HSV-2 severity/pain – not measured
HSV-2 transmission – not measured
Quality of life – not measured
Side-effects (serious – not considered related to treatment – death, hospitalization) – see details in additional table
1Randomized trialsNot seriousNot seriousNot seriousSerious4None75/1637 (4.6%)63/1640 (3.8%)RR 1.19 (0.86–1.66)7 more per 1000 (from 5 fewer to 25 more)⊕⊕⊕○
MODERATE
CRITICAL
Side-effects (not serious) – see details in additional table
3Randomized trialsSerious1Not seriousNot seriousSerious4None31/178 (17.4%)29/159 (18.2%)RR 1.07 (0.76–1.49)16 more per 1000 (from 56 fewer to 113 more)⊕⊕○○
LOW
IMPORTANT
5.0%4 more per 1000 (from 12 fewer to 25 more)
Compliance
3Randomized trialsNot serious1Not serious5Not seriousNot seriousNoneIn 2 studies (~3400 people), compliance was similar in both groups. In another study (~47 people), a greater number of patients receiving episodic aciclovir were noncompliant.⊕⊕⊕○
MODERATE
IMPORTANT

CI: confidence interval; PCR: polymerase chain reaction; RR: risk ratio

1

Randomization and allocation concealment mostly unclear; and pseudo randomization in largest trial.

2

Largest trial did not restrict recruitment by recurrences per year at baseline but this was considered with risk of bias and only downgraded to moderate level of evidence.

3

Trials with 400 × 2 or 800 mg daily; similar risk in trials with < 800 mg.

4

Few participants/events and CIs include no effect and appreciable harm or benefit. One other study (1146 patients) found similar events across groups.

5

Results inconsistent among studies – considered with risk of bias and only downgraded to moderate level of evidence

DETAILS OF SIDE-EFFECTS
StudySuppressive doseEventTotalType of eventEpisodic doseEventTotalType of eventResult
Baker 1989aciclovir 800 mg 1 × daily × 1 year29131Not seriousaciclovir 200 mg 5 × daily × 5 days27130Not seriousRR 1.07 (0.76–1.49)
16 more per 1000 (from 56 fewer to 113 more)
Mattison 1988aciclovir 200 mg 2 × daily × 1 year247Not seriousaciclovir 200 mg 5 × daily × 5 days229Not serious
Sacks 1988aciclovir 200 mg 1 × daily × 6 months1625Not seriousaciclovir 200 mg 5 × daily × 5 days1425Not serious
Mattison 1988aciclovir 200 mg 2 × daily × 1 year047Seriousaciclovir 200 mg 5 × daily × 5 days029Serious
Mertz 1988aciclovir 400 mg 2 × daily × 1 year1–3%575Not seriousaciclovir 200 mg 5 × daily × 5 days1–3%571Not serious“similar in both groups”
Straus 1984aciclovir 200 mg 3 × daily up to 125 days1217Not seriousaciclovir 200 mg 5 × daily × 5 days618Not seriousUnclear if is number of patients
Celum 2008aciclovir 400 mg 2 × daily × 12–18 months751637Serious – considered unrelated to study treatmentaciclovir 400 mg 3 × daily × 5 days631840Serious – considered unrelated to study treatmentRR 1.19 (0.86–1.66)
7 more per 1000 (from 5 fewer to 25 more)
Mostow 1988aciclovir 800 mg 1 × daily × 2 years022Seriousaciclovir 200 mg 5 × daily × 5 days024Serious
Mostow 1988aciclovir 800 mg 1 × daily × 2 years2022Not seriousaciclovir 200 mg 5 × daily × 5 days2724Not seriousNumber of episodes not patients

SUPPRESSIVE VALACICLOVIR VERSUS EPISODIC VALACICLOVIR

SuppressiveEpisodic
Fife 2006Valaciclovir 1 g × 60 daysValaciclovir 500 mg 2 × daily × 3 days
Fife 2007Valaciclovir 500 mg daily × 1 yearValaciclovir 500 mg 2 × daily × 5 days
Corey 2004Valaciclovir 500 mg daily × 8 monthsValaciclovir 500 mg 2 × daily × 5 days
Fife 2008Valaciclovir 1 g 1 × daily × 24 weeksValacylovir 500 mg 2 × daily × 3 days
Patel 1997Valaciclovir 500 mg 1 × daily × 16 weeksValaciclovir 500 mg 2 × daily × 5 days
Reitano 1998Valaciclovir 250 mg, 500 mg, or 1 g once daily, or 250 mg 2 × daily × 1 yearValaciclovir (episodic) × 5 days
Sekhin 2004Valaciclovir 500 mg 1 × daily × 8 monthsValaciclovir 500 mg 2 × daily × 5 days
Quality assessmentNo. of patientsEffectQualityImportance
No. of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOtherSuppressive antiviralEpisodic antiviralRelative (95% CI)Absolute (95% CI)
Time to first recurrent episode
4Randomized trialsNot serious1Not seriousNot seriousNot seriousNoneIn 2 studies (229 patients), mean and median times were > 60 days or 185 days, compared to episodic at 32–46 days. Two other studies reported HR 0.3 (0.26–0.35) in 1484 patients and 0.35 (0.24–0.50) in 383 patients, meaning 200/1000 fewer people had a recurrence at 40 days with suppressive therapy.⊕⊕⊕⊕
HIGH
CRITICAL
Mean number of recurrence/month
3Randomized trialsNot seriousSerious2Not seriousNot seriousNone1037908MD 0.44 recurrences lower (0.55 lower to 0.34 lower)⊕⊕⊕○
MODERATE
CRITICAL
Number of participants with at least on clinical recurrence
7Randomized trialsNot seriousSerious3Not seriousNot seriousNone1096/2535 (43.2%)922/1199 (76.9%)RR 0.52 (0.49–0.55)369 fewer per 1000 (from 346 fewer to 392 fewer)⊕⊕⊕○
MODERATE
CRITICAL
Pain (days with pain)
1Randomized trialsSerious4Not seriousNot seriousVery serious5None4040MD 5.4 days lower (7.88 lower to 2.92 lower)⊕○○○
VERY LOW
CRITICAL
HSV-2 transmission to partner
1Randomized trialsSerious6Not seriousNot seriousSerious5None14/743 (1.9%)27/741 (3.6%)7HR 0.52 (0.27–0.99)17 fewer per 1000 (from 0–26 fewer)⊕⊕○○
LOW
IMPORTANT
4.5%721 fewer per 1000 (from 0–33 fewer)
Quality of life
1Randomized trialsSerious4Not seriousNot seriousSerious5NoneQuality of life improved from baseline for both treatment arms (80 patients total). Improvement was slightly more with suppressive therapy but these differences were reported as not “statistically significant”.⊕⊕○○
LOW
CRITICAL
Compliance
4Randomized trialsNot serious1Not seriousNot seriousSerious8NoneMost studies provided a placebo or drug as a suppressive regimen. In 1 study, 70% reported taking at least 95% of the prescribed doses. In another study (152 patients), 82–93% were 80% compliant or more; and in another (384 patients), 80% took over 80% of the medication. One study compared suppressive to true episodic therapy (80 patients), average intake of medication was similar (~90%).⊕⊕⊕○
MODERATE
CRITICAL
Side-effects (serious – not related to drug) – see also detailed table below
4Randomized trialsSerious4,6Not seriousNot seriousNot seriousNone2364 patients received suppressive therapy and 1097 received episodic. There was 1 serious side-effect with suppressive but not related to the drug.⊕⊕⊕○
MODERATE
IMPORTANT
Side-effects (not serious) – see also detailed table below
5Randomized trialsSerious4,6Not seriousNot seriousNot seriousNone123/170 (72.4%)244/364 (67.0%)RR 1.06 (0.95–1.20)40 more per 1000 (from 34 fewer to 134 more)⊕⊕⊕○
MODERATE
IMPORTANT
HSV-2 shedding (assessed with: days)
2Randomized trialsSerious1Not seriousNot seriousNot seriousNone124/148 (83.8%)81/92 (88.0%)RR 0.85 (0.75–0.96)126 fewer per 1000 (from 34–209 fewer)⊕⊕⊕○
MODERATE
CRITICAL

CI: confidence interval; HR: hazard ratio; RR: risk ratio

1

Unclear randomization and blinding but not serious to downgrade evidence

2

Unclear randomization and loss to follow-up in largest study and some unexplained heterogeneity

3

Unclear randomization and loss to follow-up in studies, and high heterogeneity that could not be explained but point estimates between RR 0.2–0.6

4

Participants were not blinded

5

Few events or few participants

6

Randomization and allocation concealment mostly unclear; and pseudo randomization i largest trial – considered often with other criteria and not downgraded.

7

Risk at 240 days (duration of trial)

8

Little data for compliance to episodic treatment

DETAILS OF SIDE-EFFECTS
StudySuppressive doseEventTotalEpisodic doseEventTotalType of eventResult
Fife 2006valaciclovir 1 g 1 × daily × 60 days59109valaciclovir 500 mg 2 × daily × 3 days2542Not serious
Corey 2004valaciclovir 500 mg 1 × daily × 8 months“similar” across groups743valaciclovir 500 mg 2 × daily × 5 days“similar” across groups741Not seriousSimilar across groups
Corey 2004valaciclovir 500 mg 1 × daily × 8 months0743valaciclovir 500 mg 2 × daily × 5 days0741Serious – “considered not related to drug”
Fife 2008valaciclovir 1 g 1 × daily × 24 weeks185255valaciclovir 500 mg 2 × daily × 3 days98128Not seriousSimilar across groups
Fife 2008valaciclovir 1 g 1 × daily × 24 weeks0255valaciclovir 500 mg 2 × daily × 3 days0128Serious – “considered not related to drug”
Patel 1997valaciclovir 500 mg 1 × daily × 16 weeksadverse rate patient per day was 0.02288valaciclovir 500 mg 2 × daily × 5 daysadverse rate patient per day was 0.0394Not seriousSimilar across groups
Patel 1997valaciclovir 500 mg 1 × daily × 16 weeks1288valaciclovir 500 mg 2 × daily × 5 days094SeriousSimilar across groups
Reitano 1998valaciclovir 250 mg, 500 mg, or 1 g × 1 daily, or 250 mg 1 × daily × 1 yearNot reported per patient1078valaciclovir × 5 daysNot reported per patient134Not seriousSimilar across groups
Reitano 1998valaciclovir 250 mg, 500 mg, or 1 g × 1 daily, or 250 mg 2 × daily × 1 year1078valaciclovir × 5 days134Serious – 48 patients across all groups; 1 death not related to drugSimilar across groups

SUPPRESSIVE FAMCICLOVIR VERSUS EPISODIC FAMCICLOVIR

SuppressiveEpisodic
Bartlett 2008Famciclovir 250 mg 2 × daily × 6 monthsFamciclovir 125 mg 2 × daily × 5 days
Quality assessmentNo. of patientsEffectQualityImportance
No. of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOtherSuppressive antiviralEpisodic antiviralRelative (95% CI)Absolute (95% CI)
Time to first clinical recurrent episode
1Randomized trialsSerious1Not seriousNot seriousSerious1None1571554HR 6.30 (3.90–10.17)587 more per 1000 (from 424–696 more)⊕⊕○○
LOW
CRITICAL
25.0%4
Mean number of recurrence/month – not measured
Number of participants with at least 1 clinical recurrence in 6 months follow-up
1Randomized trialsSerious1Not seriousNot seriousSerious1None28/157 (17.8%)94/155 (60.6%)RR 0.29 (0.21–0.42)431 fewer per 1000 (from 352–479 fewer)⊕⊕○○
LOW
CRITICAL
HSV-2 duration of shedding – not measured
HSV-2 severity/pain – not measured
Quality of life (Scale from: 0 to 60, optimal)
1Randomized trialsSerious1Not seriousNot seriousSeriousNone143134MD 2.02 lower (5.14 lower to 1.09 higher)⊕⊕○○
LOW
CRITICAL
Compliance – not measured2
Side-effects (not serious)
1Randomized trialsSerious1Not seriousNot serious3Serious1None60/157 (38.2%)50/155 (32.3%)RR 1.18 (0.88–1.60)58 more per 1000 (from 39 fewer to 194 more)3⊕⊕○○
LOW
IMPORTANT
HSV-2 transmission – not measured

CI: confidence interval; HR: hazard ratio; RR: relative risk

1

Participants were not blinded, high loss to follow-up and few events or few participants

2

Study reported that 70% of people with episodic and 80% with suppressive were somewhat-to-very satisfied with treatment, and would recommend the treatment to others (no statistically significant differences)

3

Side-effects: authors reported 94% of events not related to drugs

4

Risk at 40 days of treatment.

REFERENCES
    Systematic review
    1.
    Le Cleach L, Trinquart L, Do G, Maruani A, Lebrun-Vignes B, Ravaud P, Chosidow O. Oral antiviral therapy for prevention of genital herpes outbreaks in immunocompetent and nonpregnant patients. Cochrane Database Syst Rev. 2014;(8):CD009036. [PubMed: 25086573]
    Included studies
    1.
    Baker DA, Blythe JG, Kaufman R, Hale R, Portnoy J. One-year suppression of frequent recurrences of genital herpes with oral acyclovir. Obstet Gynecol. 1989;73(1):84–7. [PubMed: 2642329]
    2.
    Bartlett BL, Tyring SK, Fife K, Gnann JW Jr, Hadala JT, Kianifard F, Berber E. Famciclovir treatment options for patients with frequent outbreaks of recurrent genital herpes: the RELIEF trial. J Clin Virol. 2008;43(2):190–5. [PubMed: 18621575] [CrossRef]
    3.
    Celum C, Wald A, Hughes J, Sanchez J, Reid S, Delany-Moretlwe S, et al. Effect of aciclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive women and men who have sex with men: a randomised, double-blind, placebo-controlled trial. Lancet. 2008;371(9630):2109–19. [PMC free article: PMC2650104] [PubMed: 18572080] [CrossRef]
    4.
    Corey L, Wald A, Patel R, Sacks SL, Tyring SK, Warren T, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med. 2004;350(1):11–20. [PubMed: 14702423] [CrossRef]
    5.
    Fife KH, Almekinder J, Ofner S. A comparison of one year of episodic or suppressive treatment of recurrent genital herpes with valacyclovir. Sex Transm Dis. 2007;34(5):297–301. [PubMed: 16960547] [CrossRef]
    6.
    Fife KH, Warren TJ, Justus SE, Heitman CK. HS2100275 Study Team. An international, randomized, double-blind, placebo-controlled, study of valacyclovir for the suppression of herpes simplex virus type 2 genital herpes in newly diagnosed patients. Sex Transm Dis. 2008;35(7):668–73. [PubMed: 18461016] [CrossRef]
    7.
    Fife KH, Warren TJ, Ferrera RD, Young DG, Justus SE, Heitman CK, et al. Effect of valacyclovir on viral shedding in immunocompetent patients with recurrent herpes simplex virus 2 genital herpes: a US-based randomized, double-blind, placebo-controlled clinical trial. Mayo Clin Proc. 2006;81(10):1321–7. [PubMed: 17036557] [CrossRef]
    8.
    Mattison HR, Rechman RC, Benedetti J, Bolgiano D, Davis LG, Bailey-Farchione A, et al. Double-blind, placebo-controlled trial comparing long-term suppressive with short-term oral acyclovir therapy for management of recurrent genital herpes. Am J Med. 1988;85(2 A):20–5. [PubMed: 3044086]
    9.
    Mertz GJ, Jones CC, Millis J, Fife KH, Lemon SM, Stapleton JT, et al. Long-term acyclovir suppression of frequently recurring genital herpes simplex virus infection. A multicenter double-blind trial. JAMA. 1988;260(2):201–6. [PubMed: 3290517]
    10.
    Straus SE, Croen KD, Sawyer MH, Freifeld AG, Felser JM, Dale JK, et al. Acyclovir suppression of frequently recurring genital herpes. Efficacy and diminishing need during successive years of treatment. JAMA. 1984;260(15):2227–30. [PubMed: 2845160]
    11.
    Mostow SR, Mayfield JL, Marr JJ, Drucker JL. Suppression of recurrent genital herpes by single daily dosages of acyclovir. Am J Med. 1988;85(2 A):30–3. [PubMed: 3044089]
    12.
    Patel R, Bodsworth NJ, Woolley P, Peters B, Vejlsgaard G, Saari S, et al. International Valaciclovir HSV Study Group. Valaciclovir for the suppression of recurrent genital HSV infection: a placebo controlled study of once daily therapy. Genitourin Med. 1997;73(2):105–9. [PMC free article: PMC1195782] [PubMed: 9215091]
    13.
    Reitano M, Tyring S, Lang W, Thoming C, Worm AM, Borelli S, et al. International Valaciclovir HSV Study Group. Valaciclovir for the suppression of recurrent genital herpes simplex virus infection: a large-scale dose range-finding study. J Infect Dis. 1998;178(3):603–10. [PubMed: 9728526]
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    Sekhin SV, Averchenkov NA, Petrochenkova N, Melekhova Y, Stratchounkski LS. Efficacy of long-term suppressive therapy with valacyclovir in recurrent genital herpes. Clin Microbiol Infect. 2004;10(Suppl 3):43–4.

COMPARISON OF SIMILAR DRUGS FOR SUPPRESSIVE THERAPY AT DIFFERENT DOSAGES

Suppressive aciclovir versus suppressive aciclovir
SuppressiveSuppressive
Douglas 1984aciclovir 200 mg 2 × dailyaciclovir 200 mg 5 × daily
Quality assessmentNo. of patientsEffectQualityImportance
No. of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOtherAciclovir 200 mg 1 × dailyAciclovir 200 mg 5 × dailyRelative (95% CI)Absolute (95% CI)
Time to first recurrent episode
1Randomized trialsSerious1Not seriousNot seriousSerious2NoneMedian number of days was 120 in both groups⊕⊕○○
LOW
CRITICAL
Number of episodes/month
1Randomized trialsSerious1Not seriousNot seriousSerious2NoneMean in 2 × daily was 0.14 days (+/− 0.25) and in 5 × daily was 0.13 (+/− 0.27)⊕⊕○○
LOW
CRITICAL
Number of participants with at least one clinical recurrence (follow-up: 4 months)
1Randomized trialsSerious1Not seriousNot seriousSerious2None19/52 (36.5%)19/51 (37.3%)RR 1.02 (0.62–1.69)7 more per 1000 (from 142 fewer to 257 more)⊕⊕○○
LOW
CRITICAL
HSV-2 severity/pain – not measured
HSV-2 quality of life – not measured
HSV-2 duration of shedding – not measured
Compliance
1Randomized trialsSerious1Not seriousNot seriousSerious2NoneMean number of pills missed and ratio of pills missed to pills prescribed were “similar” across 2 × and 5 × daily regimens.⊕⊕○○
LOW
IMPORTANT
Side-effects – any
1Randomized trialsSerious1Not seriousNot seriousSerious2None1 patient taking ACV 5 × daily discontinued due to side-effects. Gastrointestinal effects, headache, fever, laboratory values, etc., were similar between groups.⊕⊕○○
LOW
IMPORTANT

CI: confidence interval; RR: risk ratio;

1

Randomization and loss to follow-up not done or unclear

2

Number of participants too low

3

Few events across studies and some inconsistency.

4

Results reported for 1 study and similar to the other study.

5

Study participants were not blinded to the treatment

SUPPRESSIVE VALACICLOVIR VERSES SUPPRESSIVE VALACICLOVIR
SuppressiveSuppressiveSuppressiveSuppressive
Reitano 1998valaciclovir 250 mg × 1 dailyvalaciclovir 250 mg × 2 dailyvalaciclovir 500 mg × 1 dailyvalaciclovir 1 g × 1 daily
Johnston 2012 study 3 (assessed whether higher doses of antiviral drugs or changes in the dosing schedule could provide more potent suppression of short shedding episodes.)valaciclovir 500 mg × 1 dailyvalaciclovir 1–3 g daily
Quality assessmentNo. of patientsEffectQualityImportance
No. of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOtherValaciclovir 500 mg dailyValaciclovir 1 to 3 g dailyRelative (95% CI)Absolute (95% CI)
Episode duration (assessed with: hours)
1Randomized trialsSerious5Not seriousNot seriousVery serious2None4343median 0 (10 to 7 more)⊕○○○
VERY LOW
CRITICAL
HSV-2 shedding annualised episode rate
1Randomized trialsSerious5Not seriousNot seriousVery serious2None4343Comparison 0 14.9 – 16.5 (14.9–16.5 higher)⊕○○○
VERY LOW
CRITICAL
Number of participants with at least one clinical recurrence
1Randomized trialsSerious1Not seriousNot seriousNot seriousnone373/540 (69.1%)178/269 (66.2%)RR 1.04 (0.94–1.16)26 more per 1000 (from 40 fewer to 106 more)⊕⊕⊕○
MODERATE
CRITICAL
HSV-2 duration of shedding – not measured
HSV-2 severity/pain – not measured
HSV-2 quality of life – not measured
Compliance – not measured
Side-effects – serious
2Observational studiesSerious1Not seriousNot seriousNot seriousNoneNo serious adverse events reported. Single arm from another study reported no adverse events with 500 mg 1 × daily.⊕○○○
VERY LOW
IMPORTANT

CI: confidence interval; RR: relative risk

1

Randomization and loss to follow-up not done or unclear

2

Number of participants too low

3

Few events across studies and some inconsistency.

4

Results reported for 1 study and similar to the other study.

5

Study participants were not blinded to the treatment

SUPPRESSIVE FAMCICLOVIR VERSES SUPPRESSIVE FAMCICLOVIR
SuppressiveSuppressiveSuppressiveSuppressiveSuppressive
Diaz-Mitoma 1998famciclovir 125 mg × 3 dailyfamciclovir 250 mg × 2 dailyfamciclovir 250 mg × 3 daily
Mertz 1997famciclovir 125 mg × 1 dailyfamciclovir 125 mg × 2 dailyfamciclovir 250 mg × 1 dailyfamciclovir 250 mg × 2 dailyfamciclovir 500 mg × 1 daily
Sacks 2004famciclovir 125 mg × 3 dailyfamciclovir 250 mg × 3 daily
Quality assessmentNo. of patientsEffectQualityImportance
No. of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsFamciclovir ≤ 250 mg 2/dayFamciclovir> 250 mg 2/dayRelative (95% CI)Absolute (95% CI)
Time to first recurrent episode (median) (follow-up: range 4–12 months)
3Randomized trialsSerious1Not seriousNot seriousNot seriousNoneTime was not consistently shorter with < 250 mg 2 × daily and not consistently longer with > 250 mg. Authors reported “similar” time (see additional tables).⊕⊕⊕○
MODERATE
CRITICAL
Number of episodes/month (follow-up: range 4–12 months)
2Randomized trialsSerious1Not seriousNot seriousSerious2None0.08 mean episodes/month with 250 mg 2 × daily but 0.15 with 500 mg 1 × daily; consistently more episodes (0.16–0.23) with < 250 mg.⊕⊕○○
LOW
CRITICAL
Number of participants with at least one clinical recurrence (follow-up: range 4–12 months)
2Randomized trialsSerious1Not seriousNot seriousSerious3None131/417 (24.0%)39/142 (35.7%)RR 0.92 (0.58–1.45)25 fewer per 1000 (from 132 fewer to 141 more)⊕⊕○○
LOW
CRITICAL
HSV-2 duration of shedding (positive viral cultures – asymptomatic or symptomatic swabs)
1Randomized trialsSerious1Not seriousNot seriousSerious2NoneTime to the first HSV-positive culture (HR 1.5; 95% CI, 0.9–2.6) in favour of greater dose. But 54% had shedding with greater dose versus 40% with smaller dose after 120 days.⊕⊕○○
LOW
CRITICAL
HSV-2 severity/pain – not measured
HSV-2 quality of life – not measured
Compliance
2Randomized trialsserious1not seriousnot seriousserious2none2 studies report from 92% to 98% of patients taking more than 80% of medication across all dosages⊕⊕○○
LOW
IMPORTANT
Side-effects - non-serious and serious (follow-up: range 4 to 12 months)
2Randomized trialsNot seriousNot serious4Not seriousSerious3,2None75/117 (64.1%)67/112 (59.8%)RR 1.07 (0.87–1.31)42 more per 1000 (from 78 fewer to 185 more)⊕⊕○○
LOW
IMPORTANT

CI: confidence interval; RR: risk ratio

1

Randomization and loss to follow-up not done or unclear

2

Number of participants too low

3

Few events across studies and some inconsistency.

4

Results reported for 1 study and similar to the other study.

5

Study participants were not blinded to the treatment

SUPPRESSIVE VALACICLOVIR VERSUS SUPPRESSIVE ACICLOVIR
SuppressiveSuppressive
Johnston 2012 study 2valaciclovir standard dose 500 mg 1 × dailyaciclovir high dose 800 mg 3 × daily
Reitano 1998valaciclovir 250 mg, 500 mg, or 1 g 1 × daily or 250 mg 2 × dailyaciclovir 400 mg 2 × daily
Quality assessmentNo. of patientsEffectQualityImportance
No. of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsSuppressive valaciclovirSuppressive aciclovirRelative (95% CI)Absolute (95% CI)
Episode duration (assessed with: hours)
1Randomized trialsSerious1Not seriousNot seriousVery serious2None2727median 0 hours⊕○○○
VERY LOW
CRITICAL
HSV-2 shedding annualised episode rate
1Randomized trialsSerious1Not seriousNot seriousVery serious2None272722.6–20.2 more⊕○○○
VERY LOW
IMPORTANT
Number of participants with at least 1 clinical recurrence
1Randomized trialsSerious3Not seriousNot seriousNot seriousNone581/1078 (53.9%)124/267 (46.4%)RR 1.16 (1.01–1.34)74 more per 1000 (from 5–158 more)⊕⊕⊕○
MODERATE
CRITICAL
HSV-2 severity/pain – not measured
HSV-2 quality of life – not measured
HSV-2 duration of shedding – not measured
Compliance (follow-up: range 4–7 weeks)
1Randomized trialsSerious3Not seriousNot seriousSeriousNone78–96% of participants reported > 85% adherence⊕⊕⊕○
MODERATE
IMPORTANT
Side-effects – serious (follow-up: 12 months)
2Randomized trialsSerious3Not seriousNot seriousSeriousNone1 study reported no serious adverse events; another study single arm with valaciclovir reported grade 2 neutropenia⊕⊕⊕○
MODERATE
IMPORTANT

CI: confidence interval; MD: mean difference; RR: relative risk

1

Participants were not blinded to the study treatment

2

Few events or participants

3

Randomization was unclear, and incomplete outcome assessment.

SUPPRESSIVE FAMCICLOVIR VERSUS SUPPRESSIVE VALACICLOVIR
SuppressiveSuppressive
Wald 2006 Study 1 (the effect of the treatments on suppression of clinical genital herpes recurrences.)famciclovir 250 mg 2 ’ dailyvalaciclovir 500 mg 1 ’ daily
Wald 2006 Study 2 (the effect of the treatments on HSV shedding from the genital area.)famciclovir 250 mg 2 ’ dailyvalaciclovir 500 mg 1 ’ daily
Quality assessmentNo. of patientsEffectQualityImportance
No. of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOtherFamciclovir 250 mg ’2/dayValaciclovir 500 mg ’1/dayRelative (95% CI)Absolute (95% CI)
Time to first clinical recurrence
1Randomized trialsSerious1Not seriousNot seriousSerious2NoneTime to first clinical recurrence of genital herpes was similar in both groups, HR 1.17 (95% CI: 0.78 –1.76) for famciclovir compared with valaciclovir⊕⊕○○
LOW
CRITICAL
Mean number of recurrences over the study period
1Randomized trialsSerious1Not seriousNot seriousSerious2None0.11 with famciclovir versus 0.10 with valaciclovir (P = 0.39)⊕⊕○○
LOW
CRITICAL
Number of participants with at least one clinical recurrence
1Randomized trialsSerious1Not seriousNot seriousSerious2None55/159 (34.6%)47/161 (29.2%)RR 1.18 (0.86–1.63)63 more per 1000 (from 49 fewer to 220 more)⊕⊕○○
LOW
CRITICAL
HSV-2 severity/pain – not measured
HSV-2 quality of life – not measured
HSV-2 shedding (assessed with: days HSV detected – asymptomatic and symptomatic)
1Randomized trialsSerious1Not seriousNot seriousSerious23.2% of days with famciclovir (n=34) and 1.3% with valaciclovir (n=36) – RR 2.23 (1.18–4.89) in favour of valaciclovir⊕⊕○○
LOW
CRITICAL
Compliance
2Randomized trialsSerious1Not seriousNot seriousSerious2NoneMedian adherence ranged from 97–100% in both groups⊕⊕○○
LOW
IMPORTANT
Side-effects – not serious (follow-up: range 10–16 weeks)
2Randomized trialsSerious1Not seriousNot seriousSerious2None27/193 (14.0%)29/197 (14.7%)RR 0.95 (0.59–1.54)7 fewer per 1000 (from 57 fewer to 76 more)⊕⊕○○
LOW
IMPORTANT
Side-effects – serious – not related to drug (follow-up: range 10–16 weeks)
2Randomized trialsSerious1Not seriousNot seriousSerious2None0/193 (0%)3/197 (1.5%)RR 0.26 (0.03–2.35)11 fewer per 1000 (from 15 fewer to 21 more)⊕⊕○○
LOW
IMPORTANT

CI: confidence interval; HR: hazard ratio; RR: risk ratio

1

Randomization and loss to follow-up unclear, unclear assessment of side-effects.

2

Few participants or events.

REFERENCES
    Systematic review
    1.
    Le Cleach L, Trinquart L, Do G, Maruani A, Lebrun-Vignes B, Ravaud P, Chosidow O. Oral antiviral therapy for prevention of genital herpes outbreaks in immunocompetent and nonpregnant patients. Cochrane Database Syst Rev. 2014;(8):CD009036. [PubMed: 25086573]
    Included studies
    1.
    Diaz-Mitoma F, Sibbald RG, Shafran SD, Boon R, Saltzman RL. Oral famciclovir for the suppression of recurrent genital herpes: a randomized controlled trial. JAMA. 1998;280(10):887–92. [PubMed: 9739972]
    2.
    Douglas JM, Critchlow C, Benedetti J. A double-blind study of oral acyclovir for suppression of recurrences of genital herpes simplex virus infection. N Engl J Med. 1984;310(24):1551–6. [PubMed: 6328298]
    3.
    Johnston C, Saracino M, Kuntz S, Magaret A, Selke S, Huang ML, et al. Standard-dose and high-dose daily antiviral therapy for short episodes of genital HSV-2 reactivation: three randomised, open-label, cross-over trials. Lancet. 2012;379(9816):641–7. [PMC free article: PMC3420069] [PubMed: 22225814] [CrossRef]
    4.
    Mertz GJ, Loveless MO, Levin MJ, Kraus SJ, Fowler SL, Goade D, et al. Collaborative Famciclovir Genital Herpes Research Group. Oral famciclovir for suppression of recurrent genital herpes simplex virus infection in women. A multicenter, double-blind, placebo-controlled trial. Arch Intern Med. 1997;157(3):343–9. [PubMed: 9040303]
    5.
    Sacks SL. Famciclovir suppression of asymptomatic and symptomatic recurrent anogenital herpes simplex virus shedding in women: a randomized, double-blind, double-dummy, placebo-controlled, parallel-group, single-center trial. J Infect Dis. 2004;189(8):1341–7. [PubMed: 15073669] [CrossRef]
    6.
    Reitano M, Tyring S, Lang W, Thoming C, Worm AM, Borelli S, et al. International Valaciclovir HSV Study Group. Valaciclovir for the suppression of recurrent genital herpes simplex virus infection: a large-scale dose range-finding study. J Infect Dis. 1998;178(3):603–10. [PubMed: 9728526]
    7.
    Wald A, Selke S, Warren T, Aoki FY, Sacks S, Diaz-Mitoma F, et al. Comparative efficacy of famciclovir and valacyclovir for suppression of recurrent genital herpes and viral shedding. Sex Transm Dis. 2006;33(9):529–33. [PubMed: 16540883] [CrossRef]
SUPPRESSIVE THERAPY FOR PEOPLE LIVING WITH HIV
Efficacy of different suppressive drugs versus no treatment for people living with HIV
Quality assessmentSummary of findings
No. of participants (studies)Risk of biasInconsistencyIndirectnessImprecisionPublication biasOverall quality of evidenceStudy event rates (%)Relative effect (95% CI)Anticipated absolute effects
With placeboWith SuppressiveRisk with placeboRisk difference with Suppressive therapy
Aciclovir 400 mg 2 × daily vs placebo: HIV/HSV-2 transmission and acquisition
8354 (3 RCTs)Not seriousNot seriousNot seriousSerious1None⊕⊕⊕○
MODERATE
92/4179 (2.2%)115/4175 (2.8%)RR 1.26 (0.96–1.64)Moderate
31 per 10008 more per 1000 (1 fewer to 20 more)
Aciclovir 400 mg 2 × daily vs placebo: HIV viral load
1579 (2 RCTs)Not seriousNot seriousNot seriousSerious1None⊕⊕⊕○
MODERATE
416/721 (57.7%)518/858 (60.4%)RR 1.04 (0.96–1.13)Moderate
533 per 100021 more per 1000 (21 fewer to 69 more)
Aciclovir 400 mg 2 × daily vs placebo: incidence of genital ulcers
6972 (3 RCTs)Not seriousNot seriousNot seriousNot seriousNone⊕⊕⊕⊕
HIGH
1227/3488 (35.2%)468/3484 (13.4%)RR 0.38 (0.35–0.42)Moderate
328 per 1000203 fewer per 1000 (213 fewer to 190 fewer)
Aciclovir 400 mg 2 × daily vs placebo: side-effects
4994 (2 RCTs)Not seriousNot seriousNot seriousVery serious1None⊕⊕○○
LOW
63/2502 (2.5%)75/2492 (3.0%)RR 1.20 (0.86–1.66)Moderate
20 per 10004 more per 1000 (3 fewer to 13 more)
Aciclovir 800 mg 2 × daily for 1 month vs placebo: percentage of times of HIV cervical shedding
128 (1 RCT)Not seriousNot seriousNot seriousVery serious1None⊕⊕○○
LOW
53/66 (80.3%)40/62 (64.5%)RR 0.80 (0.64–1.00)Moderate
803 per 1000161 fewer per 1000 (289 fewer to 0 fewer)
Aciclovir 800 mg 2 × daily for 1 month vs placebo: the mean plasma concentration of HIV-1
128+60 (2 RCTs)Not seriousNot seriousNot seriousVery serious1None⊕⊕○○
LOW
One study reported that HIV-1 log10 copies/mL, plasma in placebo: mean 4.26 (4.07–4.44) in aciclovir: mean 3.78 (3.50–4.05). Another study reported that: aciclovir versus control: plasma HIV-1 RNA detection OR 1.93; 95% CI: 0.66–5.68 (P = 0.23).
Valaciclovir 500 mg 2 × daily for 6 months vs placebo: no recurrent clinical episodes
293 (1 RCT)Not seriousNot seriousNot seriousVery serious1None⊕⊕○○
LOW
26/99 (26.3%)126/194 (64.9%)RR 2.47 (1.75–3.49)Moderate
263 per 1000386 more per 1000 (197 more to 654 more)
Valaciclovir 500 mg 2 × daily vs placebo for 6 months: side-effects
293 (1 RCT)Not seriousNot seriousNot seriousVery serious1None⊕⊕○○
LOW
57/99 (57.6%)145/194 (74.7%)RR 1.30 (1.08–1.57)Moderate
576 per 1000173 more per 1000 (46 more to 328 more)
Valaciclovir 500 mg 2 × daily vs placebo for 3 months: impact on plasma HIV-1 RNA/genital HIV-1 RNA detected
196 (2 RCTs)Not seriousNot seriousNot seriousVery serious1None⊕⊕○○
LOW
68/98 (69.4%)55/98 (56.1%)RR 0.74 (0.39–1.37)694 per 1000180 fewer per 1000 (423 fewer to 257 more)
Famciclovir 500 mg 2 × daily vs placebo: no lesion present
48 (1 RCT)Not seriousNot seriousNot seriousVery serious1None⊕⊕○○
LOW
5/24 (20.8%)0/24 (0.0%)RR 0.09 (0.01 to 1.56)Moderate
208 per 1000190 fewer per 1000 (206 fewer to 117 more)

CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio

1

Imprecise results due to wide CI and/or few events/sample size

Efficacy of different suppressive drugs for HIV patients
Quality assessmentSummary of findings
No. of participants (studies) Follow-upRisk of biasInconsistencyIndirectnessImprecisionPublication biasOverall quality of evidenceStudy event rates (%)Relative effect (95% CI)Anticipated absolute effects
With aciclovirWith valaciclovirRisk with aciclovirRisk difference with valaciclovir
Valaciclovir 500 mg 2 × daily vs aciclovir 400 mg 2 × daily: number of people healed (ulcer healing)
704 (1 RCT)Not seriousNot seriousNot seriousSerious1None⊕⊕⊕○
MODERATE
272/349 (77.9%)291/355 (82.0%)RR 1.05 (0.98–1.13)779 per 100039 more per 1000 (16 fewer to 101 more)
Valaciclovir 1000 mg 1 × daily vs aciclovir 400 mg 2 × daily: number of people healed (ulcer healing)
707 (1 RCT)Not seriousNot seriousNot seriousSerious1None⊕⊕⊕○
MODERATE
272/349 (77.9%)254/358 (70.9%)RR 0.91 (0.83–0.99)779 per 100070 fewer per 1000 (132 fewer to 8 fewer)
Valaciclovir 500 mg 2 × daily vs aciclovir 400 mg 2 × daily: side-effects
704 (1 RCT)Not seriousNot seriousNot seriousSerious1None⊕⊕⊕○
MODERATE
267/349 (76.5%)268/355 (75.5%)RR 0.99 (0.91–1.07)765 per 10008 fewer per 1000 (69 fewer to 54 more)
Valaciclovir 1000 mg once daily vs aciclovir 400 mg twice daily: side-effects
707 (1 RCT)Not seriousNot seriousNot seriousSerious1None⊕⊕⊕○
MODERATE
267/349 (76.5%)284/358 (79.3%)RR 1.04 (0.96–1.12)765 per 100031 more per 1000 (31 fewer to 92 more)

CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio

1

Imprecise results due to wide CIs and/or few events/sample size

REFERENCES
1.
Celum C, Wald A, Hughes J, Sanchez J, Reid S, Delany-Moretlwe S, et al. Effect of aciclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive women and men who have sex with men: a randomised, double-blind, placebo-controlled trial. Lancet. 2008;371(9630):2109–19. [PMC free article: PMC2650104] [PubMed: 18572080] [CrossRef]
2.
Celum C, Wald A, Lingappa JR, Magaret AS, Wang RS, Mugo N, et al. Partners in Prevention HSV/HIV Transmission Study Team. Aciclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2. N Engl J Med. 2010;362(5):427–39. [PMC free article: PMC2838503] [PubMed: 20089951] [CrossRef]
3.
Cowan FM, Pascoe SJ, Barlow KL, Langhaug LF, Jaffar S, Hargrove JW, et al. A randomised placebo-controlled trial to explore the effect of suppressive therapy with aciclovir on genital shedding of HIV-1 and herpes simplex virus type 2 among Zimbabwean sex workers. Sex Transm Infect. 2008;84(7):548–53. [PubMed: 18684855] [CrossRef]
4.
DeJesus E, Wald A, Warren T, Schacker TW, Trottier S, Shahmanesh M, et al. Valaciclovir for the suppression of recurrent genital herpes in human immunodeficiency virus-infected subjects. J Infect Dis. 2003;188(7):1009–16. [PubMed: 14513421] [CrossRef]
5.
Dunne EF, Whitehead S, Sternberg M, Thepamnuay S, Leelawiwat W, McNicholl JM, et al. Suppressive aciclovir therapy reduces HIV cervicovaginal shedding in HIV- and HSV-2-infected women, Chiang rai, Thailand. J Acquir Immune Defic Syndr. 2008;49(1):77–83. [PubMed: 18667923] [CrossRef]
6.
Mujugira A, Magaret AS, Celum C, Baeten JM, Lingappa JR, Morrow RA, et al. Daily aciclovir to decrease herpes simplex virus type 2 (HSV-2) transmission from HSV-2/HIV-1 coinfected persons: a randomized controlled trial. J Infect Dis. 2013;208(9):1366–74. [PMC free article: PMC3789565] [PubMed: 23901094] [CrossRef]
7.
Nagot N, Ouédraogo A, Foulongne V, Konaté I, Weiss HA, Vergne L, Defer MC, et al. Reduction of HIV-1 RNA levels with therapy to suppress herpes simplex virus. N Engl J Med. 2007;356(8):790–9. [PubMed: 17314338]
8.
Nijhawan AE, Delong AK, Chapman S, Rana A, Kurpewski J, Ingersoll J, et al. Effect of HSV-2 suppressive therapy on genital tract HIV-1 RNA shedding among women on HAART: a pilot randomized controlled trial. Infect Dis Obstet Gynecol. 2012;868526 [PMC free article: PMC3299258] [PubMed: 22505800] [CrossRef]
9.
Ouedraogo A, Nagot N, Vergne L, Konate I, Weiss HA, Defer MC, et al. Impact of suppressive herpes therapy on genital HIV-1 RNA among women taking antiretroviral therapy: a randomized controlled trial. AIDS. 2006;20(18):2305–13. [PubMed: 17117016] [CrossRef]
10.
Reynolds SJ, Makumbi F, Newell K, Kiwanuka N, Ssebbowa P, Mondo G, et al. Effect of daily aciclovir on HIV disease progression in individuals in Rakai, Uganda, co-infected with HIV-1 and herpes simplex virus type 2: a randomised, double-blind placebocontrolled trial. Lancet Infect Dis. 2012;12(6):441–8. [PMC free article: PMC3420068] [PubMed: 22433279] [CrossRef]
11.
Schacker T, Hu HL, Koelle DM, Zeh J, Saltzman R, Boon R, et al. Famciclovir for the suppression of symptomatic and asymptomatic herpes simplex virus reactivation in HIV-infected persons: a double-blind, placebo-controlled trial. Ann Intern Med. 1998;128(1):21–8. [PubMed: 9424977]
12.
Tanton C, Weiss HA, Rusizoka M, Legoff J, Changalucha J, Baisley K, et al. Long-term impact of aciclovir suppressive therapy on genital and plasma HIV RNA in Tanzanian women: a randomized controlled trial. J Infect Dis. 2010;201(9):1285–97. [PMC free article: PMC2948536] [PubMed: 20235836] [CrossRef]
13.
Warren T, Harris J, Brennan CA. Efficacy and safety of valaciclovir for the suppression and episodic treatment of herpes simplex virus in patients with HIV. Clin Infect Dis. 2004;39(Suppl 5):S258–S66. [PubMed: 15494897]
a. Conant MA, Schacker TW, Murphy RL, Gold J, Crutchfield LT, Crooks RJ. Valaciclovir versus aciclovir for herpes simplex virus infection in HIV-infected individuals: two randomized trial. Int J STD AIDS. 2002;13(1):12–21. [PubMed: 11802924]
Patient values and preferences, acceptability and cost: specific to herpes simplex virus infections
1.
Scalone L, Ryan M, Kotsopoulos N, Patel R. Evaluation of patients’ preferences for genital herpes treatment. Sex Transm Dis. 2011;38(9):802–7. [PubMed: 21844733] [CrossRef]
2.
International drug price indicator guide, 2014 edition (updated annually). Medford (MA): Management Sciences for Health; 2015. [accessed 6 June 2016]. http://erc​.msh.org/dmpguide​/pdf/DrugPriceGuide_2014.pdf.
Patient values and preferences, acceptability and cost: other sexually transmitted infections and conditions
1.
Nagarkar A, Mhaskar P. A systematic review on the prevalence and utilization of health care services for reproductive tract infections/sexually transmitted infections: evidence from India. Indian J Sex Transm Dis. 2015;36(1):18–25. [PMC free article: PMC4555893] [PubMed: 26392649] [CrossRef]
2.
Ryan R, Santesso N, Lowe D, Hill S, Grimshaw J, Prictor M, et al. Interventions to improve safe and effective medicines use by consumers: an overview of systematic reviews. Cochrane Database Syst Rev. 2014;(4):CD007768. [PMC free article: PMC6491214] [PubMed: 24777444]
Additional references
1.
Benedetti JK, Corey L, Ashley R. Recurrence rates in genital herpes after symptomatic first episode infection. Ann Intern Med. 1994;121:847–54. [PubMed: 7978697]
2.
Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386(9995):743–800. [PMC free article: PMC4561509] [PubMed: 26063472] [CrossRef]
3.
Newman L, Rowley J, Vander Hoorn S, Wijesooriya NS, Unemo M, Low N, et al. Global estimates of the prevalence and incidence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting. PLoS One. 2015;10(12):e0143304. [PMC free article: PMC4672879] [PubMed: 26646541] [CrossRef]
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