For adults and adolescents with a recurrent clinical episode of genital HSV infection, the WHO STI guideline suggests treatment without treatment. Recurrent clinical episodes of genital HSV infection that are frequent, severe or cause distress (suppressive therapy).
OVERVIEW OF THE GUIDELINES FOR THE PREVENTION, TREATMENT AND MANAGEMENT OF STIs
It is recommended that national guidelines for the effective management of STIs be developed in close consultation with local STI, public health and laboratory experts. Report of the expert consultation and review of the latest evidence to update guidelines for the management of sexually transmitted infections.
Global estimates of the incidence and prevalence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting. Progress report on the implementation of the global strategy for the prevention and control of sexually transmitted infections: 2006–2015.
INTRODUCTION
- EPIDEMIOLOGY, BURDEN AND CLINICAL CONSIDERATIONS
- RATIONALE FOR NEW RECOMMENDATIONS The 2003 WHO STI guidelines for treatment of genital
- OBJECTIVES
- TARGET AUDIENCE
- STRUCTURE OF THE GUIDELINES These guidelines provide evidence-based
- GUIDELINE DEVELOPMENT GROUP (GDG) To update the WHO guidelines for the prevention,
- QUESTIONS AND OUTCOMES
- REVIEWS OF THE EVIDENCE
- MAKING RECOMMENDATIONS
- MANAGEMENT OF CONFLICTS OF INTEREST Management of conflicts of interest was a key priority
These guidelines are primarily intended for healthcare providers at all levels (primary, secondary and tertiary) of the healthcare system involved in the treatment and management of people with STIs in low, middle and high income countries. These guidelines were developed according to the methods outlined in the 2014 edition of the WHO Guideline Development Manual (10) (see Appendix B for a detailed description). High – We are confident that the actual effect is close to that of the estimate of the effect.
Moderate – We are moderately confident in the effect estimate; the true effect is probably close to the estimate of the effect, but there is a possibility that it differs substantially. Very low – We have very little confidence in the effect estimate; the true effect is likely to differ materially from the estimate of the effect. However, no votes were taken because the GDG reached consensus during discussion for all the recommendations.
DISSEMINATION, UPDATING AND
THE GUIDELINES
DISSEMINATION
UPDATING THE STI GUIDELINES AND USER FEEDBACK
IMPLEMENTATION OF THE WHO GUIDELINES FOR THE TREATMENT OF
IDENTIFYING AND PURCHASING STD MEDICINES It is important to identify not only the medications that are recommended as first-line treatment for STDs, but also the estimated quantities of the medications that will be needed. Quantifying medication needs is important to estimate costs, reconcile financial requirements with available budget, and place orders in advance so unit and freight costs can be minimised. In order to estimate the amount of drugs needed, it will be necessary to review the drugs recommended for treatment, their unit prices, the amount needed per treatment and the epidemiological information on the prevalence of infection.
At the national level it is important that decision makers, politicians and fiscal controllers understand the need to subsidize STI drugs. Low-cost STI drugs can be obtained through international generic sellers, non-profit organizations with procurement schemes such as UNICEF, UNFPA and UNHCR, and through joint drug procurement schemes. Placing STI drugs on national essential drug lists increases the likelihood of achieving a low-cost supply of these drugs.
RECOMMENDATIONS FOR TREATMENT OF
GENITAL HERPES SIMPLEX VIRUS
FIRST CLINICAL EPISODE OF GENITAL HSV INFECTION
The overall quality of evidence for comparisons between acyclovir, valacyclovir and famciclovir was moderate to low. However, in some settings follow-up visits during treatment may not be possible and symptoms of the first clinical episode may be prolonged, and neurological complications such as meningitis and urinary retention tend to occur towards the end of the episode. Although these complications are rare, the GDG agreed that treatment should be given for longer than 5 days given the safety of the drug, the potential benefits of the drug, and the lack of concern about resistance.
Viral shedding was measured in some studies, but the GDG agreed that this measure is not a useful surrogate for. The GDG agreed that there would be little variation in patient values and preferences regarding the different medicines and treatment regimens. In summary, there are probably moderate benefits of treatment over no treatment, and small differences between medicines in terms of benefits and adverse events.
RECURRENT CLINICAL EPISODE OF GENITAL HSV INFECTION (EPISODIC THERAPY)
The findings suggest that duration of symptoms, viral shedding and pain, and levels of compliance and risk of adverse events are likely to be similar between the two drugs. The findings suggest that the duration of lesions, symptoms and viral shedding, and the risk of adverse effects are likely to be similar between the two drugs and likely to be similar between 5- or 10-day treatment durations with 250 mg and 500 mg famciclovir. Valacyclovir at various doses likely shortens the duration of viral shedding by a median of 2 days and lesions and symptoms by 1–2 days compared with placebo.
Famciclovir in various doses is likely to reduce the duration of virus shedding, lesions and symptoms by an average of 1-2 days compared to placebo. Two studies compared aciclovir and valacyclovir and found that there is likely little to no difference between the two drugs in duration of virus shedding, lesions and symptoms, and risk of side effects (moderate quality evidence). The findings indicate that there may be little to no difference between the different doses in terms of duration of symptoms, lesions and viral shedding, and side effects.
RECURRENT CLINICAL EPISODES OF GENITAL HSV INFECTION THAT ARE
One study compared valaciclovir suppressive therapy with acyclovir and found that there may be little or no difference in outcomes. Another study compared famciclovir with valaciclovir and found that there may be little or no difference in recurrence and there may also be little or no difference in side effects and compliance, but there may be more days of genital HSV clearance with famciclovir (report of The CI GDG agreed that there is probably no variability in patient values and preferences regarding different drugs and treatment regimens.
However, the greater value is likely to be in avoiding genital transmission of HSV (but there was little data) and in reducing the number and frequency of pills taken. Although the cost to the individual may be high, there is a small population with frequent clinical episodes of genital HSV infection that requires suppressive therapy. The equity impact was unclear, as genital HSV infection occurs most in disadvantaged populations who may not have access to suppressive treatment.
RESEARCH IMPLICATIONS
Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. Gray RH, Wawer MJ, Brookmeyer R, Sewankambo NK, Serwadda D, Wabwire-Mangen F et al.; Rakai project team. Probability of HIV-1 Transmission by Coital Act in Monogamous, Heterosexual, HIV-1 Discordant Couples in Rakai, Uganda, Lancet.
Lingappa JR, Baeten JM, Wald A, Hughes JP, Thomas KK, Mujugira A et al.; Partners in Prevention Research Team HSV/HIV transmission. Daily acyclovir for HIV-1 disease progression in humans dually infected with HIV-1 and herpes simplex virus type 2: a randomized placebo-controlled trial. Introducing WHO reproductive health guidelines and resources into national programs: principles and processes of adaptation and implementation.
ANNEX A
STI GUIDELINE DEVELOPMENT TEAMS
David Geffen School of Medicine en Fielding School of Public Health University of California, Los Angeles. University of Washington Virology Research Clinic Harborview Medical Center 325 9th Ave, Box 359928 Seattle, WA 98104 VS. Department of Diseases Control Bureau van AIDS, TBC en soa's Ministerie van Volksgezondheid Nonthaburi.
National Institute of Allergy and Infectious Diseases (NIAID) United States Department of Health and Human Services National Institutes of Health. Professional Guidelines and Division of Public Health Practice, Center for Infectious Diseases and Infection Control, Public Health Agency of Canada. Division of AIDS Control (National AIDS Control Organization) Ministry of Health and Family Welfare of India.
ANNEX B
DETAILED METHODS FOR GUIDELINE DEVELOPMENT
The number of comparisons for each question also decreased; only "critical" interventions were compared with each other and with important interventions. Additional critical outcomes for pregnant women: maternal outcomes (caesarean section), fetal outcomes (neonatal herpes [including meningoencephalitis, fever, hepatitis], teratogenicity, fetal loss, toxicity, neonatal death). RECURRENT CLINICAL EPISODES OF GENITAL HSV INFECTIONS THAT ARE FREQUENT, SEVERE, OR CAUSING DISTRESS (SUPPRESSIVE THERAPY) (RECOMMENDATIONS 5 AND 6).
Important: HSV severity/pain, quality of life, adverse events, HIV viral load, adherence, ulcer healing, duration of clinical episode Additional critical outcomes for pregnant women: maternal outcomes (cesarean delivery), fetal outcomes (neonatal herpes, teratogenicity , fetal loss, toxicity, neonatal death). Important: Adverse Reactions, HIV Transmission and Acquisition, HIV Viral Load, Adherence Additional Critical Outcomes for Pregnant Women: Maternal Outcomes (Caesarean Section), Fetal Outcomes (Neonatal Herpes, Teratogenicity, Fetal Loss, Toxicity, Neonatal Mortality). SEVERE CLINICAL EPISODE OF GENITAL OR ANORECTAL HSV INFECTION (ALL POPULATIONS, INCLUDING PREGNANT WOMEN) (RECOMMENDATION 1).
REVIEW OF THE EVIDENCE
The hierarchical approach consisted of identifying already existing synthesized evidence, including from previously published guidelines that included systematic reviews of the literature. The strategies included using keywords from the database's controlled vocabulary and text words based on the PICO questions. Results were presented in tables (eg, median effects with interquartile ranges) or were narratively described by direction of effect or by statistical significance as reported in the primary study.
Based on the list of possible treatments identified by the GDG, an estimate of the costs associated with each alternative was calculated. A final price for a full course of treatment for each drug after dosing was calculated as the number of doses per day multiplied by the number of treatment days plus 25%. The unit price of the drug was obtained from the median prices in the 2014 MSH International Drug Price Indicator Guide and information available on the Internet.
APPLYING THE GRADE APPROACH TO MAKING THE RECOMMENDATIONS
To determine an accurate and reliable estimate, the unit price (all expressed in US dollars) was provided only when the available information matched the dose of interest (grams per . pill or 1000 units per vial). No calculations were made based on assumptions regarding the unit cost of hypothetical packaging that is not listed in the directory. In addition, when examining studies of treatment effects, two investigators also identified studies of potential cost relevance.
ANNEX C
LISTS OF REFERENCES FOR REVIEWED EVIDENCE
Patient-initiated once-daily famciclovir therapy for recurrent genital herpes: a randomized, double-blind, placebo-controlled trial. Two-day regimen of acyclovir for the treatment of recurrent genital herpes simplex virus type 2 infection. Double-blind comparison of weekend and daily regimens of oral acyclovir for the suppression of recurrent genital herpes.
Clinic-initiated twice-daily oral famciclovir for treatment of recurrent genital herpes: a randomized, double-blind, controlled trial. Valaciclovir for suppression of recurrent genital herpes simplex virus infection: a large-scale dose-range-finding study. A double-blind study of oral acyclovir for suppression of recurrences of genital herpes simplex virus infection.
