Sexually transmitted infections (STIs) are a major public health problem worldwide, affecting quality of life and causing serious morbidity and mortality. STIs have a direct impact on reproductive and child health through infertility, cancers and pregnancy complications, and they have an indirect impact through their role in facilitating sexual transmission of human immunodeficiency virus (HIV) and thus they also have an impact on national and individual economies. More than a million STIs are acquired every day.
Herpes simplex virus type 2 (HSV-2) is the most common cause of genital ulcers in many countries. An estimated 19.2 million new HSV-2 infections occurred among adults and adolescents aged 15–49 years worldwide in 2012, with the highest rates among younger age groups. HSV-2 is a lifelong infection; the estimated global HSV-2 prevalence of 11.3% translates into an estimated 417 million people with the infection in 2012.
HSV type 1 (HSV-1) typically causes non-sexually-transmitted oral herpes infection. However, HSV-1 can also be transmitted to the genitals through oral sex and is increasingly noted as a cause of genital HSV, especially in high-income countries. Globally, an estimated 140 million people had genital HSV-1 infection in 2012.
HSV-2 infection is of particular concern due to its epidemiological synergy with HIV infection and transmission. People who are infected with HSV-2 are approximately three times more likely to become infected with HIV, and people with both HIV and genital HSV are more likely to transmit HIV to others.
Symptomatic genital HSV is a lifelong condition that can be characterized by frequent symptomatic recurrences. Most initial infections are asymptomatic or atypical, therefore the majority of people with HSV-2 infection have not been diagnosed. The classical clinical presentation of the first episode of symptoms of primary genital HSV infection is characterized by bilateral clusters of erythematous papules, vesicles or ulcerations on the external genitalia, in the perianal region or on the buttocks, occurring 4–7 days after sexual exposure. This classical syndrome occurs only in 10–25% of primary infections. Although HSV-1 and HSV-2 are usually transmitted by different routes and affect different areas of the body, the signs and symptoms overlap. The first episode of symptoms of genital HSV-1 infection cannot be clinically differentiated from genital HSV-2 infection; it is only through laboratory tests that these infections can be differentiated. When vesicles are not present, laboratory confirmation may be needed to rule out other causes of genital ulcers.
Most people will experience one or more symptomatic recurrences within one year after the first symptomatic episode of HSV-2 infection. With genital HSV-1 infection, symptomatic episodes are much less likely to recur. Symptomatic recurrences are generally less severe than the first episode. Established HSV-2 infection typically leads to intermittent viral shedding from the genital mucosa, even in the absence of symptoms. As a result, HSV-2 is often transmitted by people who are unaware of their infection or who are asymptomatic at the time of sexual contact.
RATIONALE FOR THE GUIDELINES
Since the publication of the World Health Organization (WHO) Guidelines for the management of sexually transmitted infections in 2003, changes in the epidemiology of STIs and advancements in prevention, diagnosis and treatment necessitate changes in STI management. These guidelines provide updated treatment recommendations for genital HSV infection based on the most recent evidence; they form one of several modules of guidelines for specific STIs. Other modules will focus on treatments for Neisseria gonorrhoeae (gonorrhoea), C. trachomatis (chlamydial infection) and Treponema pallidum (syphilis). In addition, future work will provide guidance for syphilis screening and treatment of pregnant women, STI syndromic approach, clinical management, STI prevention, and treatments of other STIs. It is strongly recommended that countries take updated global guidance into account as they establish standardized national protocols, adapting this guidance to the local epidemiological situation and antimicrobial susceptibility data.
OBJECTIVES
The objectives of these guidelines are:
METHODS
These guidelines were developed following the methods outlined in the 2014 WHO handbook for guideline development. The Guideline Development Group (GDG) included international STI experts, clinicians, researchers and programme managers. The GDG prioritized questions and outcomes related to treatment of genital HSV infections to include in this update, and a methodologist and a team of systematic reviewers from McMaster University, the WHO Collaborating Centre for Evidence-Informed Policy, independently conducted systematic reviews of the effectiveness of different treatments for genital HSV infections. The evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach and presented to the GDG. Conflicts of interest were managed according to WHO guidelines and declared before the recommendations were discussed and finalized. Research implications were also developed by the GDG.
RECOMMENDATIONS
The current guidelines provide six treatment recommendations for genital HSV infections. Recommendations were not updated for rare conditions including HSV meningo-encephalitis and other conditions for which no new information became available since the 2003 WHO STI guidelines. Treatment recommendation for neonatal HSV and treatment of pregnant women to prevent neonatal HSV infection will be made in a separate module.
The recommendations summarized in apply to all adults, adolescents (10–19 years of age), pregnant women, people living with HIV, people who are immunocompromised and key populations, including sex workers, men who have sex with men (MSM) and transgender persons.
Tables
Table 1Summary of recommendations for treatment of chlamydial infections
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| Recommendations | Strength of recommendation and quality of evidence |
|---|
| First clinical episode of genital HSV infection | |
|---|
For adults and adolescents with a first clinical episode of genital HSV infection, the WHO STI guideline recommends treatment over no treatment.
Remarks: This recommendation also applies to people living with HIV, people who are immunocompromised, people with a severe episode and pregnant women. | Strong recommendation, moderate quality evidence |
For adults and adolescents with a first clinical episode of genital HSV infection, the WHO STI guideline suggests a standard dose of aciclovir over valaciclovir or famciclovir.
Dosages:
aciclovir 400 mg orally thrice daily for 10 days (standard dose) aciclovir 200 mg orally five times daily for 10 days valaciclovir 500 mg orally twice daily for 10 days famciclovir 250 mg orally thrice daily for 10 days
Remarks: Given that follow-up visits may not be possible during the course of treatment and symptoms of the first clinical episode may be prolonged, therapy is provided for 10 days. Although the benefits of the medicines are probably similar, the costs of valaciclovir and famciclovir are higher than aciclovir, and therefore aciclovir is preferred. The choice of medicine may also depend on compliance considerations. This recommendation also applies to people living with HIV, people who are immunocompromised, people with a severe episode and pregnant women. | Conditional recommendation, moderate quality evidence |
| Recurrent clinical episode of genital HSV infection (episodic therapy) | |
|---|
For adults and adolescents with a recurrent clinical episode of genital HSV infection, the WHO STI guideline suggests treatment over no treatment.
Remarks: Treatment should be given within the first 24 hours of the onset of symptoms or during the prodromal phase. That recommendation also applies to people living with HIV, people who are immunocompromised and pregnant women. | Conditional recommendation, moderate quality evidence |
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.
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 orally 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. | Conditional recommendation, moderate quality evidence |
| Recurrent clinical episodes of genital HSV infection that are frequent, severe or cause distress (suppressive therapy) | |
|---|
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.
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. | Conditional recommendation, moderate quality evidence |
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.
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. | Conditional recommendation, low quality evidence |