1.1. EPIDEMIOLOGY, BURDEN AND CLINICAL CONSIDERATIONS
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. The prevalence of HSV-2 is highest in the WHO African Region (31.5%), followed by the Region of the Americas (14.4%). Despite lower prevalence, the WHO South-East Asia and Western Pacific Regions also harbour a large number of people with the infection due to the large populations of some countries in the region. The HSV-2 infection rate is consistently higher in females compared to males; there were an estimated 11.8 million new infections and 267 million prevalent infections among women in 2012 versus 7.4 million new and 150 million prevalent infections among men. The higher infection rate among women is most likely due to their greater biological susceptibility to HSV-2 infection (1).
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 infection, especially in high-income countries. Globally, an estimated 140 million people had genital HSV-1 infection in 2012.
HSV-2 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 (2), and people with both HIV and HSV-2 are more likely to transmit HIV to others (3). In addition, infection with HSV-2 in people living with HIV is often more severe and can lead to serious, although rare, complications, such as brain, eye or lung infections (4).
CLINICAL PRESENTATION
HSV-2 infection is the most common cause of recurrent genital ulcer disease (GUD) worldwide. 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. Patients present with genital pain and itching and 80% of women also report dysuria. Constitutional symptoms, such as fever, headache, myalgias and malaise are common. Cervicitis and tender inguinal and femoral lymphadenopathy frequently accompany initial infections. Over a period of 2–3 weeks, new lesions appear and existing lesions progress to vesicles and pustules and then coalesce into ulcers before crusting over and healing. Lesions on mucosal surfaces may be ulcerative without initially presenting as vesicles (5). Atypical presentations of infections due to HSV-2 may include small erosions and fissures, as well as dysuria or urethritis without lesions.
Although HSV-1 and HSV-2 are usually transmitted by different routes and affect different areas of the body, the signs and symptoms overlap (6). 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.
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. After initial infection, chronic 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. Recurrences are often preceded by prodromal symptoms (including tingling, paresthesias and pain), are characterized by fewer lesions than the first episode, and are usually present unilaterally and without systemic symptoms. Pain is less severe during recurrences, and the lesions heal in 5–10 days without antiviral treatment. Immunocompromised patients, including those with HIV, generally have more frequent recurrences with more severe symptoms. Recurrent ulcers can cause significant physical and psychological morbidity (5).
LABORATORY DIAGNOSIS
Genital HSV infection is often diagnosed clinically. However, laboratory testing is required to differentiate between HSV-1 and HSV-2. When vesicles are not present, laboratory confirmation may be needed to rule out other causes of genital ulcers. Laboratory methods for the diagnosis of HSV-2 include direct detection from lesions and indirect serological methods. Available tests for HSV-2 include antigen detection, isolation of virus by culture and nucleic acid amplification tests (NAATs) for viral DNA. Serological assays are also available to screen for HSV-2 infection by detection of type-specific antibodies, which develop in the first several weeks after initial infection and persist indefinitely. Although viral culture has previously been considered the gold standard for HSV-2 diagnosis, NAATs are increasingly preferred due to higher sensitivity, ease of specimen collection and transportation, and faster results (7).
1.2. RATIONALE FOR NEW RECOMMENDATIONS
The 2003 WHO STI guidelines for treatment of genital HSV infection (8) need to be updated to respond to the changing epidemiology of HSV-2, taking into account the synergy between HSV-2 and HIV transmission. HSV-2 has become, in many countries, the most common causative agent of GUD. Global guidance on the optimal dose and duration of aciclovir treatment for symptomatic initial and recurrent episodes is essential. As recommended during a WHO STI expert consultation in Montreux, Switzerland, in April 2008, a longer duration of treatment with aciclovir should be explored. Since the presentation of genital HSV infection is more severe in people who are immunocompromised, recommendations for treatment of HSV-2 infections in people living with HIV should also be updated. Suppressive therapy has been shown to reduce HIV viral shedding and HSV-2 viral shedding and recurrences, and recommendations that take into account the most recent body of evidence for when to provide suppressive therapy are needed, especially in areas of high HIV prevalence (9).
1.3. OBJECTIVES
The objectives of these guidelines are:
1.4. TARGET AUDIENCE
These guidelines are primarily intended for health-care providers at all levels (primary, secondary and tertiary) of the health-care system involved in the treatment and management of people with STIs in low-, middle- and high-income countries. They are also intended for individuals working in sexual and reproductive health programmes, such as HIV/AIDS, family planning, maternal and child health and adolescent health, to ensure appropriate STI diagnosis and management.
The guidelines are also useful for policy-makers, managers, programme officers and other professionals in the health sector who are responsible for implementing STI management interventions at regional, national and subnational levels.
1.5. STRUCTURE OF THE GUIDELINES
These guidelines provide evidence-based recommendations for the treatment of specific clinical conditions caused by genital HSV infection. These guidelines provide direction for countries as they develop national treatment recommendations; however, national guidelines should also take into account the local pattern of antimicrobial resistance (AMR), as well as health service capacity and resources.
Updated treatment recommendations based on the most recent evidence are included for the most important common conditions caused by HSV. 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 recommendations were issued (8). Treatment recommendations for neonatal HSV infection, and for treatment of pregnant women to prevent neonatal HSV infection, will be made in a separate module.
Treatment recommendations for the following conditions caused by HSV are included in these guidelines:
first clinical episode of genital HSV infection;
recurrent clinical episode of genital HSV infection (episodic therapy);
recurrent clinical episodes of genital HSV infection that are frequent, severe or cause distress (suppressive therapy).
