Epidemiology
Anogenital herpes is caused by herpes simplex virus (HSV) type 1 (HSV1) or type 2 (HSV2). Infections caused by this virus are common across the world but there are variations in prevalence between countries and population groups.
HSV disease is not a notifiable disease in Australia so there are limited data regarding disease prevalence. A nationwide population seroprevalence survey of HSV infection from 1999-2000 found an overall HSV2 seroprevalence of 12% (115). HSV2 seroprevalence was two-fold higher in females compared with males (16% vs 8%, respectively), 18% amongst indigenous Australians, and higher in metropolitan compared with remote areas (13% vs 9%) (115). The overall seroprevalence of HSV1 infection was 76% (115).
Historically, HSV1 was the most common cause of orolabial herpes and HSV2 the most common cause of anogenital herpes. However, recent data from a large sexual health clinic in Melbourne suggests that HSV1 is now the most common cause of anogenital herpes among women, people younger than 28 years and MSM (116).
HSV2 infection may increase the risk of HIV acquisition (117). HSV co-infection can increase transmission of HIV via activation of HIV replication with increased plasma and genital tract HIV RNA levels (118). Conversely, suppression of HSV2 infection with valaciclovir has been found to reduce asymptomatic shedding of HIV in the female genital tract (119). However, suppression with acyclovir does not appear to reduce the risk of HIV transmission (120), thus should not be considered as an alternative to rapid initiation of ART in people diagnosed with HIV infection. Likewise, suppression of HSV infection with oral acyclovir does not reduce the risk of HIV acquisition, so suppressive therapy to reduce the risk of acquiring HIV among HSV2 seropositive individuals is not indicated (121).
Clinical manifestations
Genital HSV disease typically presents in the anogenital area with blistering, ulceration and lymphangitis (especially in primary episodes). It is a common cause of proctitis in MSM, although only one-third of men will have externally visible ulcers (16). Herpes proctitis is more common among HIV-positive, compared with HIV-negative, MSM (16).
Prolonged symptoms with atypical appearing ulcers may be more common in people with HIV infection (122). Chronic erosive ulcers and progressive hypertrophic genital herpes have been reported as part of an immune reconstitution inflammatory syndrome (IRIS) following ART initiation and have required treatment with less commonly used therapies including topical cidofovir, foscarnet, thalidomide and imiquimod (122, 123, 124).
Serious non-genital presentations of HSV infection, such as keratitis, retinitis, encephalitis, hepatitis, and pneumonitis are more commonly reported in people with HIV infection. Although the clinical presentations are similar among HIV-negative individuals, they may be more severe and/or life threatening in people with HIV infection (125).
The diagnosis of HSV infection is usually made by NAAT on a sample taken from a lesion, or rectal mucosa in the case of proctitis. HSV type-specific serology is not generally recommended for diagnosis, irrespective of HIV status. Type-specific serology may be useful in certain situations such as recurrent genital disease of unknown aetiology or to inform management decisions if a woman who has a first-recognised episode of HSV disease in pregnancy (126).
Management
Among individuals with HSV infection, HIV co-infection increases the frequency of symptomatic reactivations and episodes of asymptomatic shedding, especially if the HIV-positive individual with moderate-to-severe immunodeficiency (127, 128). Treatment with suppressive antivirals reduces the frequency of symptomatic recurrences among people with HIV infection experiencing frequent (> 6/year) outbreaks (129). Long term ART use reduces the frequency of genital ulcer disease (130), although patients may experience an increase in symptoms at the time of ART initiation (126). Effective ART does not appear to reduce the frequency of asymptomatic shedding of HSV (131).
Treatment of genital herpes in people with HIV infection is with standard antiviral therapy. Occasionally, higher doses and prolonged duration of therapy may be required. Recommended regimens should be tailored to the severity of disease and degree of immunodeficiency (126,132):
Orolabial HSV disease (duration: 5–10 days)
- Valaciclovir 500mg - 1 g PO BID
- Famciclovir 250 - 500 mg PO BID
- Acyclovir 400 mg PO TID
Initial or recurrent genital lesions (duration: 5–10 Days)
- Valaciclovir 500mg - 1 g PO BID
- Famciclovir 250mg - 500 mg PO BID (not licensed for use in first-episode of genital HSV disease in Australia)
- Acyclovir 400 mg PO, 3- 5 times daily
Severe mucocutaneous HSV disease
- Initial: acyclovir 5-10 mg/kg IV q8h
- Once lesions begin to heal, change to oral therapy as above.
Chronic suppressive therapy is indicated in people with HIV infection who have frequent or severe recurrences but may be less effective than in people who are HIV-negative (129). Annual evaluation of ongoing need for suppressive therapy should occur. Recommended regimens include (126, 132):
- Valaciclovir 500 mg PO BID
- Famciclovir 500 mg PO BID
- Acyclovir 400 mg PO BID
Drug resistant HSV has been reported among 5-7% of genital HSV lesions in HIV-positive individuals (126). These drug-resistant isolates may be of reduced pathogenicity but can cause serious disease in immunodeficient individuals. Partially resistant strains of HSV may respond to higher doses of acyclovir but fully resistant strains will require alternative antiviral therapy with a different mode of action, such as foscarnet or cidofovir. Recommended regimens include (132):
For acyclovir-resistant mucocutaneous HSV infections:
Preferred therapy:
- Foscarnet 80–120 mg/kg/day IV in 2–3 divided doses until clinical response
Alternative Therapy (Duration: 21–28 days or longer, based on clinical response):
- Topical trifluridine, or
- Topical cidofovir 1% gel, or
- Topical imiquimod 5% cream three times/week, or
- IV cidofovir 5 mg/kg IV once weekly