The PubMed database was searched under the following headings: HIV or AIDS and herpes simplex virus or HSV or genital herpes or HSV encephalitis or HSV CNS disease.
6.3.2 Background and epidemiology
Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are double-stranded DNA viruses of the Herpesviridae family. HSV infection most commonly causes genital or orolabial ulcerative disease. Genital HSV is the leading cause of genital ulcerative disease worldwide. Infection occurs from contact with infectious secretions on oral, genital or anal mucosa or abraded skin.
Following primary infection, HSV establishes viral latency in the cells of local sensory ganglia. Reactivation results in symptomatic clinical disease or asymptomatic viral shedding.
Some studies suggest the natural history of HSV in HIV-seropositive individuals is altered with reports of more severe clinical episodes of primary infection, and increased risk of symptomatic or more severe reactivation, in most studies, particularly in those involving individuals with more advanced HIV disease [35–38]. In addition individuals with lower CD4 counts or higher HIV viral loads are more likely to have recurrence of disease and to have HSV isolated from lesions or to shed virus asymptomatically [39,40]. There is, however, limited data and the exact consequences still require clarification.
The prevalence of HSV-1 and HSV-2 infections varies across different populations and is associated with several factors including age, gender, ethnicity and sexual behaviour. HSV-1 infection is largely acquired during childhood with prevalence rates rising to approximately 70% or higher in adults. HSV-2 is primarily sexually transmitted and prevalence steadily increases in adults with start of sexual activity in adolescence. HSV-2 infection is more common in HIV-seropositive than HIV-seronegative persons with prevalence rates of 60–90%, the highest rates being reported in sub-Saharan Africa [41,42]. The prevalence of HSV-2 infection in HIV-seropositive individuals in the UK has been reported as 63% and was associated with female gender, older age and black ethnicity .
There is an interaction between HSV and HIV infections, with evidence that genital HSV-2 infection increases acquisition risk of HIV and that co-infected individuals are more likely to transmit infection . Genital herpes caused by HSV-2 infection has been shown to double the risk of becoming infected with HIV through sexual transmission . HSV-2 has also been shown to increase the transmission of HIV, possibly due to high titres of HIV in genital secretions during HSV-2 reactivation .
Orolabial herpes infection is most commonly caused by HSV type 1 and may involve the lips or the buccal and gingival mucosa. Intraoral ulceration usually indicates primary infection and is often associated with fever. Recurrent infection is usually limited to the lips. Typically, sensory prodromal symptoms of burning or tingling are rapidly followed by the development of vesicles that ulcerate and then crust over. Untreated lesions usually resolve within 7–10 days. Despite the observations above there is limited data on the impact of HIV infection on the clinical features of HSV-1 infection.
Primary genital herpes is defined as the first infection with either HSV-1 or HSV-2 in an individual with no pre-existing antibodies to either HSV type. Non-primary first episode genital herpes is defined as the first infection with either HSV-1 or HSV-2 in an individual with pre-existing antibodies to the other HSV type .
In individuals with reduced immune function, primary HSV may not resolve spontaneously but persist with the development of progressive, eruptive and coalescing mucocutaneous anogenital lesions [48–50]. In addition, healing of uncomplicated lesions may be delayed beyond 2–3 weeks, and is often associated with systemic symptoms such as fever and myalgia . In rare cases, severe systemic complications, such as hepatitis, pneumonia, aseptic meningitis and autonomic neuropathy with urinary retention may develop and may be life-threatening.
In recurrent genital herpes, groups of vesicles or ulcers develop in a single anatomical dermatomal site and usually heal within 5–10 days. In HIV-seronegative persons, recurrences average five clinical episodes per year for the first two years and reduce in frequency thereafter. The frequency and severity of recurrent disease is significantly greater in HIV-infected persons with low CD4 cell counts [39,40]. HAART reduces the number of days with HSV lesions although it does not appear to normalize the frequency of reactivation to rates seen in HIV-seronegative individuals [52,53].
Atypical presentations of genital herpes have been reported in HIV-seropositive persons, including chronic erosive and chronic hypertrophic lesions in association with more severe immune deficiency, aciclovir resistance and starting HAART [53,54].
Nonmucosal or systemic HSV infection is more common and may be more severe in immunocompromised patients, though the clinical presentation may be similar to immunocompetent individuals . HSV eye disease includes keratoconjunctivitis and acute retinal necrosis. Systemic HSV infection may result in pneumonia, hepatitis, oesophagitis and CNS disease. HSV infection of the CNS can cause aseptic meningitis, encephalitis, myelitis and radiculopathy. Preceding mucocutaneous disease is frequently absent. Aseptic meningitis is usually a consequence of primary HSV-2 infection and may be recurrent. HSV encephalitis has been reported in HIV-seropositive adults, but is uncommon. Clinical presentation includes fever, headache, decreased or fluctuating level of consciousness and seizures. Brainstem involvement may occur.
188.8.131.52 Detection of HSV in clinical lesions (see Table 6.1). Swabs should be taken from the base of the lesion or fluid from the vesicle. For culture tests it is essential that the cold chain (4 °C) is maintained and appropriate media are used. PCR testing is most useful as less scrupulous handling of specimens is required . PCR testing is rapid and sensitive resulting in increased identification of HSV-2 in lesions . In one study the sensitivity of culture for HSV-2 was 73% as compared to 98% with PCR and both tests had 100% specificity .
Table 6.1. Comparison of detection methods for HSV in clinical lesions [46,57,59].
|Comments||Demonstrates giant cells from lesions. Provides presumptive evidence of infection.||‘Gold standard’. Sensitivity declines as lesions heal.||Low cost and rapid.||Rapid but expensive. Useful in late clinical lesions. Test of choice in CSF examination. Used for research studies.|
Histopathology and PCR for HSV DNA may be helpful in the diagnosis of systemic disease. A positive PCR test must be interpreted in context with the clinical presentation and histology.
184.108.40.206 Serology. Commercial tests that use complement fixation are not type-specific. Seroconversion from a zero baseline is usually diagnostic of a primary infection. In the case of recurrent infection, an immune response from a non-zero baseline may be detected. However, these tests cannot distinguish between initial and recurrent infections and have been replaced by sensitive tests such as ELISAs and RIAs.
Type-specific serology tests (TSSTs) that detect HSV-specific glycoprotein G2, which is specific to HSV-2, and glycoprotein G1, which is specific to HSV-1 infection, are the only commercially available diagnostic tools to identify individuals with asymptomatic HSV infection, and can effectively distinguish HSV-1 and HSV-2 with high sensitivities (80–98%) and specificities (≥96%) . Case-controlled studies have shown that there are certain clinical situations where these tests may provide an aid to the diagnosis of HSV infection [59,60].
The clinical diagnosis of genital HSV infection has a low sensitivity and specificity; laboratory confirmation of infection and typing of HSV is essential as it influences the management, prognosis and counselling of patients.
220.127.116.11 CNS disease. In patients with HSV encephalitis or meningitis, typical CSF findings include a lymphocytosis and mildly elevated protein [61,62]. Low CSF glucose levels may also occur. Abnormal findings on magnetic resonance imaging and electroencephalogram are supportive of a diagnosis of HSV encephalitis but not diagnostic. For both HSV meningitis and encephalitis, PCR detection of HSV DNA in the CSF is the diagnostic method of choice and has a high specificity and sensitivity [62,63]. For HSV encephalitis, false-negative results for PCR may occur within the first 72 h of the illness and then 10–14 days after the onset of symptoms. Incidence of false-positive PCR is extremely low. Culture of the CSF for HSV is of little value in HSV encephalitis and not recommended.
- •PCR for HSV DNA in the CSF is the diagnostic method of choice for diagnosis of HSV encephalitis or meningitis (category III recommendation).
18.104.22.168 Orolabial herpes
- •First episode or severe recurrent orolabial herpes infection should be treated with antiviral therapy. Aciclovir 200–400 mg orally five times a day for 7–10 days is recommended (category II recommendation), Alternative treatments are valaciclovir or famciclovir. For severe oral mucocutaneous disease treatment should be initiated with aciclovir intravenously 5–10 mg/kg every 8 h (category III recommendation).
Most episodes of recurrent orolabial herpes are mild and self limiting. Episodic or suppressive antiviral therapy may be considered for those with severe or frequent recurrences. A study has shown equivalent efficacy of famciclovir 500 mg orally bd in comparison to aciclovir 400 mg orally five times a day in a mixed group of HIV-seropositive individuals with either orolabial (38%) or genital HSV . There is not comparable data for the use of valaciclovir in treatment but on the basis of its activity in other settings and its efficacy in preventing recurrence of HSV in HIV-seropositive individuals  many clinicians would consider it as an alternative to aciclovir or famciclovir (category IV recommendation). Valaciclovir and famciclovir may be more expensive than aciclovir. There is no role for topical antiviral agents.
22.214.171.124 Genital herpes. The following recommendations for treatment of genital herpes are based on the BASHH and CDC guidelines for treatment of STIs in HIV-infected individuals All patients must receive information and support about their diagnosis and the clinician should document this and any issues arising from it. All patients should be strongly advised to inform a sexual partner about their infection [47,66].
126.96.36.199.1 First episode genital herpes
As for HIV-seronegative persons, the following general measures should be employed: cleaning of affected areas with normal saline; analgesia (systemic or local, e.g. lignocaine gel); and treatment of secondary bacterial infection.
- •In view of the potential for more severe disease, prompt treatment with aciclovir 400 mg orally, five times daily for 7–10 days is recommended , (category II recommendation). Alternative regimens are valaciclovir 1 g orally twice daily for 5–10 days or famciclovir 250–750 mg orally three times daily for 10 days, but as above the recommendations for valaciclovir are extrapolated from other settings (category IV recommendation). In patients with severe cutaneous disease or systemic complications, aciclovir 5–10 mg/kg iv every 8 h should be considered (category III recommendation).
188.8.131.52.2 Recurrent genital herpes
Recurrent genital herpes in HIV-seropositive patients may be prolonged and more severe, however, most episodes are mild and self-limiting and can be managed with supportive and general measures only. The severity of recurrent episodes is reduced with immune reconstitution with HAART, although rates of genital HSV shedding are unchanged [52,67].
Suppressive antiviral therapy has been shown in meta-analyses of randomized controlled trials to significantly reduce (by 70–80%) the number of recurrences in patients with frequently recurring (more than six recurrences per year) genital herpes but the efficacy of this therapy in HIV-infected individuals appears to be less than that in HIV-negative individuals with one meta-analysis showing a 66% reduction in recurrences . Individual randomised controlled trials have also demonstrated the efficacy of famciclovir and valaciclovir as suppressive agents in HIV-seropositive individuals [66,69,70].
- •Recommended regimens for suppressive antiviral therapy include: aciclovir 400–800 mg orally two or three times a day (category Ia recommendation); valaciclovir 500 mg orally twice daily; or famciclovir 500 mg orally twice daily (category Ib recommendation)
Episodic antiviral therapy is also an option in patients who do not want to take regular suppressive therapy and who have a recognizable prodrome. The strategy has shown efficacy in HIV-seronegative individuals [71–73], though specific data from HIV-seropositive individuals is more limited. Antiviral therapy should be initiated during the prodrome or early in an attack and aciclovir 200–400 mg orally five times daily for 5 days is recommended . Alternative regimens are aciclovir 400 mg orally three times a day for 5 days; valaciclovir 500 mg orally twice daily for 3–5 days; valaciclovir 1 g orally, twice daily for 5 days; famciclovir 500 mg orally twice daily for 5 days. There is no evidence of clear superiority of the alternative regimens over standard doses of aciclovir.
In more immunocompromised HIV-seropositive persons, episodes may be prolonged and more severe, requiring a longer duration of antiviral treatment.
In HIV negative individuals, discontinuation of suppressive or episodic antiviral therapy after 12 months is recommended in order to assess the ongoing frequency of recurrences. In an HIV-seropositive individual with a low CD4 cell count, the interruption may be delayed. The timing of this treatment interruption should be agreed with the patient and they should be given a supply of antiviral therapy to enable prompt administration of episodic treatment if recurrences recur.
184.108.40.206 Non-mucosal (or systemic) herpes. There is limited data on the treatment of systemic HSV disease in HIV-seropositive individuals. Recommendations are based on evidence from studies in both immunocompetent and immunocompromised patient populations.
Systemic infection should be treated with intravenous aciclovir 5–10 mg/kg every 8 h for 10–21 days. HSV meningitis can be treated with 10 mg/kg every 8 h .
For HSV encephalitis, aciclovir 10 mg/kg every 8 h for 14–21 days is recommended  and quantitative PCR in the CSF may be helpful in monitoring response to treatment. Mortality and morbidity is high. Joint care with a neurologist is essential and there should be a low threshold for referral to a brain ITU.
Patients with HSV keratoconjunctivitis or acute retinal necrosis should be seen urgently by an ophthalmologist and managed jointly.
220.127.116.11 Antiviral-resistant HSV infection. In prospective studies, aciclovir-resistant HSV variants have been described in up to 7% of isolates from HIV-seropositive patients [76,77]. The threshold for resistance is a greater than 1–3 mg/mL aciclovir concentration for viral inhibition. This is most usually due to a mutation affecting the gene encoding viral thymidine kinase (TK), the enzyme that phosphorylates aciclovir in HSV-infected cells. TK-deficient strains are of reduced pathogenesis in immunocompetent individuals but cause significant clinical disease in immunosuppressed patients.
Although partial resistance can occur, most TK mutants are resistant to aciclovir, valaciclovir and ganciclovir and the majority to famciclovir. However, foscarnet and cidofovir therapy do not require TK-dependent phosphorylation but directly inhibit viral DNA polymerase.
- •Any immunocompromised HIV patient developing clinical HSV lesions despite adequate doses of aciclovir, valaciclovir or famciclovir must have a sample taken for viral culture and testing for antiviral sensitivity. If new lesions are forming after 5 days, despite increasing the doses of antiviral drugs then therapy should be reviewed and changed (category IV recommendation).
Topical 1% foscarnet cream or 1% cidofovir gel have been reported to increase lesion healing, reduce symptom score and virological effect [78–80]. In the UK 1% foscarnet cream is not commercially available; however, a 2% formulation is available from Idis Pharmaceuticals.
Systemic therapy with either iv foscarnet 40 mg/kg bd or tid iv has been shown to be effective for aciclovir resistant strains with the length of therapy depending on treatment response  and , (category Ib recommendation). In rare cases with aciclovir and foscarnet resistance cidofovir topically  or iv 5 mg/kg weekly infusion is the preferred agent  (category III recommendation).
6.3.6 Antiretroviral therapy
In patients with prolonged cutaneous ulceration or who have systemic disease, consideration should be given to initiating combination antiretroviral therapy or changing therapy in those experiencing virological failure [category IV recommendation].