Category Archives: Herpes Simplex

Herpes simplex

– Christian Hoffmann –

Infections with herpes simplex viruses are a frequent problem for HIV-infected patients (Chang 1995). Chronic disease is frequent, particularly with severe immunodeficiency (below 100 CD4 T cells/µl). Two viruses should be distinguished.

HSV-1 is transmitted by direct contact with mucosal membranes such as kissing, and causes the typical, itchy perioral blisters on the lips, tongue, gums, or buccal mucosa.

HSV-2 is sexually transmitted and leads to lesions on the penis, vagina, vulva and anus. HSV-2–associated lesions significantly increase the risk of transmission of HIV (Freeman 2006, Ouedraogo 2006, see prevention).

In severe cases, other organs may be affected. These include mainly the esophagus (ulcers), CNS (encephalitis), eyes (keratitis, keratoconjunctivitis, uveitis) and respiratory tract (pneumonitis, bronchitis). In such cases and with persistence of lesions for a period of more than four weeks, herpes simplex infection is an AIDS-defining illness.

Signs and symptoms

The typical blisters itch and burn. Oral involvement may impair food intake. In cases of genital or anal herpes (proctitis), urination and defecation can be very painful. Extensive lesions may occur with severe immunosuppression. Regional lymph nodes are often enlarged. The clinical symptoms of disseminated disease depend on the organs affected.

Diagnosis

Diagnosis of oral, genital or perianal herpes can often be made clinically. If there is doubt, then swabs should be taken, placed in viral culture media, and quickly transported to the laboratory. The diagnosis of organ manifestations usually requires histology. Diagnosis is particularly difficult for HSV encephalitis, as cerebrospinal fluid often does not help. Serologies are only useful if they are negative, therefore making HSV infection improbable.

Treatment

In general, every treatment, whether topical, oral or systemic, is more effective when started early. For patients with a good immune status and only discrete lesions, topical treatment with acyclovir cream or ointment is adequate. Penciclovir cream is probably as effective as acyclovir (Chen 2000) and allegedly less irritant, although significantly more expensive.

The nucleoside analog acyclovir remains the treatment of choice for systemic treatment. Acyclovir inhibits the DNA polymerase of herpes viruses. Resistance is rare, despite the fact that this agent has been used since 1977 and numerous generics are now available (Levin 2004). Acyclovir is usually well tolerated and effective against both HSV-1 and HSV-2. Severe cases with mucocutaneous or organ involvement should be treated immediately intravenously. As CNS levels are lower than in plasma, the dose should be increased to treat encephalitis. If acyclovir is to be given intravenously, renal blood values should be checked.

Valacyclovir and famcyclovir are equally effective alternatives to acyclovir (Ormrod 2000, Conant 2002), though substantially more expensive. The main advantage is their improved oral bioavailability; they require less frequent dosages. In cases of recurrent genital herpes lesions shorter therapeutic regimens (i.e., two days of famciclovir) may be as effective as standard 5-day courses (Bodsworth 2008).

Brivudine remains a good alternative for HSV-1 and VZV. However, it is possible that this dihydropyrimidine dehydrogenase inhibitor causes mitotoxicity and reduces the efficacy of HIV drugs (U. Walker 2005, personal communication). Foscarnet should only be used in exceptional cases due to its toxicity. However, it may be helpful in extensive, refractory cases.

Newer drugs, unlike acyclovir, that do not inhibit DNA polymerase but rather helicase, another herpes virus enzyme, have been more effective than acyclovir and well tolerated in animal studies – their actual value remains to be shown (Kleymann 2003).

A local anesthetic that can be produced by the pharmacist can be prescribed in addition for painful mucocutaneous lesions. Unfortunately, the approved tetracaine solution (HervirosÔ) has been taken off the market. Some pharmacists can, however, make-up something similar.

Prophylaxis

Primary prophylaxis is not recommended. However, a meta-analysis of almost 2,000 patients in eight randomized studies showed that acyclovir can reduce the risk of both HSV and HZV disease by more than 70%. Even mortality was reduced by 22% (Ioannidis 1998). The introduction of ART has changed the relevance of this data. Nevertheless, it can still make sense, even today, to treat persistent recurrences with long-term low dose acyclovir or valacyclovir (DeJesus 2003, Warren 2004).

Treatment/prophylaxis of HSV infection (daily doses)
Acute therapy Duration: 7-14 days
Treatment of choice Acyclovir Acyclovir 1 tbl. at 400 mg 5x/day
Severe cases Acyclovir ½-1 amp. at 500 mg tid (5-10 mg/kg tid) i.v.
Alternatives Valacyclovir Valacyclovir 2 tbl. at 500 mg tid
Alternatives Famciclovir Famciclovir 1 tbl. at 250 mg tid
Alternatives Brivudin Brivudin 1 tbl. at 125 mg qd
Prophylaxis Not recommended

Interactions between HIV and Herpes simplex

Prevalent HSV-2 infection is associated with a three-fold increased risk of HIV transmission among both men and women (Freeman 2006) – see also the prevention section in the ART chapter. Large randomized studies could demonstrate that during an anti-HSV therapy, HIV replication is also inhibited. During treatment with valgancyclovir and acyclovir, HIV plasma viremia is decreased by 0.26-0.53 log (Nagot 2007, Baeten 2008) and by 0,25-0.34 log (Delany 2008, Celum 2010), respectively. This reduction is at first sight not very impressive, but nevertheless it is significant. These results have recently revived the HSV and especially the acyclovir therapy (Vanpouille 2009) despite the fact that acyclovir could not prevent the transmission of HIV (Celum 2008+2010, Watson-Jones 2008). All at once an old drug, such as acyclovir has become interesting again. Possibly new derivatives will be developed which are better tolerated and more effective in terms of antiviral potency towards HIV.

References

Baeten JM, Strick LB, Lucchetti A, et al. Herpes simplex virus (HSV)-suppressive therapy decreases plasma and genital HIV-1 levels in HSV-2/HIV-1 coinfected women: a randomized, placebo-controlled, cross-over trial. J Infect Dis 2008, 198:1804-8.

Bodsworth N, Bloch M, McNulty A, et al. 2-day versus 5-day famciclovir as treatment of recurrences of genital herpes: results of the FaST study. Short-Course Herpes Therapy Study Group. Sex Health 2008, 5:219-25.

Celum C, Wald A, Hughes J, et al. Effect of aciclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive women and men who have sex with men: a randomised, double-blind, placebo-controlled trial. Lancet 2008, 371:2109-19.

Celum C, Wald A, Lingappa JR, et al. Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2. NEJM 2010, 362:427-39.

Chen XS, Han GZ, Guo ZP, et al. A comparison of topical application of penciclovir 1% cream with acyclovir 3% cream for treatment of genital herpes: a randomized, double-blind, multicentre trial. Int J STD AIDS 2000, 11:568-73.

Conant MA, Schacker TW, Murphy RL, et al. Valaciclovir versus aciclovir for herpes simplex virus infection in HIV-infected individuals: two randomized trials. Int J STD AIDS 2002, 13:12-21.

DeJesus E, Wald A, Warren T, et al. Valacyclovir for the suppression of recurrent genital herpes in HIV-infected subjects. J Infect Dis 2003; 188: 1009-16.

Delany S, Mlaba N, Clayton T, et al.  Impact of aciclovir on genital and plasma HIV-1 RNA in HSV-2/HIV-1 co-infected women: a randomized placebo-controlled trial in South Africa. AIDS 2009, 23:461-9.

Freeman EE, Weiss HA, Glynn JR, Cross PL, Whitworth JA, Hayes RJ. Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. AIDS 2006, 20:73-83.

Ioannidis JP, Collier AC, Cooper DA, et al. Clinical efficacy of high-dose acyclovir in patients with HIV infection: a meta-analysis of randomized individual patient data. J Infect Dis 1998, 178:349-59.

Kleymann G. New antiviral drugs that target herpesvirus helicase primase enzymes. Herpes 2003, 10:46-52.

Levin MJ, Bacon TH, Leary JJ. Resistance of herpes simplex virus infections to nucleoside analogues in HIV-infected patients. Clin Infect Dis 2004, 39 Suppl 5:S248-57.

Nagot N, Ouedraogo A, Foulongne V, et al. Reduction of HIV-1 RNA levels with therapy to suppress herpes simplex virus. N Engl J Med 2007;356:790-9.

Ormrod D, Scott LJ, Perry CM. Valaciclovir: a review of its long term utility in the management of genital herpes simplex virus and cytomegalovirus infections. Drugs 2000, 59:839-63.

Ouedraogo A, Nagot N, Vergne L, et al. Impact of suppressive herpes therapy on genital HIV-1 RNA among women taking antiretroviral therapy: a randomized controlled trial. AIDS 2006, 20:2305-13.

Safrin S. Treatment of acyclovir-resistant herpes simplex virus infections in patients with AIDS. J Acquir Immune Defic Syndr 1992, Suppl 1:S29-32.

Vanpouille C, Lisco A, Margolis L. Acyclovir: a new use for an old drug. Curr Opin Infect Dis 2009, 22:583-7.

Vinh DC, Aoki FY. Famciclovir for the treatment of recurrent genital herpes: a clinical and pharmacological perspective. Expert Opin Pharmacother 2006, 7:2271-86.

Warren T, Harris J, Brennan CA. Efficacy and safety of valacyclovir for the suppression and episodic treatment of herpes simplex virus in patients with HIV. Clin Infect Dis 2004, 39 Suppl 5:S258-66.

Watson-Jones D, Weiss HA, Rusizoka M, et al. Effect of herpes simplex suppression on incidence of HIV among women in tanzania. N Engl J Med 2008, 358:1560-71.

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Filed under 11. Opportunistic Infections, Herpes Simplex, Part 3 - AIDS