Viral Infections: Herpes Simplex

Herpes Simplex

Pathogen

Acyclovir-Resistant Herpes Simplex

References

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Pathogen:

Herpes simplex virus types 1 and type 2 (HSV-1, HSV-2).

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Sites of Infection:

Herpesviruses typically infect epithelial and nerve tissues. Reactivation of these infections are common in AIDS patients. Lesions resulting from HSV-1 most commonly affect the mouth and lips, and those resulting from HSV-2 affect the genitals and anus.

A recent report (Heng et al.) showed that in vitro co-infection with HSV-1 allows HIV-1 to infect cells not normally permissive to HIV-1 infection (in this case, keratinocytes which do not express the CD4 receptor). The authors also noted unique morphological and replicative characteristics of the virus in the co-infected cells which suggested the presence of an HSV-l/HIV-1 hybrid virus. These data may support the concept of suppressive treatment for herpes simplex in HIV-1 infected people.

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Symptoms:

Herpes simplex virus infection usually causes painful blisters on an inflamed base.

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Diagnosis:

By virus culture of the lesion or fluorescent antibody testing.

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Treatment Results:

Oral acyclovir (800 mg tid) is approved for the treatment of HSV-related syndromes and reduces the severity and duration of HSV symptoms.

Famciclovir and valacyclovir have been shown to be effective treatments for herpes simplex infection. However, neither compound has demonstrated superiority to acyclovir.

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Acyclovir-Resistant Herpes Simplex:

The development of acyclovir-resistant herpes simplex has been well documented in HIV-infected patients who were receiving long-term acyclovir treatment (1- 5 months). Foscarnet is the only available agent in the U.S. shown to be effective for acyclovir-resistant HSV infection and is used frequently for this indication. Foscarnet has been approved by the Food and Drug Administration (FDA) for the treatment of acyclovir-resistant herpes simplex in immunocompromised patients. Recent evidence reported by Safrin et al. (1994) suggest that foscarnet-resistant HSV infections may be recognized with increasing frequency.

Erlich et al. treated four AIDS patients with severe acyclovir-resistant HSV-2 disease with foscarnet (60 mg/kg IV every 8 hours) for 12 to 50 days. Marked clinical improvement, marked clearing of lesions, and eradication of HSV from mucous membranes were noted.

Tan et al. treated six patients with acyclovir-resistant HSV with foscarnet. Significant or complete healing of lesions occurred in all patients by the end of day 14. Foscarnet maintenance suppressed the recurrence of lesions for up to 10 weeks. Recurrent lesions were successfully treated with a second induction course of foscarnet. No significant renal or neurological toxicities were seen. One patient developed persistent penile ulcerations.

A randomized multicenter trial (ACRG 095) established that foscarnet is superior to vidarabine (Ara-A) for acyclovir-resistant mucocutaneous HSV (Safiin et al.). Eight patients received foscarnet (40 mg/kg IV three times daily) and 6 received vidarabine (15 mg/kg IV daily). Lesion reduction and healing were observed in foscarnet recipients after 10-24 days of therapy; no patient on vidarabine healed. Recurrences in acyclovir-resistant HSV occurred in all patients who had healed; the median time to relapse was 42.5 days after discontinuing foscarnet.

Hardy et al, recently completed an open-label study of topical foscarnet cream in 20 patients with acyclovir-resistant herpes simplex. Median time to 50% and 100% decrease in lesion size was 22 days and 44 days, respectively. Among 15 patients with pain at baseline, 11 had complete resolution of pain and 2 had 50% reduction; among 5 patients with no pain at baseline, 2 remained pain free and 3 developed pain. Adverse events included skin ulcerations in 6 patients and fever in 4 patients.

Kessler et al. enrolled 26 AIDS subjects in an open-label study (ACTG 172) of topica trifluridine (TFT) for ACV-resistant chronic mucocutaneous HSV Interim data reported on 9 subjects showed that 7/9 subjects responded to treatment. Lesions completely healed in 5/7 responders (mean duration to healing 32 days) and 2/7 had a partiaL response. No toxicities were reported. Weaver et al. treated two AIDS patients with acyclovir-resistant HSV with topical TFT solution. TFT was applied three times daily; all lesions healed completely within 11 to 34 days.

Lalezari J et al. recently reported results from a randomized, double-blind, placebo- controlled study of cidofovir topical gel for the treatment of acyclovir-resistant herpes simplex. A total of 30 patients were randomized to receive either one of two concentrations (1% and 0.3%) topical HPMPC or placebo. Complete responses to treatment were reported in 3/11 patients receiving the 0.3% topical, gel and 3/9 patients receiving the 1% topical gel at day 15. However, these data were not statistically significant.

A phase I trial (ACTG 253) to evaluate the pharmacokinetics, safety, and tolerance of valacyclovir in HIV-positive children (ages 12 and under) with herpes zoster or herpes simplex infection is currently underway.

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REFERENCES:

Bentley et al. Absolute bioavailability of acyclovir is substantially increased following oral valacyclovir. Abstract #PBO 523, X Intl Conf AIDS, Japan, 1994.

Erlich KS et a]. Foscarnet therapy for severe acyclovir-resistant herpes simplex virus type-2 infections in patients with AIDS. Ann Int Med 110: 710-13, 1989.

Hardy et al. Phase I pilot study of the safety and efficacy of foscarnet cream for treatment of acyclovir-resistant herpes simplex. Abstract #167, 3rd Conf on Human Retro and Opport Infect. Washington DC, 1996.

Heng M et al. Co-infection and synergy of human immunodeficiency virus-1 and herpes simplex virus-1. Lancet 343: 255-260, 1994.

Kessler H et al. ACTG 172: treatment of acyclovir-resistant (ACV-R) mucocutaneous herpes simplex virus (HSV) infection in patients with AIDS: open label pilot study of topical trifluridine (TFT). Abstract WeB 1056, VIII Intl Conf AIDS, Amsterdam, 1992.

Lalezari J et al. A randomized, double-blind, placebo-controlled study of cidofovir topical gel for acyclovir-resistant herpes simplex virus infection in patients with AIDS. Abstract #174, 3rd Conf on Humm Retro and Oppot Infect, Washington DC, 1996.

Safrin S et al. Foscarnet-resistant herpes simplex virus infection in patients with AIDS. JID 169: l93-6, 1994.

Safrin S et al. A controlled trial comparing foscarnet with vidarabine for acyclovir-resistant mucocutaneous herpes simplex in acquired immunodeficiency syndrome. NEJM 325: 551-5, 1991.

Tan C et al. Foscarnet induction and maintenance therapy for acyclovir-resistant herpes simplex infections in AIDS. VI Intl Conf AIDS, San Francisco, Abstract #Th.B. 447, 1990.

Weaver D et al. Topical trifluridine treatment of acyclovir-resistant herpes simplex disease. 31st ICAAC, Abstract #507, 1991.

OTHER REPORTS:

Kaplowitz L et al. Prolonged continuous acyclovir treatment of normal adults with frequently recurring genital herpes simplex virus infection. JAMA 265(6): 747-751, 1991.

Murphy M et al. Topical trifluridine for mucocutaneous acyclovir-resistant herpes simplex II in AIDS patient. Lancet 340:1040, 1992.

Pottage J et al. Acyclovir-resistant (ACV-R) herpes simplex: susceptibility to alternative antiviral agents. Abstract PoB 3238, VIII Intl Conf AIDS, Amsterdam, 1992.

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