Correspondence

A New Topical Treatment for Resistant Herpes Simplex Infections

N Engl J Med 1993; 329:968-969September 23, 1993

Article

To the Editor:

For persistent mucocutaneous infections due to herpes simplex virus (HSV) in immunosuppressed patients, acyclovir is the drug of choice1. Foscarnet is an alternative agent,2,3 but it too may lead to resistance. A new approach to the therapy of HSV infections is based on the use of an acyclic nucleoside phosphonate, (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC), a potent and selective inhibitor of various DNA viruses, including HSV types 1 and 2 and thymidine kinase-deficient mutants of HSV4,5.

We used HPMPC (1 percent, in Beeler base or Orabase), applied topically once a day on three consecutive days a week, to treat persistent mucocutaneous infections. Patient 1 had AIDS and a perineal HSV type 2 infection unresponsive to acyclovir and was not eligible for foscarnet treatment. Patient 2 had undergone bone marrow transplantation and had HSV type 1 orofacial lesions unresponsive to either acyclovir or foscarnet.

Isolates of HSV type 2 obtained from Patient 1 before HPMPC treatment was started were resistant to acyclovir. After one course of HPMPC the lesions resolved completely. They recurred three weeks later but regressed with three additional weeks of HPMPC (applied daily for three days a week). Seven weeks later the lesions relapsed. Because the recurring virus was sensitive to acyclovir, the patient was given the drug. Again acyclovir-resistant HSV type 2 lesions appeared, but they responded to HPMPC treatment. After HPMPC was stopped, the disease relapsed; HSV type 2 isolates were sensitive to acyclovir. The patient died of AIDS.

Patient 2 had HSV type 1 isolates resistant to both acyclovir and foscarnet. The lesions regressed after HPMPC treatment, but one week later a second course of HPMPC was begun to treat recurrent infection. The lesions regressed but reappeared later. The recurring virus was sensitive to acyclovir. The patient was then treated successfully with acyclovir and was cured. All the isolates obtained from both patients during the courses of treatment (34 HSV type 2 isolates from Patient 1 and 11 HSV type 1 isolates from Patient 2) remained sensitive to HPMPC.

We conclude that topical HPMPC is useful in the treatment of HSV infections resistant to acyclovir alone or combined with foscarnet. A regimen of acyclovir alternating with HPMPC may become a new approach to the treatment of severe mucocutaneous herpesvirus infections in severely immunocompromised patients.

R. Snoeck, M.D.
G. Andrei, Ph.D.
E. De Clercq, M.D., Ph.D.
Rega Institute for Medical Research, B-3000 Leuven, Belgium

M. Gerard, M.D.
N. Clumeck, M.D., Ph.D.
St. Pierre Hospital, B-1000 Brussels, Belgium

G. Tricot, M.D., Ph.D.
Indiana University Hospital, Indianapolis, IN 46202

C. Sadzot-Delvaux, Ph.D.
Universite de Liege, B-4000 Sart-Tilman, Liege, Belgium

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   S Santoyo, E.Ga de Jalón, P Ygartua, M.J Renedo, M.J Blanco-Prı́eto. (2002) Optimization of topical cidofovir penetration using microparticles. International Journal of Pharmaceutics 242:1-2, 107-113
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   S Santoyo, E.G de Jalón, M.A Campanero, P Ygartua. (2002) Determination of cidofovir in both skin layers and percutaneous penetration samples by HPLC. Journal of Pharmaceutical and Biomedical Analysis 29:5, 819-826
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   Julie Bestman-Smith, Guy Boivin. (2002) Herpes simplex virus isolates with reduced adefovir susceptibility selected in vivo by foscarnet therapy. Journal of Medical Virology 67:1, 88-91
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   Christian Gilbert, Julie Bestman-Smith, Guy Boivin. (2002) Resistance of herpesviruses to antiviral drugs: clinical impacts and molecular mechanisms. Drug Resistance Updates 5:2, 88-114
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   Daniel T. Leung, Stephen L. Sacks. (2000) Current Recommendations for the Treatment of Genital Herpes. Drugs 60:6, 1329-1352
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   D Calista. (2000) Topical cidofovir for severe cutaneous human papillomavirus and molluscum contagiosum infections in patients with HIV/AIDS. A pilot study. Journal of the European Academy of Dermatology and Venereology 14:6, 484-488
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    Kenneth C. Cundy, Geoffrey Lynch, William A. Lee. (1997) Bioavailability and metabolism of cidofovir following topical administration to rabbits. Antiviral Research 35:2, 113-122
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    Elena Aspe, Richard H. Guy, William A. Lee, James A. Kennedy, Gary C. Visor, Richard D. Ennis. (1995) Optimization ofin vitro flux through hairless mouse skin of cidofovir, a potent nucleotide analog. Journal of Pharmaceutical Sciences 84:6, 750-754
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    E. Van Cutsem, J. Janssens, P. Rutgeerts, G. Vantrappen, R. Snoeck, M. Van Ranst, P. Fiten, G. Opdenakker, E. De Clercq, K. Geboes. (1995) Successful treatment of a squamous papilloma of the hypopharynx-esophagus by local injections of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine. Journal of Medical Virology 45:2, 230-235
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    Sharon Safrin, George McKinley, Mark McKeough, Dana Robinson, Spotswood L. Spruance. (1994) Treatment of acyclovir-unresponsive cutaneous herpes simplex virus infection with topically applied SP-303. Antiviral Research 25:3-4, 185-192
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