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Famciclovir for the Suppression of Symptomatic and Asymptomatic Herpes Simplex Virus Reactivation in HIV-Infected Persons: A Double-Blind, Placebo-Controlled Trial

Timothy Schacker, MD; Hui-lin Hu, PhD; David M. Koelle, MD; Judith Zeh, PhD; Robin Saltzman, MD; Ron Boon, BSc; Mary Shaughnessy, RN; Gail Barnum, ARNP; and Lawrence Corey, MD
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From University of Washington, Seattle, Washington; and Smith-Kline Beecham Pharmaceuticals, Philadelphia, Pennsylvania. Acknowledgments: The authors thank Gill Atkinson, Regina Jurewicz, and Christine Fletcher for support during the conduct and analysis of the trial; Klaus Esser of Smith-Kline Beecham Pharmaceuticals for supplying penciclovir; Aimee Ekstrom for assistance with antiviral susceptibility assays; Romesh Goutom, PhD, for assistance with assay validation; Stacy Selke for managing the data and providing files for statistical analysis; and the study participants for their time and commitment. Grant Support: In part by National Institutes of Health grant AI-01228 and a grant from SmithKline Beecham Pharmaceuticals. Requests for Reprints: Lawrence Corey, MD, Fred Hutchinson Cancer Research Center, 1124 Columbia Street, M115, Seattle, WA 98104. Current Author Addresses: Dr. Schacker: University of Minnesota, 516 Delaware Street, Box 250, Minneapolis, MN 55455.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1998;128(1):21-28. doi:10.7326/0003-4819-128-1-199801010-00004
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Background: Herpes simplex virus (HSV) infection is one of the most common opportunistic infections in HIV-infected persons. However, most documentation of the effectiveness of antiviral therapy in reducing HSV reactivation is anecdotal.

Objective: To evaluate the quantitative effect of antiviral therapy on the frequency of HSV reactivation in HIV-infected persons.

Design: Double-blind, placebo-controlled, crossover trial.

Setting: Research clinic at a university hospital.

Patients: 48 persons (45 men and 3 women) who were HIV positive and HSV seropositive.

Intervention: Patients were randomly assigned to receive famciclovir, 500 mg orally twice daily, or placebo for 8 weeks. They then crossed over to receive the other regimen after a 1-week washout period.

Measurements: Patients obtained daily cultures of their perirectal, urethral, oral, and genital areas and kept diary records of signs and symptoms of genital and oral-labial herpes.

Results: The median CD4 cell count at study entry was 384 cells/mm3. In the intention-to-treat analysis of the first study period, HSV was isolated on 122 of 1114 (11%) placebo days compared with 9 of 1071 (1%) famciclovir days (relative risk, 0.15; P < 0.001). For patients who completed the crossover, the median difference in days with symptoms between placebo and famciclovir was 13.8% of days and the median difference in days on which HSV was isolated was 5.4% of days (P < 0.001 for both). Percentage of days with HSV-2 shedding was reduced from 9.7% to 1.3%. Breakthrough reactivations that occurred while patients were receiving famciclovir were infrequent, short, and often asymptomatic; HSV-2 isolates from these reactivations were susceptible to penciclovir in vitro.

Conclusions: Antiviral chemotherapy with famciclovir results in clinically and statistically significant reductions in the symptoms associated with HSV infection and the symptomatic and asymptomatic shedding of HSV among HIV-positive persons.


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Figure 1.
Time to first isolation of herpes simplex virus (HSV). Top.Middle.Bottom.

Time to first isolation of HSV-1 or HSV-2 among all 48 participants in the first treatment period. Marks on the curves indicate censoring times due to study dropout or completion of the first period without a positive culture. Time to first isolation of HSV-1 among the 30 participants seropositive for HSV-1 in the first treatment period. Time to first isolation of HSV-2 among the 45 participants seropositive for HSV-2 in the first treatment period.

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