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The Effect of the Interaction of Acyclovir with Zidovudine on Progression to AIDS and Survival: Analysis of Data in the Multicenter AIDS Cohort Study

Daniel S. Stein, MD; Neil M. H. Graham, MBBS, MD; Lawrence P. Park, MSE; Donald R. Hoover, PhD; John P. Phair, MD; Roger Detels, MD; Monto Ho, MD; and Alfred J. Saah, MD
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From the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; Johns Hopkins University School of Hygiene and Public Health and the Johns Hopkins School of Medicine, Baltimore, Maryland; Northwestern University, Chicago, Illinois; the University of California at Los Angeles, Los Angeles, California; the University of Pittsburgh, Pittsburgh, Pennsylvania. For the Multicenter AIDS Cohort Study. Requests for Reprints: Daniel S. Stein, MD, Clinical Pharmacology Studies Unit A-142, Albany Medical Center, 47 New Scotland Avenue, Albany, NY 12208. Acknowledgments: The authors thank Drs. Lewis K. Schrager and Sten H. Vermund for their help and encouragement and Dr. Steven Piantadosi for his helpful comments and suggestions on the statistical analyses. Presented in part at the 1st National Conference on Human Retroviruses and Related Infections, Washington, D.C., December 12-16, 1993. Grant Support: Grants UO1-AI-35039, UO1-AI-35040, UO1-AI-35041, UO1-AI-35042, UO1-AI-35043 from the National Institute of Allergy and Infectious Diseases.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1994;121(2):100-108. doi:10.7326/0003-4819-121-2-199407150-00004
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Objective: To examine the effect of acyclovir use on disease progression and survival in human immunodeficiency virus (HIV)-seropositive persons treated with zidovudine.

Setting: Four university-based or -affiliated clinics.

Design: Prospective cohort study of homosexual and bisexual men with semi-annual follow-up. Intent-to-treat Cox models were fit to determine the relation between the use of acyclovir (modeled as a time-dependent covariate) and disease progression, controlling for baseline and time-dependent clinical and laboratory prognostic variables. The acquired immunodeficiency syndrome (AIDS)-free duration and survival time were calculated from the first use of zidovudine. Analysis included study visits 7 to 17 (from 1987 to 1992).

Patients: 786 HIV-seropositive participants in the Multicenter AIDS Cohort Study who began zidovudine therapy before a clinical diagnosis of AIDS; of these, 515 subsequently received acyclovir. Participants were asked at each visit whether they had “used any medication for health reasons not related to AIDS or if they had taken any medication to help fight AIDS or the HIV virus”; 488 patients indicated acyclovir use under either or both questions, and 242 patients indicated only the latter use.

Results: The use of acyclovir for any indication was not associated with an effect on progression to AIDS but was associated with a 26% decrease in the risk for death (relative hazard, 0.74; P = 0.07). The use of acyclovir for HIV infection was also not associated with an effect on progression to AIDS but was associated with a 36% decrease in the risk for death (relative hazard, 0.64; P = 0.01). To further investigate these findings, we examined dose, constancy, and timing of acyclovir use. The median daily dose of acyclovir used for HIV infection was between 600 and 800 mg. No apparent dose effect on survival was found. Longer uninterrupted use of acyclovir for any indication was associated with an 18% decrease in the risk for death for three or more consecutive visits (relative hazard, 0.82; P = 0.23), a 28% decrease for four or more consecutive visits (relative hazard, 0.72; P = 0.09), and a 7% decrease per visit based on the cumulative number of visits while the patient received acyclovir (relative hazard, 0.93 per visit increase; P = 0.03). Use of acyclovir for any indication and use of acyclovir for HIV infection were each associated with a 44% decreased probability of death if the drug was used after AIDS developed (P = 0.007 and P = 0.005, respectively) but not before. To further investigate the prolongation of survival, two landmark analyses were done. The first analysis began at a landmark of 1 year after initiation of zidovudine therapy and compared three groups of patients: those who used acyclovir at or before this landmark, those who had never started acyclovir or started the drug after the landmark, and those who had never used acyclovir. The 90% survival times were 1325, 1059, and 982 days, respectively. The second analysis began at a landmark of developing either a CD4 count less than 50 cells/µL or clinical AIDS. The 90% survival times for the three groups were 398, 261, and 176 days, respectively.

Conclusions: Our analysis suggests that consistent use of acyclovir at a dose sufficient to suppress herpetic recurrences (that is, 600 to 800 mg/d) has a clinically significant effect on prolonging survival in a well-characterized cohort with extensive previous exposure to herpesvirus infections. Further clinical investigation of low-dose acyclovir with concomitant antiretroviral therapy is warranted.

Figures

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Figure 1.
Relative hazards with 95% CIs from time-dependent multivariate Cox models.

The relative hazard for cumulative acyclovir use (diamonds) reflects the modeling of acyclovir use as a continuous variable in which the relative hazard refers to the per visit increase (6-month intervals on drug). All other relative hazards reflect the modeling of acyclovir use as a dichotomous variable. A relative hazard of 1.0 suggests no difference; a relative hazard greater than 1.0, an increased risk; and a relative hazard less than 1.0, a decreased risk for the group using acyclovir and the outcome listed. The three analyses of constancy of acyclovir use were based on patients who had used acyclovir for any indication. For a description of the time-dependent model, the covariates used, and the populations, see Methods. CMV = cytomegalovirus disease; AIDS = the acquired immunodeficiency syndrome; AIDS → death = the time from the development of an AIDS-defining condition to death.

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Figure 2.
Landmark analyses of estimated survival.Left.9nnnRight.9nnn

Multivariate Cox models that used the mean value of the continuous covariates and set the dichotomous covariates to discrete values at the time of the landmark point were constructed to give estimated survival curves. Estimated survival curves using a landmark of 1 year after initiation of zidovudine therapy. The curves are estimated for a patient with symptomatic HIV infection who is receiving zidovudine but had no other antiretroviral use, herpetic episodes, or antipneumocystis prophylaxis for before the landmark and who has a CD4 count of 300 cells/µL, a hemoglobin concentration of 135 g/L, and a platelet count of 212.5 × 10 /L. Group 1 started acyclovir therapy at or before this landmark ( = 131; 15 deaths); group 2 either never used acyclovir or started it after this landmark ( = 502; 145 deaths); and group 3 never used acyclovir ( = 351; 108 deaths). Estimated survival curves using a landmark of a CD4 count of 50 cells/µL or a clinical AIDS diagnosis. The curves are estimated for a patient with symptomatic HIV infection who is receiving zidovudine but had no other antiretroviral use, herpetic episodes, or antipneumocystis prophylaxis before the landmark, and has a CD4 count of 75 cells/µL, a hemoglobin concentration of 122 g/L, and a platelet count of 187.5 × 10 /L. Group 1 started acyclovir therapy at or before this landmark ( = 85; 28 deaths); group 2, either never used acyclovir or started it after this landmark ( = 203; 142 deaths); and group 3 never used acyclovir ( = 154; 112 deaths). AZT = zidovudine; ACV = acyclovir.

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