Journal Article

Effect of Highly Active Antiretroviral Therapy on Time to Acquired Immunodeficiency Syndrome or Death using Marginal Structural Models

Stephen R. Cole, Miguel A. Hernán, James M. Robins, Kathryn Anastos, Joan Chmiel, Roger Detels, Carolyn Ervin, Joseph Feldman, Ruth Greenblatt, Lawrence Kingsley, Shenghan Lai, Mary Young, Mardge Cohen and Alvaro Muñoz

in American Journal of Epidemiology

Published on behalf of Johns Hopkins Bloomberg School of Public Health

Volume 158, issue 7, pages 687-694
Published in print October 2003 | ISSN: 0002-9262
Published online October 2003 | e-ISSN: 1476-6256 | DOI: http://dx.doi.org/10.1093/aje/kwg206
Effect of Highly Active Antiretroviral Therapy on Time to Acquired Immunodeficiency Syndrome or Death using Marginal Structural Models

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To estimate the net (i.e., overall) effect of highly active antiretroviral therapy (HAART) on time to acquired immunodeficiency syndrome (AIDS) or death, the authors used inverse probability-of-treatment weighted estimation of a marginal structural model, which can appropriately adjust for time-varying confounders affected by prior treatment or exposure. Human immunodeficiency virus (HIV)-positive men and women (n = 1,498) were followed in two ongoing cohort studies between 1995 and 2002. Sixty-one percent (n = 918) of the participants initiated HAART during 6,763 person-years of follow-up, and 382 developed AIDS or died. Strong confounding by indication for HAART was apparent; the unadjusted hazard ratio for AIDS or death was 0.98. The hazard ratio from a standard time-dependent Cox model that included time-varying CD4 cell count, HIV RNA level, and other time-varying and fixed covariates as regressors was 0.81 (95% confidence interval: 0.61, 1.07). In contrast, the hazard ratio from a marginal structural survival model was 0.54 (robust 95% confidence interval: 0.38, 0.78), suggesting a clinically meaningful net benefit of HAART. Standard Cox analysis failed to detect a clear net benefit, because it does not appropriately adjust for time-dependent covariates, such as HIV RNA level and CD4 cell count, that are simultaneously confounders and intermediate variables.

Keywords: acquired immunodeficiency syndrome; antiretroviral therapy, highly active; causality; confounding factors (epidemiology); Abbreviations: AIDS, acquired immunodeficiency syndrome; CI, confidence interval; HAART, highly active antiretroviral therapy; HIV, human immunodeficiency virus; HR, hazard ratio; NRTI, nucleoside reverse transcriptase inhibitor; PCP, Pneumocystis carinii pneumonia.

Journal Article.  5811 words.  Illustrated.

Subjects: Public Health and Epidemiology

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