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; Alvaro Muñoz

doi:10.1093/aje/kwg206

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, Alvaro Muñoz

^*Corresponding author for this work

Preventive Medicine

Research output: Contribution to journal › Article › peer-review

226 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	687-694
Number of pages	8
Journal	American journal of epidemiology
Volume	158
Issue number	7
DOIs	https://doi.org/10.1093/aje/kwg206
State	Published - Oct 1 2003

Funding

The Multicenter AIDS Cohort Study is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute (grants UO1-AI-35042, 5-MO1-RR-00722 (General Clinical Research Center), UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, and UO1-AI-35041). The Women’s Interagency HIV Study is funded by the National Institute of Allergy and Infectious Diseases, with supplemental funding from the National Cancer Institute, the National Institute of Child Health and Human Development, the National Institute on Drug Abuse, the National Institute of Dental and Craniofacial Research, the Agency for Health Care Policy and Research, and the Centers for Disease Control and Prevention (grants U01-AI-35004, U01-AI-31834, U01-AI-34994, U01-AI-34989, U01-HD-32632 (National Institute of Child Health and Human Development), U01-AI-34993, U01-AI-42590, and M01-RR00083). (Study websites are located at http:// www.statepi.jhsph.edu.) Dr. Miguel Hernán was supported by National Institutes of Health grant K08-AI-49392, and Dr. James Robins was supported by National Institutes of Health grant R01-AI-32475.

Keywords

Acquired immunodeficiency syndrome
Antiretroviral therapy
Causality
Confounding factors (epidemiology)
Highly active

ASJC Scopus subject areas

General Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/aje/kwg206

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Cole, S. R., Hernán, M. A., Robins, J. M., Anastos, K., Chmiel, J., Detels, R., Ervin, C., Feldman, J., Greenblatt, R., Kingsley, L., Lai, S., Young, M., Cohen, M., & Muñoz, A. (2003). Effect of highly active antiretroviral therapy on time to acquired immunodeficiency syndrome or death using marginal structural models. American journal of epidemiology, 158(7), 687-694. https://doi.org/10.1093/aje/kwg206

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title = "Effect of highly active antiretroviral therapy on time to acquired immunodeficiency syndrome or death using marginal structural models",

abstract = "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, Causality, Confounding factors (epidemiology), Highly active",

author = "Cole, {Stephen R.} and Hern{\'a}n, {Miguel A.} and Robins, {James M.} and Kathryn Anastos and Joan Chmiel and Roger Detels and Carolyn Ervin and Joseph Feldman and Ruth Greenblatt and Lawrence Kingsley and Shenghan Lai and Mary Young and Mardge Cohen and Alvaro Mu{\~n}oz",

note = "Funding Information: The Multicenter AIDS Cohort Study is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute (grants UO1-AI-35042, 5-MO1-RR-00722 (General Clinical Research Center), UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, and UO1-AI-35041). The Women{\textquoteright}s Interagency HIV Study is funded by the National Institute of Allergy and Infectious Diseases, with supplemental funding from the National Cancer Institute, the National Institute of Child Health and Human Development, the National Institute on Drug Abuse, the National Institute of Dental and Craniofacial Research, the Agency for Health Care Policy and Research, and the Centers for Disease Control and Prevention (grants U01-AI-35004, U01-AI-31834, U01-AI-34994, U01-AI-34989, U01-HD-32632 (National Institute of Child Health and Human Development), U01-AI-34993, U01-AI-42590, and M01-RR00083). (Study websites are located at http:// www.statepi.jhsph.edu.) Dr. Miguel Hern{\'a}n was supported by National Institutes of Health grant K08-AI-49392, and Dr. James Robins was supported by National Institutes of Health grant R01-AI-32475.",

year = "2003",

month = oct,

day = "1",

doi = "10.1093/aje/kwg206",

language = "English (US)",

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journal = "American journal of epidemiology",

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Cole, SR, Hernán, MA, Robins, JM, Anastos, K, Chmiel, J, Detels, R, Ervin, C, Feldman, J, Greenblatt, R, Kingsley, L, Lai, S, Young, M, Cohen, M & Muñoz, A 2003, 'Effect of highly active antiretroviral therapy on time to acquired immunodeficiency syndrome or death using marginal structural models', American journal of epidemiology, vol. 158, no. 7, pp. 687-694. https://doi.org/10.1093/aje/kwg206

TY - JOUR

T1 - Effect of highly active antiretroviral therapy on time to acquired immunodeficiency syndrome or death using marginal structural models

AU - Cole, Stephen R.

AU - Hernán, Miguel A.

AU - Robins, James M.

AU - Anastos, Kathryn

AU - Chmiel, Joan

AU - Detels, Roger

AU - Ervin, Carolyn

AU - Feldman, Joseph

AU - Greenblatt, Ruth

AU - Kingsley, Lawrence

AU - Lai, Shenghan

AU - Young, Mary

AU - Cohen, Mardge

AU - Muñoz, Alvaro

N1 - Funding Information: The Multicenter AIDS Cohort Study is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute (grants UO1-AI-35042, 5-MO1-RR-00722 (General Clinical Research Center), UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, and UO1-AI-35041). The Women’s Interagency HIV Study is funded by the National Institute of Allergy and Infectious Diseases, with supplemental funding from the National Cancer Institute, the National Institute of Child Health and Human Development, the National Institute on Drug Abuse, the National Institute of Dental and Craniofacial Research, the Agency for Health Care Policy and Research, and the Centers for Disease Control and Prevention (grants U01-AI-35004, U01-AI-31834, U01-AI-34994, U01-AI-34989, U01-HD-32632 (National Institute of Child Health and Human Development), U01-AI-34993, U01-AI-42590, and M01-RR00083). (Study websites are located at http:// www.statepi.jhsph.edu.) Dr. Miguel Hernán was supported by National Institutes of Health grant K08-AI-49392, and Dr. James Robins was supported by National Institutes of Health grant R01-AI-32475.

PY - 2003/10/1

Y1 - 2003/10/1

N2 - 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.

AB - 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.

KW - Acquired immunodeficiency syndrome

KW - Antiretroviral therapy

KW - Causality

KW - Confounding factors (epidemiology)

KW - Highly active

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VL - 158

SP - 687

EP - 694

JO - American journal of epidemiology

JF - American journal of epidemiology

IS - 7

ER -

Effect of highly active antiretroviral therapy on time to acquired immunodeficiency syndrome or death using marginal structural models

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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