Determining the effect of highly active antiretroviral therapy on changes in human immunodeficiency virus type 1 RNA viral load using a marginal structural left-censored mean model

Abstract

Highly active antiretroviral therapy (HAART) dramatically reduces the load of circulating human immunodeficiency virus type 1 (HIV-1) by blocking replication at multiple points in the viral life cycle, but the long-term effect of HAART on viral load remains unclear. In the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study, 918 HIV-1-infected men and women who were not using antiretroviral therapy were followed for a median of 5.8 years between 1996 and 2005. Follow-up yielded 3,629 person-years of observation, during which 286 (31%) of the participants initiated HAART. A marginal structural left-censored linear model for semiannual repeated assessments of viral load showed a 1.9 log(10) decrease in viral load after HAART initiation as compared with nonuse (95% confidence interval: 1.7, 2.2), which remained stable over the course of follow-up but was stronger among men (interaction p < 0.001). This association was attenuated by 10% when the authors ignored the left-censoring of viral load measurements (which comprised 20% of measurements (1,420/7,258)) and attenuated by 57% when the authors adjusted for time-varying covariates in a standard fashion rather than using the marginal structural model. In conclusion, the clinically important protective effect of HAART on dampening viral load appears to be rapid, present at CD4 cell counts greater than 350 cells/mm(3), and sustained beyond 6 years.