Viremia Copy-Years Predicts Mortality Among Treatment-Naive HIV-Infected Patients Initiating Antiretroviral Therapy

Background. Cross-sectional plasma human immunodeficiency virus (HIV) viral load (VL) measures have proven invaluable for clinical and research purposes. However, cross-sectional VL measures fail to capture cumulative plasma HIV burden longitudinally. We evaluated the cumulative effect of exposure to HIV replication on mortality following initiation of combination antiretroviral therapy (ART). Methods. We included treatment-naive HIV-infected patients starting ART from 2000 to 2008 at 8 Center for AIDS Research Network of Integrated Clinical Systems sites. Viremia copy-years, a time-varying measure of cumulative plasma HIV exposure, were determined for each patient using the area under the VL curve. Multivariable Cox models were used to evaluate the independent association of viremia copy-years for all-cause mortality. Results. Among 2027 patients contributing 6579 person-years of follow-up, the median viremia copy-years was 5.3 log(10) copy X y/mL (interquartile range: 4.9-6.3 log(10) copy X y/mL), and 85 patients (4.2%) died. When evaluated separately, viremia copy-years (hazard ratio [HR] = 1.81 per log(10) copy X y/mL; 95% confidence interval [CI], 1.51-2.18 per log(10) copy X y/mL), 24-week VL (1.74 per log(10) copies/mL; 95% CI, 1.48-2.04 per log(10) copies/mL), and most recent VL (HR 5 1.89 per log(10) copies/mL; 95% CI: 1.63-2.20 per log(10) copies/mL) were associated with increased mortality. When simultaneously evaluating VL measures and controlling for other covariates, viremia copy-years increased mortality risk (HR = 1.44 per log(10) copy X y/mL; 95% CI, 1.07-1.94 per log(10) copy X y/mL), whereas no cross-sectional VL measure was independently associated with mortality. Conclusions. Viremia copy-years predicted all-cause mortality independent of traditional, cross-sectional VL measures and time-updated CD4+ T-lymphocyte count in ART-treated patients, suggesting cumulative HIV replication causes harm independent of its effect on the degree of immunodeficiency.