Viremia copy-years predicts mortality among treatment-naive HIV-infected patients initiating antiretroviral therapy

Abstract

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 log₁₀ copy × y/mL (interquartile range: 4.9-6.3 log₁₀ copy × y/mL), and 85 patients (4.2%) died. When evaluated separately, viremia copy-years (hazard ratio [HR] = 1.81 per log₁₀ copy × y/mL; 95% confidence interval [CI], 1.51-2.18 per log(10) copy × y/mL), 24-week VL (1.74 per log₁₀ copies/mL; 95% CI, 1.48-2.04 per log₁₀ copies/mL), and most recent VL (HR = 1.89 per log₁₀ copies/mL; 95% CI: 1.63-2.20 per log₁₀ 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 log₁₀ copy × y/mL; 95% CI, 1.07-1.94 per log₁₀ copy × 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.

Figure 1.

Adjusted survival curve for time-varying viremia copy-years among 2027 treatment-naive HIV-infected patients, CFAR Network of Integrated Clinical Systems (CNICS), 2000–2008. Adjusted survival curves modeling all-cause mortality among 2027 treatment-naive HIV-infected patients following antiretroviral therapy (ART) initiation stratified by levels of time-updated viremia copy-years. Viremia copy-years, the principal exposure of interest, is a time-varying measure of cumulative plasma HIV burden calculated as described in the methods section. Viral load values prior to 24 weeks of ART initiation were excluded from calculating viremia copy-years to best capture the effect of cumulative viral load exposure on mortality after allowing patients a reasonable window to respond to therapy. The survival curves were adjusted for confounding and selection bias due to age, sex, race/ethnicity, HIV transmission risk group, initial ART, year of ART initiation, CNICS site, most recent CD4 count, and visit frequency using inverse probability unstabilized weights, which were a product of viremia copy-years density weight, censoring weight, and visit attendance weight.