Influence of the Timing of Antiretroviral Therapy on the Potential for Normalization of Immune Status in Human Immunodeficiency Virus 1-Infected Individuals

IMPORTANCE In individuals with human immunodeficiency virus 1 (HIV-1) infection who are receiving antiretroviral therapy (ART), factors that promote full immune recovery are not well characterized. OBJECTIVE To investigate the influence of the timing of ART relative to HIV-1 infection on normalization of CD4(+) T-cell counts, AIDS risk, and immune function. DESIGN, SETTING, AND PARTICIPANTS Participants in the observational US Military HIV Natural History Study with documented estimated dates of seroconversion (EDS) who achieved virologic suppression with ART were evaluated. Markers indicative of immune activation, dysfunction, and responsiveness were determined. Responses to hepatitis B virus (HBV) vaccine, an indicator of in vivo immune function, were also assessed. The timing of ART was indexed to the EDS and/or entry into the cohort. The CD4(+) counts in HIV-1-uninfected populations were surveyed. MAIN OUTCOMES AND MEASURES Normalization of CD4(+) counts to 900 cells/mu L or higher, AIDS development, HBV vaccine response, as well as T-cell activation, dysfunction, and responsiveness. RESULTS The median CD4(+) count in HIV-1-uninfected populations was approximately 900 cells/mu L. Among 1119 HIV-1-infected participants, CD4(+) normalization was achieved in 38.4% vs 28.3% of those initiating ART within 12 months vs after 12 months from the EDS (P=.001). Incrementally higher CD4(+) recovery (<500, 500-899, and >= 900 cells/mu L) was associated with stepwise decreases in AIDS risk and reversion of markers of immune activation, dysfunction, and responsiveness to levels approximating those found in HIV-1-uninfected persons. Participants with CD4(+) counts of 500 cells/mu L or higher at study entry (adjusted odds ratio [aOR], 2.00; 95% CI, 1.51-2.64; P<.001) or ART initiation (aOR, 4.08; 95% CI, 3.14-5.30; P<.001) had significantly increased CD4(+) normalization rates compared with other participants. However, even among individuals with a CD4(+) count of 500 cells/mu L or higher at both study entry and before ART, the odds of CD4(+) normalization were 80% lower in those initiating ART after 12 months from the EDS and study entry (aOR, 0.20; 95% CI, 0.07-0.53; P=001). Initiation of ART within 12 months of EDS vs later was associated with a significantly lower risk of AIDS (7.8% vs 15.3%; P=.002), reduced T-cell activation (percent CD4(+) HLA-DR+ effector memory T cells, 12.0% vs 15.6%; P=.03), and increased responsiveness to HBV vaccine (67.9% vs 50.9%; P=.07). CONCLUSIONS AND RELEVANCE Deferral of ART beyond 12 months of the EDS diminishes the likelihood of restoring immunologic health in HIV-1-infected individuals.