Influence of the timing of antiretroviral therapy on the potential for normalization of immune status in human immunodeficiency virus 1-infected individuals

Abstract

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/μL 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/μL. 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/μL) 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/μL 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/μL 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.

Figure 1. Study Participants From the US Military HIV (Human Immunodeficiency Virus) Natural History Study (NHS) Evaluated for Outcomes of Normalization of CD4⁺ T-Cell Counts and AIDS

The flowchart depicts the inclusion criteria applied to the NHS participants in whom the associations of CD4⁺ normalization with AIDS and antiretroviral therapy (ART) timing with CD4⁺ normalization and AIDS were evaluated. CDC indicates Centers for Disease Control and Prevention; EDS, estimated date of seroconversion; and HIV, human immunodeficiency virus.

Figure 2. Clinical and Immunologic BenefitsofCD4⁺ T-Cell Count Normalization

A, CD4⁺ T-cell counts in human immunodeficiency virus–uninfected (HIV⁻) persons. CD4⁺ T-cell counts are from the HIV Neurobehavioral Research Center (HNRC) and US National Health and Nutrition Examination Survey (NHANES) and from an updated MEDLINE literature review of 27 reports. The dashed line across the plot indicates a CD4⁺ T-cell count of 900 cells/μL. B, Associations between CD4⁺ T-cell count strata achieved on viral load (VL)-suppressive antiretroviral therapy (ART) and the proportion developing AIDS during the study period in 1119 US Military HIV Natural History Study participants. Associations for the 1993 AIDS criteria were derived from 956 NHS participants; individuals with pre-ART CD4⁺ counts of less than 200 cells/μL (n = 163) were excluded from these analyses. C, Association between the current CD4⁺ count during VL-suppressive ART and the percentage of CD4⁺HLA-DR⁺ effector memory (EM) T cells. D, Association between the current CD4⁺ count during VL-suppressive ART and the percentage of programmed cell death protein-1⁺ CD4⁺ (CD4⁺PD1⁺) T cells. E, Association between the current CD4⁺ count during VL-suppressive ART and the percentage of CD3⁺ T cells positive for phosphorylated signal transducer and activator of transcription 5 (CD3⁺pSTAT5⁺) T cells after ex vivo interleukin 7 (IL-7) stimulation. Levels of these markers in HIV⁻ individuals are also shown; CD4⁺ T cell counts in these HIV⁻ participants were unavailable. In panels A and C through E, the box-and-whisker plots depict the median (horizontal line in box), upper and lower quartiles (ends of box), and extremes (symbols outside of box). The symbols inside the boxes indicate the mean.

Figure 3. CD4⁺ Normalization Rates in 1119 US Military HIV (Human Immunodeficiency Virus) Natural History Study Participants According to Antiretroviral Therapy (ART) Timing Indexed by the Estimated Date of Seroconversion (EDS) and CD4⁺ T-Cell Counts at Study Entry and ART Initiation

A, Schema of CD4⁺ trajectory in therapy-naive persons and time windows after infection within which initiation of ART is optimal for CD4⁺ normalization in persons presenting with lower vs higher CD4⁺ counts (<500 vs ≥500 cells/μL). The schema was derived based on results presented in a previous study. B, Stratification schema for categorizing participants into 4 sets by CD4⁺ counts at study entry and pre-ART The median CD4⁺ count at study entry and pre-ART in each of the 4 CD4⁺-defined sets are depicted as circles; the median interval in the 1119 NHS participants between EDS and study entry was 10 months. C and D, Kaplan-Meier plots for the rates of achieving CD4⁺ normalization in participants categorized according to the schema shown. The CD4-derived sets 1 to 4 shown in panel B were stratified into the indicated 8 groups depending on whether ART was initiated within or after 12 months of EDS. The rate ratio was adjusted (aRR) for calendar year of ART initiation, ART regimen, duration of viral load (VL)-suppressive ART indexed from the date of starting ART, and time from ART initiation to VL suppression.

Figure 4. Likelihood of CD4⁺ Normalization in 1119 US Military HIV (Human Immunodeficiency Virus) Natural History Study Participants Categorized by Duration of Untreated HIV Infection Coindexed by Estimated Date of Seroconversion (EDS) and Study Entry, as Well as CD4⁺ Counts at Study Entry and Antiretroviral Therapy (ART) Initiation

The 4 CD4-defined sets shown in Figure 3B were stratified into 12 subsets according to the entry and pre-ART CD4⁺ counts as well as timing of ART co-indexed from the EDS and study entry. Earlier/earlier (E/E), later/earlier (L/E), and later/later (L/L) indicate whether ART was initiated earlier (≤12 months) vs later (>12 months) from both the EDS and study entry. Median time from EDS to ART, entry to ART, and EDS to study entry as well as median CD4⁺ counts at entry and pre-ART are shown. P values are for the differences in the percent change in CD4⁺ counts between study entry and ART initiation and for the differences in the percent achieving CD4⁺ normalization among the indicated subsets. Odds ratios (ORs) were adjusted for covariates that were significant in univariate logistic regression analyses for the likelihood of achieving CD4⁺ normalization; the covariates were ethnicity, calendar year of therapy, ART regimen, time from ART to VL suppression, duration of viral load–suppressive ART, and each increase of 10 CD4⁺ T cells at ART initiation. NS indicates not significant. Limit lines represent 95% CI. ^aP < .05. ^bP < .01.

Figure 5. Association of Antiretroviral Therapy (ART) Timing With Development of AIDS and Duration of Untreated Infection With T-Cell Activation and In Vivo Functional Responses

A and B, Kaplan-Meier plots depict progression to AIDS in participants who were classified to the E/E, L/E, and L/L time-indexed subsets shown in Figure 4. Incidence rate ratios (IRRs) and hazard ratios (HRs) were adjusted for the calendar year of ART, higher vs lower CD4⁺ counts at study entry and pre-ART, ART regimen, interval from ART initiation to viral load (VL) suppression, and duration of VL-suppressive ART. Data in panel A were derived from 1119 US Military HIV Natural History Study (NHS) participants; data in panel B were derived from 956 NHS participants because individuals with pre-ART CD4⁺ counts of less than 200 cells/μL (n = 163) were excluded from these analyses. C, Association of the duration between estimated date of seroconversion (EDS) and ART initiation with the percentage of CD4⁺HLA-DR⁺ effector memory (EM) T cells in participants receiving VL-suppressive ART. The box-and-whisker plots depict the median (horizontal line in box), upper and lower quartiles (ends of box), and extremes (symbols outside of box). The symbols inside the boxes indicate the mean. D, The proportion of the responders (filled box) vs nonresponders (open box) to hepatitis B virus (HBV) vaccine in HIV-infected patients who received the vaccine while they were therapy naive within or after 12 months of the EDS. E, The proportion of the responders (filled box) vs nonresponders (open box) to HBV vaccine in HIV-infected patients who received the vaccine while receiving VL-suppressive ART; patients were stratified according to whether VL-suppressive ART was initiated within or after 12 months of the EDS. Anti-HBs indicates HBV surface antibody.