Enhanced CD4+ T-cell recovery with earlier HIV-1 antiretroviral therapy

Abstract

Background: The relationship between the timing of the initiation of antiretroviral therapy (ART) after infection with human immunodeficiency virus type 1 (HIV-1) and the recovery of CD4+ T-cell counts is unknown.

Methods: In a prospective, observational cohort of persons with acute or early HIV-1 infection, we determined the trajectory of CD4+ counts over a 48-month period in partially overlapping study sets: study set 1 included 384 participants during the time window in which they were not receiving ART and study set 2 included 213 participants who received ART soon after study entry or sometime thereafter and had a suppressed plasma HIV viral load. We investigated the likelihood and rate of CD4+ T-cell recovery to 900 or more cells per cubic millimeter within 48 months while the participants were receiving viral-load-suppressive ART.

Results: Among the participants who were not receiving ART, CD4+ counts increased spontaneously, soon after HIV-1 infection, from the level at study entry (median, 495 cells per cubic millimeter; interquartile range, 383 to 622), reached a peak value (median, 763 cells per cubic millimeter; interquartile range, 573 to 987) within approximately 4 months after the estimated date of infection, and declined progressively thereafter. Recovery of CD4+ counts to 900 or more cells per cubic millimeter was seen in approximately 64% of the participants who initiated ART earlier (≤4 months after the estimated date of HIV infection) as compared with approximately 34% of participants who initiated ART later (>4 months) (P<0.001). After adjustment for whether ART was initiated when the CD4+ count was 500 or more cells per cubic millimeter or less than 500 cells per cubic millimeter, the likelihood that the count would increase to 900 or more cells per cubic millimeter was lower by 65% (odds ratio, 0.35), and the rate of recovery was slower by 56% (rate ratio, 0.44), if ART was initiated later rather than earlier. There was no association between the plasma HIV RNA level at the time of initiation of ART and CD4+ T-cell recovery.

Conclusions: A transient, spontaneous restoration of CD4+ T-cell counts occurs in the 4-month time window after HIV-1 infection. Initiation of ART during this period is associated with an enhanced likelihood of recovery of CD4+ counts. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Figure 1. Study Sets and Inclusion Criteria

A total of 468 participants with human immunodeficiency virus type 1 (HIV-1) infection for whom an estimated date of infection (EDI) could be calculated were stratified into two partially overlapping study sets according to the inclusion criteria indicated and as described in the Methods section. A total of 384 participants met the inclusion criteria for study set 1. Data from this study set were used to compute the trajectories of CD4+ counts and viral load after infection with HIV-1. A total of 248 participants assigned to study set 1 subsequently started ART; 176 of these participants met the inclusion criteria for study set 2, which comprised these 176 participants, along with an additional 37 participants who received ART soon after entry (precluding their inclusion in study set 1). Data from study set 2 were used to determine the relationship between the timing of the initiation of ART after infection with HIV-1 and the recovery of CD4+ T-cell counts. Study set 2 was further stratified according to whether participants initiated ART earlier or later: 97 participants in study set 2 initiated ART earlier (≤4 months after the EDI) and 116 initiated ART later (>4 months after the EDI); 164 participants received ART for a minimum of 18 months.

Figure 2. Trajectories of CD4+ T-Cell Counts before and after Initiation of ART

Shown are trajectories of CD4+ counts with 95% pointwise confidence bands, modeled with the use of nonlinear generalized estimating equations. The y axes in all panels show the square root–transformed CD4+ counts (left) and the corresponding absolute counts (right). Panel A shows the cohort-level trajectory of CD4+ counts after the EDI among HIV-infected participants during the time they were not receiving ART, for a maximum of 48 months after the EDI (study set 1). Panel B shows the cohort-level trajectory among participants assigned to study set 2, computed from a maximum of 16 months before the initiation of ART to the time of initiation of ART (at arrow) and from the time of initiation of ART ahead to a maximum of 48 months. Panels C and D show the trajectories among participants in study set 2 according to whether they initiated ART earlier (≤4 months after the EDI) (Panel C) or later (>4 months after the EDI) (Panel D) and according to whether the CD4+ count at the time of initiation of ART was lower (<500 cells per cubic millimeter) or higher (≥500 cells per cubic millimeter). For Panels C and D, the differences between the study groups in the least-squares mean CD4+ counts from the time of initiation of ART were calculated with the use of linear mixed-effects models adjusted for age, sex, race, viral load at the time of the initiation of ART, and length of follow-up after the initiation of ART; the between-group difference in the absolute CD4+ T-cell counts was 232 cells per cubic millimeter (95% CI, 169 to 296) among participants who initiated ART 4 months or less after the EDI (Panel C) and 273 cells per cubic millimeter (95% CI, 219 to 327) among those who initiated ART more than 4 months after the EDI (Panel D) (P<0.001 for both comparisons).

Figure 3. Rate of Recovery of CD4+ T-Cell Counts after Initiation of ART, According to Timing of Initiation of ART and CD4+ T-Cell Count at Initiation of ART

Panel A shows the classification of participants into six groups according to whether they initiated ART when their CD4+ cell count was higher (≥500 cells per cubic millimeter) or lower (<500 cells per cubic millimeter) and whether they initiated ART during the time window of 0 to 4 months after the EDI, between 4 and 12 months after the EDI, or more than 12 months after the EDI. The line schema beneath the boxes shows the changes in CD4+ counts that occurred during these time windows among participants who were not receiving ART. Panels B and C are Kaplan–Meier plots of the proportion of participants in the six groups who had at least one CD4+ count of 900 or more cells per cubic millimeter (Panel B) or 800 or more cells per cubic millimeter (Panel C) while they were receiving ART. In Panel B, the rate ratio for meeting the criterion of 900 cells per cubic millimeter (the primary end point) was 0.55 (95% CI, 0.32 to 0.96) in the comparison of group 2 with group 1 (the reference group) and 0.31 (95% CI, 0.14 to 0.69) in the comparison of group 3 with group 1.