Antiretroviral therapy initiated within 6 months of HIV infection is associated with lower T-cell activation and smaller HIV reservoir size

Abstract

Background. CD4(+)/CD8(+) T-cell activation levels often remain elevated in chronic human immunodeficiency virus (HIV) infection despite initiation of antiretroviral therapy (ART). T-cell activation predicts early death and blunted CD4+ T-cell recovery during ART and may affect persistent HIV reservoir size. We investigated whether very early ART initiation is associated with lower on-therapy immune activation and HIV persistence. Methods. From a cohort of patients with early HIV infection (<6 months duration since infection) we identified persons who started ART early (<6 months after infection) or later (≥2 years after infection) and maintained ≥2 years of virologic suppression; at-risk HIV-negative persons were controls. We measured CD4(+)/CD8(+) T-cell activation (percent CD38(+)/HLA-DR(+)) and HIV reservoir size (based on HIV DNA and cell-associated RNA levels). Results. In unadjusted analyses, early ART predicted lower on-therapy CD8(+) T-cell activation (n = 34; mean, 22.1%) than achieved with later ART (n = 32; mean, 28.8%; P = .009), although levels in early ART remained elevated relative to HIV-negative controls (P = .02). Early ART also predicted lower CD4+ T-cell activation than with later ART (5.3% vs 7.5%; P = .06). Early ART predicted 4.8-fold lower DNA levels than achieved with later ART (P = .005), and lower cell-associated RNA levels (difference in signal-to-cutoff ratio (S/Co), 3.2; P = .035). Conclusions. ART initiation <6 months after infection is associated with lower levels of T-cell activation and smaller HIV DNA and RNA reservoir size during long-term therapy.

Keywords: HIV antiretroviral therapy; HIV cure; HIV eradication; HIVreservoir; T-cell activation; early ART; inflammation.

Figure 1.

CD4⁺ and CD8⁺ T-cell activation in participants initiating early versus later antiretroviral therapy (ART). A, Box plots showing median proportions (line), interquartile range (IQR; box), and adjacent values (1.5 × IQR; whiskers) of patients with CD4⁺ T-cells positive for both CD38 and HLA-DR (CD38⁺/HLA-DR⁺) within each of 5 participant groups: (1) acute human immunodeficiency virus (HIV) infection (composite of all participants' baseline time points during acute/early HIV infection before therapy; dark blue box), (2) ART-naive (participants remaining off therapy throughout observation, assessed at final available time point; red box), (3) early ART group (assessed at final available time point; green box), (4) later ART group (assessed at final available time point; orange box), and (5) HIV-negative controls (assessed at nonbaseline time point; light blue box). Values beyond adjacent values are not shown. B, Analogous values of CD8⁺ CD38⁺/HLA-DR⁺ T-cells in the same 5 subject groups. C, CD38⁺/HLA-DR⁺ CD4⁺ T-cell levels in 34 patients with early ART initiation. Values from baseline (Acute HIV; n = 34), at 1 year after ART initiation (1 y ART; n = 34), and at the participant's final available time point (Max ART; n = 33) are shown. D, CD38⁺/HLA-DR⁺ CD8⁺ T-cell levels in patients with early ART initiation. E, CD4⁺ T-cell activation levels in 32 patients with later ART initiation during acute HIV infection (n = 32), at the final pretherapy time point (Pre-ART; n = 32), at 1 y after ART initiation (n = 32), and at the final time point (n = 25). F, CD8⁺ T-cell activation levels in patients with later ART initiation.

Figure 2.

Human immunodeficiency virus (HIV) DNA and cell-associated RNA levels in participants with early versus later ART initiation. A, Box plots showing median log₁₀ HIV DNA level, interquartile range (IQR; box), and adjacent values (1.5× IQR; whiskers) in patients receiving early ART (green boxes) or later ART (orange boxes) assessed 1 year after ART initiation (1 y ART) and at the participant's final available time point (Max ART). B, Analogous box plots depicting cell-associated HIV RNA levels for the same subject groups and time points. Abbreviation: S/Co, signal-to-cutoff ratio.