Long-Term Benefits from Early Antiretroviral Therapy Initiation in HIV Infection

Abstract

Background: For people with HIV and CD4⁺ counts >500 cells/mm³, early initiation of antiretroviral therapy (ART) reduces serious AIDS and serious non-AIDS (SNA) risk compared with deferral of treatment until CD4⁺ counts are <350 cells/mm³. Whether excess risk of AIDS and SNA persists once ART is initiated for those who defer treatment is uncertain.

Methods: The Strategic Timing of AntiRetroviral Treatment (START) trial, as previously reported, randomly assigned 4684 ART-naive HIV-positive adults with CD4⁺ counts .500 cells/mm³ to immediate treatment initiation after random assignment (n = 2325) or deferred treatment (n= 2359). In 2015, a 57% lower risk of the primary end point (AIDS, SNA, or death) for the immediate group was reported, and the deferred group was offered ART. This article reports the follow-up that continued to December 31, 2021. Cox proportional-hazards models were used to compare hazard ratios for the primary end point from randomization through December 31, 2015, versus January 1, 2016, through December 31, 2021.

Results: Through December 31, 2015, approximately 7 months after the cutoff date from the previous report, the median CD4⁺ count was 648 and 460 cells/mm³ in the immediate and deferred groups, respectively, at treatment initiation. The percentage of follow-up time spent taking ART was 95% and 36% for the immediate and deferred groups, respectively, and the time-averaged CD4⁺ difference was 199 cells/mm³. After January 1, 2016, the percentage of follow-up time on treatment was 97.2% and 94.1% for the immediate and deferred groups, respectively, and the CD4⁺ count difference was 155 cells/mm³. After January 1, 2016, a total of 89 immediate and 113 deferred group participants experienced a primary end point (hazard ratio of 0.79 [95% confidence interval, 0.60 to 1.04] versus hazard ratio of 0.47 [95% confidence interval, 0.34 to 0.65; P<0.001]) before 2016 (P=0.02 for hazard ratio difference).

Conclusions: Among adults with CD4⁺ counts >500 cells/mm³, excess risk of AIDS and SNA associated with delaying treatment initiation was diminished after ART initiation, but persistent excess risk remained. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Figure 1.

Percentage of Participants Receiving ART and Percentage with HIV RNA Levels 200 copies/ml. (Panel A) Summary of percentage of participants receiving antiretroviral therapy (ART) and percentage with HIV RNA levels ≤200 copies (cp)/ml according to month of follow-up after randomization in the pre-2016 period. (Panel B) Summary of percentage of participants receiving ART and percentage with HIV RNA levels ≤200 cp/ml according to calendar year of follow-up in the post–January 1, 2016, period.

Figure 2.

Summary of Average CD4⁺ Counts. (Panel A) Summary of average CD4⁺ counts according to month of follow-up after randomization in the pre-2016 period. (Panel B) Summary of average CD4⁺ counts according to calendar year of follow-up in the post–January 1, 2016, period.

Figure 3.

Primary and Secondary End Point Event Rates (per 100 Person-Years) According to Treatment Group and Hazard Ratios, Pre-2016 and Post–January 1, 2016. CI denotes confidence interval; and SNA, serious non-AIDS.

Figure 4.

Kaplan–Meier Plots of the Cumulative Percentage of Participants with the Primary End Point According to Treatment Group. (Panel A) Curves for the pre-2016 period. (Panel B) Curves for the post–January 1, 2016 period. CI denotes confidence interval.

Figure 5.

Primary End Point Event Rate (per 100 Person-Years) and Hazard Ratios during the Post–January 1, 2016, Period According to Treatment Group by Subgroups. CHD denotes coronary heart disease; and CI, confidence interval. The dashed line denotes the overall hazard ratio of 0.79.