Clinical and Immunologic Outcomes After Immediate or Deferred Antiretroviral Therapy Initiation During Primary Human Immunodeficiency Virus Infection: The Sabes Randomized Clinical Study

Abstract

Background: In addition to demonstrated public health benefits on reducing transmission, it remains unclear how early antiretroviral therapy (ART) must be started after acquisition of human immunodeficiency virus (HIV) to maximize individual benefits.

Methods: We conducted an open-label randomized clinical study in Lima, Peru among adult men who have sex with men and transgender women with acute (HIV-antibody negative/HIV-1 RNA positive) or recent (confirmed negative HIV-antibody or RNA test within 3 months) HIV infection, who were randomized to start ART immediately versus defer by 24 weeks. We evaluated outcomes by treatment arm and immunologic markers by days since estimated date of detectible infection (EDDI).

Results: Of 216 participants, 105 were assigned to immediate arm and 111 to deferred arm (median age 26.8 years, 37% with acute HIV). The incidence of non-ART-related adverse events was lower in immediate versus deferred arm (83 vs 123/100 person-years, IRR 0.67 (95% confidence interval [CI] .47, .95; P = .02), the difference dominated by fewer infections in those treated immediately. After 24 weeks of ART, between-group differences in CD4/CD8 cell ratio lessened (P = .09 overall), but differences between those initiating ART ≤ 30 days from EDDI (median 1.03, interquartile range [IQR] 0.84, 1.37), and those initiating > 90 days (0.88, IQR 0.61, 1.11) remained, P = .02. Principal components analysis of 20 immune biomarkers demonstrated distinct patterns between those starting ART > 90 days from EDDI versus those starting within 30 or 90 days (both P < .001).

Conclusions: To our knowledge, this is the only evaluation of randomized ART initiation during primary HIV and provides evidence to explicitly consider acute HIV in World Health Organization recommendations for universal ART.

Clinical trials registration: NCT01815580.

Keywords: acute HIV; antiretroviral therapy; immune activation; primary HIV.

© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Assignment of randomized participants to as-treated groups, by days elapsed between estimated date of detectable infection (EDDI) and actual start of antiretroviral therapy (ART). To account for different lengths of time between presumed human immunodeficiency virus (HIV) acquisition, diagnosis, and randomization, as well as ART initiation outside of assigned study visit, we also performed “as treated” analyses, in which participants were reclassified as having started ART within 30, within 90, or > 90 days after EDDI. Acute or recent HIV was determined by seropositivity (or absence thereof) on date of diagnosis and not necessarily date of enrollment/randomization. *Of 40 potential participants with eligible incident infections, 7 were not contactable, and 13 eligible by HIV infection criteria had other medical exclusions such as chronic hepatitis B infection, severely elevated transaminases, or psychiatric impairment. Twenty were screened for enrollment but declined participation.

Figure 2.

HIV-1 RNA and CD4 T-cell count in participants randomized to initiate ART immediately or 24 weeks after diagnosis of early human immunodeficiency virus (HIV) in the Sabes Study. Quantitative HIV-1 RNA and CD4 + T-cells measurements were performed cross-sectionally with blood from within-visit windows at each analysis point (intent to treat analyses with all participants randomized to that arm included). A, Change in HIV-1 RNA viral load (VL) by arm, throughout 48 weeks of the Sabes Study. Box plots represent median and interquartile ranges. Equivalent time-under-ART comparisons for 24-weeks on ART lie at study week 24 in the Immediate arm and at 48 weeks in the Deferred arm, as outlined per-protocol. Virologic suppression was calculated as a single-failure model. B, Proportion of participants with suppressed VL, defined as <40 copies/mL, by analysis week. After 48 weeks on study, the difference in cumulative proportion with virologic suppression was 84.8 vs 70.3% in Immediate vs Deferred arms. C, Box plots demonstrating median and interquartile range in absolute CD4 count by arm at each analysis point. D, CD4+/CD8 + ratio at each analysis point. In (A), (C), and (D), the P value from Kruskal-Wallis test is shown in black for the week 48 between-arm comparison, and the blue bar shows the comparison between arms 24 weeks after intended ART initiation visit (week 24 for Immediate arm, week 48 for Deferred arm). As-treated analysis by actual ART initiation since estimated date of infection presented in Figure 3. Abbreviations: ART, antiretroviral therapy; CI, confidence interval; HIV-1, human immunodeficiency virus type 1.

Figure 3.

CD4+/CD8 + T-cell ratio at ART initiation and 24 weeks after ART initiation, analyzed as treated by interval between estimated date of detectable HIV infection (EDDI) and ART initiation. Overall, the median CD4+/CD8 + T-cell ratio was different across all 3 groups (1.03 vs 0.96 vs 0.88, respectively, P = .0001 by Kruskal-Wallis test) at time of ART start, and the ratio of those starting ART after 90 days (CD4+/CD8 + T-cell ratio of 0.52) and within 90 days (0.37) differed from those starting ART within 30 days (0.76). After 24 weeks of ART, the CD4+/CD8 + T-cell ratio was not different (P = .09) overall, but those treated > 90 days from EDDI had a significantly lower ratio than those treated within 30 days (0.88 vs 1.03). Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus.

Figure 4.

Principal component analysis (PCA) plot showing multivariate variation in immune activation markers between as-treated groups in the Sabes Study. PCA was undertaken on all 23 biomarkers tested in plasma at time of study enrollment/randomization (A), at time of ART initiation (B), and after 24 weeks of ART (C). The principal components (PC) 1 and 2 are displayed, and between-group tests for difference in multivariate outcome were performed for PC1–8 (describing ~80% in total variance in biomarkers) using multivariate analysis of variance, as all PCs conformed to normalcy assumptions. At randomization, the only statistically different pairwise comparison was between the ≤30 and >90-day group (P value <.05, corrected by Bonferroni for multiple comparisons). At both time of ART start and after 24 weeks on ART, the >90-day group was different from each of the more-immediately treated groups, but the ≤30 and 31–90 day groups were not different from each other. Abbreviations: ART, antiretroviral therapy; EDDI, estimated date of detectable infection.