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.

Immune Activation in Primary Human Immunodeficiency Virus: Influence of Duration of Infection, Treatment, and Substance Use

“…The >30-day group also had higher levels of CD8; the lower levels of IFN-γ we observed in the >30-day group and proliferation defects observed in other studies suggest reduced CD8 functional capacity during the immediate post–acute infection period [ 28 ]. Among participants in the Short Pulse Anti-Retroviral Therapy at Seroconversion study and in our full analysis of the Sabes study, normalization of the CD4/CD8 ratio was seen in those treated during acute infection, but not in those treated after 6 months from infection in the former or after 90 days from infection in the latter [ 14 , 29 ].…”

“…We performed a subgroup analysis from participants in the Sabes study [ 13 , 14 ]. Between 2013 and 2017, the Sabes study evaluated an HIV treatment-as-prevention intervention among MSM and TW, the populations most affected by HIV in Lima, Peru.…”

“…For cross-sectional analysis, the primary predictor of interest was the time from estimated date of detectable HIV infection (EDDI) to enrollment (ENR). EDDI was estimated from the published Consortium for Evaluation and Performance of HIV Incidence Assays calculator that includes clinical and HIV testing history for participants, as previously described [ 14 , 24 ]. Multivariate linear regression analysis was used to assess differences in plasma biomarkers between participants with EDDI-to-ENR intervals of ≤30 vs >30 days (eg, acute infection vs later primary infection).…”

“…We examined this question using data from the Sabes study of Peruvian men who have sex with men (MSM) and transgender women (TW). Prior analyses of participants enrolled within 3 months of HIV acquisition demonstrated clinical benefits of initiating ART immediately (during early primary HIV) compared to deferring ART initiation for just 6 months [ 13 , 14 ]. In this analysis, we assessed longitudinal data from a subset of Sabes study participants to determine whether brief delays in initiation of ART during primary infection result in persistent immunologic changes, ramifications that could lead to higher risk of non-AIDS outcomes [ 15 ].…”

Single-cell immune profiling reveals the impact of antiretroviral therapy on HIV-1-induced immune dysfunction, T cell clonal expansion, and HIV-1 persistencein vivo

“…To understand why people treated with immediate versus delayed ART have different immune dysfunction [15][16][17] , we compared the immune profiles and T cell clonal expansion dynamics of CD4 + T cells from people with acute HIV-1 infection treated with immediate versus delayed ART. We used longitudinally archived blood samples from the Sabes Study in which HIV-1 infection was prospectively tested monthly for early detection and treatment stratification 44,45 . Using detailed histories of HIV-1 testing, including date, type and result of test, we calculated the estimated date of detectable infection (EDDI) using an established algorithm 46 .…”