Person:

Andersen, Janet

Background: Immune reconstitution inflammatory syndrome (IRIS) is reported widely in patients initiating antiretroviral therapy (ART). However, few studies are prospective, and no study has evaluated the impact of the timing of ART when allocated randomly during an acute opportunistic infection (OI). Methodology/Principal Findings: A5164 randomized 282 subjects with AIDS-related OIs (tuberculosis excluded), to early or deferred ART. IRIS was identified prospectively using pre-defined criteria. We evaluated associations between IRIS and baseline variables in subjects with follow-up on ART using Wilcoxon and Fisher's exact tests, logistic regression, and Cox models with time-varying covariates. Twenty of 262 (7.6%) subjects developed IRIS after a median of 33 days on ART. Subjects with fungal infections (other than pneumocystis) developed IRIS somewhat more frequently (OR = 2.7; 95% CI: 1.02, 7.2; p-value = 0.06 (using Fisher's exact test)). In Cox models, lower baseline and higher on-treatment CD4+ T-cell counts and percentage were associated with IRIS. Additionally, higher baseline and lower on-treatment HIV RNA levels were associated with IRIS. Corticosteroids during OI management and the timing of ART were not associated with the development of IRIS. Implications: In patients with advanced immunosuppression and non-tuberculous OIs, the presence of a fungal infection, lower CD4+ T-cell counts and higher HIV RNA levels at baseline, and higher CD4+ T-cell counts and lower HIV RNA levels on treatment are associated with IRIS. Early initiation of ART does not increase the incidence of IRIS, and concern about IRIS should not prompt deferral of ART.

Background: Optimal timing of ART initiation for individuals presenting with AIDS-related OIs has not been defined. Methods and Findings: A5164 was a randomized strategy trial of ‘‘early ART’’ - given within 14 days of starting acute OI treatment versus ‘‘deferred ART’’ - given after acute OI treatment is completed. Randomization was stratified by presenting OI and entry CD4 count. The primary week 48 endpoint was 3-level ordered categorical variable: 1. Death/AIDS progression; 2. No progression with incomplete viral suppression (ie HIV viral load (VL) [greater than or equal to] 50 copies/ml); 3. No progression with optimal viral suppression (ie HIV VL <50 copies/ml). Secondary endpoints included: AIDS progression/death; plasma HIV RNA and CD4 responses and safety parameters including IRIS. 282 subjects were evaluable; 141 per arm. Entry OIs included Pneumocytis jirovecii pneumonia 63%, cryptococcal meningitis 12%, and bacterial infections 12%. The early and deferred arms started ART a median of 12 and 45 days after start of OI treatment, respectively. The difference in the primary endpoint did not reach statistical significance: AIDS progression/death was seen in 20 (14%) vs. 34 (24%); whereas no progression but with incomplete viral suppression was seen in 54 (38%) vs. 44 (31%); and no progression with optimal viral suppression in 67 (48%) vs 63 (45%) in the early vs. deferred arm, respectively (p = 0.22). However, the early ART arm had fewer AIDS progression/deaths (OR = 0.51; 95% CI = 0.27–0.94) and a longer time to AIDS progression/death (stratified HR = 0.53; 95% CI = 0.30–0.92). The early ART had shorter time to achieving a CD4 count above 50 cells/mL (p<0.001) and no increase in adverse events. Conclusions: Early ART resulted in less AIDS progression/death with no increase in adverse events or loss of virologic response compared to deferred ART. These results support the early initiation of ART in patients presenting with acute AIDS-related OIs, absent major contraindications.