CROI 2016 Abstract eBook

Abstract Listing

Oral Abstracts

37 Similar Mortality With Cotrimoxazole vs Placebo in HIV-Exposed Uninfected Children

Roger L. Shapiro 1 ; Michael Hughes 1 ; Kathleen Powis 2 ; Gbolahan Ajibola 3 ; Kara Bennett 4 ; Sikhulile Moyo 3 ; Joseph Makhema 3 ; Sheryl Zwerski 5 ; M. Essex 1 ; Shahin Lockman 6 1 Harvard Sch of PH, Boston, MA, USA; 2 Massachusetts General Hosp, Boston, MA, USA; 3 Botswana Harvard AIDS Inst Partnership, Gaborone, Botswana; 4 Bennett Statistical Consulting, Inc., Ballston Lake, NY, USA; 5 NIH, Bethesda, MD, USA; 6 Brigham and Women’s Hosp, Harvard Med Sch, Boston, MA, USA Background: HIV-exposed uninfected (HEU) children experience higher mortality than HIV-unexposed children. Cotrimoxazole (CTX) reduces mortality among HIV-infected children, but no randomized clinical trials have evaluated its efficacy among HEUs. Methods: We randomized HEU children in a non-malarial region of Botswana to receive either double-blinded CTX or placebo from 14-34 days through 15 months of life. Children were followed every 1-3 months through 18 months; infants diagnosed with HIV after randomization transitioned to open-label CTX. Feeding method was chosen by mothers, with either formula (provided by the Botswana government) or breastfeeding supported with maternal or infant antiretroviral prophylaxis. Breastfed infants were randomized to either 6 or 12 months duration. Primary analysis was intent-to-treat (restricted to infants HIV negative at randomization) and compared mortality at age 18 months using Kaplan- Meier estimates. Results: FromMay 2011-April 2015, 2866 HEU children were randomized (1432 CTX, 1434 placebo); the study was then stopped at the recommendation of the Data and Safety Monitoring Board because it was unlikely to show a benefit of CTX. Loss-to-follow-up was low: 95% of infants completed study follow-up; 72% received continuous study drug through 15 months of age, death or study closure. In primary analysis, mortality was similar by randomized arm: 30 deaths in the CTX arm vs. 34 deaths in the placebo arm; estimated mortality at age 18 months was 2.4% vs. 2.6% (difference: 0.2%; 95% CI: -1.0% to 1.5%; Figure 1). The following outcomes did not differ by CTX and placebo arms: hospitalization (10.8% vs. 12.4%, p=0.24), grade 3/4 diagnosis (16.1% vs. 17.8%, p=0.36), or grade 3/4 anemia (8.0% vs. 8.2%, p=0.84). More infants in the CTX vs. placebo arm experienced grade 3/4 neutropenia (7.9% vs. 5.8%, p=0.05). Fewer infants breastfed than expected (20% overall), and few deaths (11, 2.3%) occurred in breastfed children by age 18 months: 8 vs. 3 among those randomized to breastfeed for 6 vs. 12 months, and only 3 vs. 2 deaths after 6 months. Conclusions: Prophylactic CTX did not improve 18-month survival or other clinical outcomes among HEU children in southern Botswana. In low-mortality, non-malarial settings with low risk for late MTCT, prolonged CTX for HIV-exposed children may not be required.

Oral Abstracts

38 Urgent Versus Post-Stabilization ART in Hospitalized Children: A Randomized Trial Irene N. Njuguna 1 ; Lisa M. Cranmer 2 ;Vincent O. Otieno 1 ; Helen M. Okinyi 1 ; Sarah Benki-Nugent 3 ; Joshua Stern 3 ; KenTapia 3 ; Elizabeth Maleche-Obimbo 1 ; DaltonWamalwa 1 ; Grace C. John-Stewart 3 1 Univ of Nairobi, Nairobi, Kenya; 2 Emory Univ Sch of Med, Atlanta, GA, USA; 3 Univ of Washington, Seattle, WA, USA Background: Many HIV-infected children are diagnosed with HIV at hospitalization and are at high risk of mortality. Urgent ART may accelerate recovery or worsen outcomes with immune reconstitution. We conducted a randomized trial comparing urgent versus post-stabilization ART among hospitalized ART-naïve HIV-infected children. Methods: HIV-infected children 0-12 years were enrolled at 4 hospitals in Nairobi and Kisumu, Kenya, and randomized to receive ART within 48 hours (urgent arm) or 7-14 days (post-stabilization arm) (NCT02063880). Children were followed at 1, 2, 4, 8, 12, 16, 20 and 24 weeks and monitored for mortality, drug toxicity and immune reconstitution inflammatory syndrome (IRIS). Adverse events were graded using Division of AIDS severity grading. Interim efficacy and futility analyses were performed using O-Brien-Fleming boundaries when ~50% of the expected primary endpoints (65 deaths) accrued. An alternative hypothesis of a hazard ratio (HR) of 0.5 and null hypothesis of a HR of 1.0 were used to determine efficacy and futility, respectively. Results: Of 185 enrolled, 177 were randomized; median age was 1.9 years (IQR 0.8-4.7), 45%were female, 57% had weight for age Z-scores of <-2, and were comparable between arms. CD4 counts were lower in the urgent compared to the post-stabilization arm (12.5% versus 17%, p=0.02). Pneumonia, malnutrition and anemia contributed to 61%, 32% and 24% of admission diagnoses, respectively. Among 162 (92%) children who initiated ART, 85 (52%) were in urgent arm. Post-randomization, there were 94 severe adverse events including 37 deaths. At interim analysis, 177 subjects contributed 630.4 person-months follow-up time post-randomization; 308.7 in urgent and 321.7 in the post stabilization arm. Median time to ART was 1 day (IQR 1, 1) in urgent arm and 8 days (IQR 7, 11) in post-stabilization arm. Incidence of mortality was 82.8 per 100 person-years in urgent arm and 60.6 per 100 person-years in post-stabilization arm [HR 1.36 95% CI (0.71, 2.60)] (Figure 1). Adjusting for baseline CD4 count, aHR was 1.25 (95% CI 0.65, 2.41). During interim analysis the Data Safety and Monitoring Board stopped randomization as the futility boundary was crossed. Independent adjudication on IRIS classification is ongoing. Conclusions: Urgent ART for hospitalized HIV-infected children did not decrease mortality. HIV diagnosis and initiation of ART before symptomatic disease remains critical for survival of HIV-infected children.

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CROI 2016