5764Increasing second-line antiretroviral therapy options for children with HIV in Africa: week-96 efficacy and safety results of the CHAPAS-4 randomised trial

V. Musiime^1,2, A.J. Szubert³, M. Bwakura Dangarembizi⁴, C. Chabala⁵, K. Doerholt³, N. Dukakia³, C. Kityo Mutuluza¹, A. Lugemwa⁶, J. Lungu⁵, S. Makumbi⁶, H. Mcllleron⁷, H.A. Mujuru⁴, V. Mulenga⁵, G. Musoro⁴, M. Mwamabazi⁸, E. Nambi¹, R. Nazzinda¹, W. Ndebele⁹, B. Nduna⁸, C. Shakeshaft³, G. Siziba⁹, S. Tafeni⁴, A. Turkova³, A.S. Walker³, D.M. Gibb^{3 1}Joint Clinical Research Centre, Kampala, Uganda, ²Makerere University, Kampala, Uganda, ³Medical Research Council Clinical Trials Unit at University College London, London, United Kingdom, ⁴University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe, ⁵University Teaching Hospital, Lusaka, Zambia, ⁶Joint Clinical Research Centre, Mbarara, Uganda, ⁷University of Cape Town, Cape Town, South Africa, ⁸Arthur Davison Children’s Hospital, Ndola, Zambia, ⁹Mpilo Central Hospital, Bulawayo, Zimbabwe

BACKGROUND: There are limited options for second-line antiretroviral therapy(ART) for children with HIV. CHAPAS-4(ISRCTN22964075) evaluated long-term outcomes for children starting second-line ART.
METHODS: In this 2X4 factorial trial, children from Uganda, Zambia and Zimbabwe were randomised to second-line tenofovir alafenamide/emtricitabine(TAF/FTC) or standard-of-care(SOC) backbone (abacavir(ABC) or zidovudine(AZT) with lamivudine(3TC))(randomisation 1) and to one of four anchor drugs: dolutegravir(DTG) or ritonavir-boosted darunavir(DRV/r), atazanavir(ATV/r) or lopinavir(LPV/r) (randomisation 2). Primary endpoint was viral load(VL)<400copies/mL at week-96. We hypothesised that TAF/FTC would be non-inferior to SOC(10% margin); ATV/r non-inferior to LPV/r(12% margin); DRV/r and DTG superior to LPV/r and ATV/r arms combined(superiority threshold p=0.03; as multiple comparisons). Analysis was intention-to-treat, based on logistic regression.
RESULTS: 919 children aged 3-15years (54%male, median[IQR] viral load 17,573copies/mL[5549, 55,700]; CD4 count 669[413, 971]) switching NNRTI-based ART, were randomised and spent 98% of time on allocated regimen. At week-96, 406/454(89.4%) on TAF/FTC vs 378/454(83.3%) on SOC had VL<400copies/mL (no evidence of difference between ABC and ZDV arms). For randomisation 2, 208/226(92.0%) on DTG, 203/230(88.3%) on DRV/r, 193/229(84.3%) on ATV/r, 180/223(80.7%) on LPV/r had VL<400c/ml. TAF/FTC was superior to SOC; DTG was superior to LPV/r and ATV/r; DRV/r showed a trend to superiority to LPV/r and ATV/r; ATV/r was non-inferior to LPV/r (Table). Results were similar for VL<60copies/mL and <1000copies/mL and at weeks 48 and 144. CD4 count improved in all arms. More grade 3/4 adverse events (AE), predominately hyperbilirubinemia, occurred ATV/r vs LPV/r(p<0.0001); DTG had fewer AE vs LPV/r(p=0.02). There was no evidence of excess weight-gain with DTG±TAF. Improvement in growth parameters were greater with TAF vs SOC; and with DTG, DRV/r and ATV/r vs LPV/r. Renal and bone health was similar between arms. One child died (treatment-unrelated); 3% had serious adverse events.

Week 96 VL comparisons