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Title
Increasing second-line antiretroviral therapy options for children with HIV in Africa: week-96 efficacy and safety results of the CHAPAS-4 randomised trial
Presenter
Victor Musiime
Authors
V. Musiime1,2, 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. Gibb3
Institutions
1Joint 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

<400c/ml difference (%) [95% CI]
p-value
<60c/ml: difference (%) [95% CI]
p-value
TAF vs SOC
6.3 [2.0, 10.6]
0.004
6.3 [1.0, 11.5]
0.02
ATV/r vs LPV/r
3.4 [-3.4, 10.2]
0.33
5.4 [-2.5, 13.2]
0.18
DRV/r vs LPV/r+ATV/r
5.6 [0.3, 11.0]
0.04
3.1 [-3.5, 9.8]
0.35
DTG vs LPV/r+ATV/r
9.7 [4.8, 14.5]
<0.0001
10.5 [4.4, 16.6]
0.0007

CONCLUSIONS: TAF/FTC and DTG were virologically superior to SOC backbone and comparators(ATV/r, LPV/r) respectively, with excellent safety profiles. Child-friendly fixed-dose combinations of TAF/FTC(±DTG or boosted DRV or ATV) would increase access to safe, effective second-line ART options for children.