Second-Line Antiretroviral Therapy for Children Living with HIV in Africa
Victor Musiime, Mutsa Bwakura‐Dangarembizi, Alexander J. Szubert, Vivian Mumbiro, Hilda Mujuru, Cissy Kityo, Abbas Lugemwa, Katja Doerholt, Chishala Chabala, Shafic Makumbi, Veronica Mulenga, Helen McIlleron, David Burger, Eva Natukunda, Clare Shakeshaft, Kyomuhendo Jovia Linda, Kusum Nathoo, Lara Monkiewicz, Ibrahim Yawe, Monica Kapasa, Mary Nyathi, Joyce Lungu, Bwendo Nduna, Wedu Ndebele, Annabelle South, Mwate Mwamabazi, Godfrey Musoro, Anna Griffiths, Khozya Zyambo, Rashidah Nazzinda, Kevin Zimba, Yingying Zhang, Simon Walker, Anna Turkova, A. Sarah Walker, Alasdair Bamford, Diana M. Gibb
Abstract
BACKGROUND: Children living with human immunodeficiency virus (HIV) have limited options for second-line antiretroviral therapy (ART). METHODS: In this open-label trial with a 2-by-4 factorial design, we randomly assigned children with HIV who had first-line treatment failure to receive second-line therapy with tenofovir alafenamide fumarate (TAF)-emtricitabine or standard care (abacavir or zidovudine, plus lamivudine) as the backbone and dolutegravir or ritonavir-boosted darunavir, atazanavir, or lopinavir as the anchor drug. The primary outcome was a viral load of less than 400 copies per milliliter at 96 weeks. We hypothesized that TAF-emtricitabine would be noninferior to standard care, that dolutegravir and ritonavir-boosted darunavir would each be superior to ritonavir-boosted lopinavir and atazanavir analyzed in combination, and that ritonavir-boosted atazanavir would be noninferior to ritonavir-boosted lopinavir. Safety was also assessed. RESULTS: A total of 919 children underwent randomization; 458 were assigned to receive TAF-emtricitabine, and 461 to receive standard care. Assigned anchor drugs were dolutegravir (229 participants), ritonavir-boosted darunavir (232), ritonavir-boosted atazanavir (231), and ritonavir-boosted lopinavir (227). The median age of participants was 10 years, and 497 (54.1%) were male. The median viral load at baseline was 17,573 copies per milliliter. At week 96, TAF-emtricitabine was superior to standard care: the adjusted difference in the percentage of participants with a viral load of less than 400 copies per milliliter was 6.3 percentage points (95% confidence interval [CI], 2.0 to 10.6; P = 0.004). Dolutegravir was superior to ritonavir-boosted lopinavir and atazanavir analyzed in combination (adjusted difference, 9.7 percentage points; 95% CI, 4.8 to 14.5; P<0.001), but ritonavir-boosted darunavir was not (adjusted difference, 5.6 percentage points; 95% CI, 0.3 to 11.0; P = 0.04 [prespecified threshold, P = 0.03]). Ritonavir-boosted atazanavir was noninferior to ritonavir-boosted lopinavir. One child died, and 29 (3.2%) had serious adverse events, with no significant between-group differences. CONCLUSIONS: Second-line ART regimens including TAF-emtricitabine and dolutegravir were effective for children, with no evidence of safety concerns. Ritonavir-boosted darunavir was also effective. (Funded by the European and Developing Countries Clinical Trials Partnership and others; CHAPAS-4 ISRCTN Registry number, ISRCTN22964075.).