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Clinical Trial
. 2025 May 15;392(19):1917-1932.
doi: 10.1056/NEJMoa2404597.

Second-Line Antiretroviral Therapy for Children Living with HIV in Africa

Victor Musiime  1   2 , Mutsa Bwakura-Dangarembizi  3   4 , Alexander J Szubert  5 , Vivian Mumbiro  4 , Hilda A Mujuru  3 , Cissy M Kityo  2 , Abbas Lugemwa  6 , Katja Doerholt  5 , Chishala Chabala  7 , Shafic Makumbi  8 , Veronica Mulenga  7 , Helen McIlleron  9 , David Burger  10 , Eva Natukunda  2 , Clare Shakeshaft  5 , Kyomuhendo Jovia Linda  2 , Kusum Nathoo  4 , Lara Monkiewicz  5 , Ibrahim Yawe  11 , Monica Kapasa  12 , Mary Nyathi  13 , Joyce Lungu  7 , Bwendo Nduna  14 , Wedu Ndebele  15 , Annabelle South  5 , Mwate Mwamabazi  14 , Godfrey Musoro  4 , Anna Griffiths  5 , Khozya Zyambo  12 , Rashidah Nazzinda  2 , Kevin Zimba  12 , Yingying Zhang  16 , Simon Walker  16 , Anna Turkova  5 , A Sarah Walker  5 , Alasdair Bamford  5   17 , Diana M Gibb  5 ; CHAPAS-4 Trial Team
Collaborators, Affiliations
Clinical Trial

Second-Line Antiretroviral Therapy for Children Living with HIV in Africa

Victor Musiime et al. N Engl J Med. .

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.).

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Figures

Figure 1
Figure 1. CONSORT flow diagram
ABC denotes abacavir, ATV/r ritonavir-boosted atazanavir, DRV/r ritonavir-boosted darunavir, DTG dolutegravir, FTC emtricitabine, LPV/r ritonavir-boosted lopinavir, NNRTI non-nucleoside reverse transcriptase inhibitor, NRTI nucleoside/nucleotide reverse transcriptase inhibitor, TAF tenofovir alafenamide fumarate, VL HIV viral load, and ZDV zidovudine. * Reasons are not mutually exclusive therefore total to more than the total number of non-randomisations. Other reasons: declined to participate (n=7), did not return for enrolment within window (n=4), not aged 3-15 (n=4), biochemical (n=3), previously failed ritonavir-boosted lopinavir (n=2), contraception (n=1), contraindications (n=1), co-morbidities (n=1), died (n=1), other (n=9)
Figure 2
Figure 2
For the backbone (a) and anchor (b) randomisations, percentage of children with HIV viral load <400 copies/ml (i), <60 copies/ml (ii) and <1000 copies/ml (iii), over time during the main trial and during extended follow-up ABC denotes abacavir, ATV/r ritonavir-boosted atazanavir, DRV/r ritonavir-boosted darunavir, DTG dolutegravir, LPV/r ritonavir-boosted lopinavir, TAF tenofovir alafenamide fumarate and ZDV zidovudine
Figure 3
Figure 3. For the backbone (a) and anchor (b) randomisations, change in (i) weight- and (ii) height-for-age Z-scores
Extended follow-up mean differences include all of extended follow-up. ABC denotes abacavir, ATV/r denotes ritonavir-boosted atazanavir, DRV/r ritonavir-boosted darunavir, DTG dolutegravir, LPV/r ritonavir-boosted lopinavir, TAF tenofovir alafenamide fumarate & ZDV zidovudine
See this image and copyright information in PMC

References

    1. Njom-Nlend A-E, Efouba N, Brunelle Sandie A, Fokam J. Determinants of switch to paediatric second-line antiretroviral therapy after first-line failure in Cameroon. Tropical Medicine & International Health. 2021;26:927–35. - PubMed
    1. Boerma RS, Bunupuradah T, Dow D, et al. Multicentre analysis of second-line antiretroviral treatment in HIV-infected children: adolescents at high risk of failure. J Int AIDS Society. 2017;20(20):21930. doi: 10.7448/IAS.20.1.21930. - DOI - PMC - PubMed
    1. The Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) Global Cohort Collaboration. Incidence of switching to second-line antiretroviral therapy and associated factors in children with HIV: an international cohort collaboration. Lancet HIV. 2019;6(6):e105–e115. doi: 10.1016/S2352-3018(18)30319-9. - DOI - PMC - PubMed
    1. Townsend CL, O’Rourke J, Milanzi E, et al. Effectiveness and safety of dolutegravir and raltegravir for treating children and adolescents living with HIV: a systematic review. Journal of the International AIDS Society. 2022;25:e25970. doi: 10.1002/jia2.25970. - DOI - PMC - PubMed
    1. Mulenga L, Fwoloshi S, Mweemba A, et al. Dolutegravir with recycled NRTIs is noninferior to PI-based ART: VISEND trial; CROI; 12–16 February; 2022. Oral abstract ( https://www.croiconference.org/abstract/dolutegravir-with-recycled-nrtis...)

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