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CHAPAS-4 trial: second-line anchor drugs for children with HIV in Africa

Article scientifique 2024 Anglais

Résumé

Abstract Background Children living with HIV requiring second-line antiretroviral therapy (ART) have limited options, an unmet need considering children require life-long ART. Methods Children from Uganda, Zambia, Zimbabwe were randomised to one of four second-line anchor drugs: dolutegravir(DTG), ritonavir-boosted darunavir(DRV/r), atazanavir(ATV/r), or lopinavir(LPV/r) in the factorial CHAPAS-4 trial (second randomisation to tenofovir alafenamide fumarate(TAF) or standard-of-care(SOC) backbone, reported elsewhere). Dosing followed WHO weight-bands. The primary endpoint was viral load(VL) <400copies/mL at week-96, analysed using logistic regression, hypothesising that DTG and DRV/r would be superior (threshold p=0.03) to LPV/r and ATV/r arms combined and ATV/r would be non-inferior to LPV/r(12% margin). Secondary endpoints included immunology and safety. Analyses were intention-to-treat. Results 919 children, median(IQR) age 10(8-13) years, 54% male, baseline VL 17,573(5549,55700) copies/mL, CD4 669(413, 971) cells/mm 3 , weight-for-age Z-score -1.6(-2.4,-0.9), had spent median(IQR) 5.6(3.3,7.8) years on first-line ART. At week-96, DTG was superior (by 9.7%(95% CI 4.8%, 14.5%); p<0.0001) and DRV/r showed a trend to superiority(by 5.6%(0.3%, 11.0%); p=0.04) compared to LPV/r and ATV/r arms combined. ATV/r was non-inferior to LPV/r(+3.4%(-3.4%,+10.2%); p=0.33). CD4 counts increased with no differences between arms. Toxicity was lowest with DTG. All arms except LPV/r showed age-appropriate weight/height gains at week-96. DTG was not associated with excess absolute weight-gain(<1kg) vs. DRV/r or ATZ/r, irrespective of backbone randomisation. Conclusions DTG-based regimens are safe and cost-effective for second-line ART. DRV/r and ATV/r are also good options. Fixed-dose combinations of DTG, DRV/r or ATV/r with nucleoside/nucleotide-reverse-transcriptase-inhibitors(NRTIs) would increase access to robust, essential second-line options for children.( ISRCTN22964075 )

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Bwakura‐Dangarembizi, M., Szubert, A., Mumbiro, V., Kityo, C., Lugemwa, A., Doerholt, K., Chabala, C., Nyathi, M., Nduna, B., Burger, D., Shakeshaft, C., Nathoo, K., Musiime, V., Yawe, I., South, A., Lungu, J., Ndebele, W., Mwamabazi, M., Griffiths, A., Nazzinda, R., Zimba, K., Zhang, Y., Walker, S., Turkova, A., Walker, A., Bamford, A., Gibb, D., Team, C. (2024). CHAPAS-4 trial: second-line anchor drugs for children with HIV in Africa. https://doi.org/10.1101/2024.04.12.24305333

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Auteur(s)

Mutsa Bwakura‐Dangarembizi Alexander J. Szubert Vivian Mumbiro Cissy Kityo Abbas Lugemwa Katja Doerholt Chishala Chabala Mary Nyathi Bwendo Nduna David M. Burger Clare Shakeshaft Kusum Nathoo Victor Musiime Ibrahim Yawe Annabelle South Joyce Lungu Wedu Ndebele Mwate Mwamabazi Anna Griffiths Rashidah Nazzinda Kevin M. Zimba Yingying Zhang Simon Walker Anna Turkova A Sarah Walker Alasdair Bamford Diana M. Gibb CHAPAS-4 Trial Team

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