Basic Medical Sciences

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Browsing Basic Medical Sciences by Author "Bwakura-Dangarembizi, M."

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    Bwakura-Dangarembizi, M., Szubert, A.J., Mumbiro, V., Kityo, C.M., Lugemwa, A., Doerholt, K., Chabala, C., Nyathi, M., Nduna, B., Burger, D. and Shakeshaft, C.
    (medRxiv, 2024-04-15) Bwakura-Dangarembizi, M.; Szubert, A.J.; Mumbiro, V.; Kityo, C.M.; Lugemwa, A.; Doerholt, K.; Chabala, C.; Nyathi, M.; Nduna, B; Burger, D.; Shakeshaft, C.
    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, 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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    Second-line tenofovir alafenamide for children with HIV in Africa
    (medRxiv, 2024-04-21) Musiime, V.; Musiime, V., Szubert, A.J.; Mujuru, H.A.; Kityo, C.; Doerholt, K.; Makumbi, S.; Mulenga, V.; Ndebele, W.; Mwamabazi, M.; McIlleron, H.; Bwakura-Dangarembizi, M.
    Background Children living with HIV have few second-line antiretroviral therapy(ART) options, especially fixed-dose-combinations(FDC). Methods Children from Uganda, Zambia, Zimbabwe were randomised to second-line tenofovir alafenamide(TAF)/emtricitabine(FTC) or standard-of-care(SOC) backbone (abacavir(ABC) or zidovudine(ZDV) with lamivudine(3TC)) in the factorial CHAPAS-4 trial. The second randomisation (reported elsewhere) was to dolutegravir(DTG), ritonavir-boosted darunavir(DRV/r), atazanavir(ATV/r) or lopinavir(LPV/r) as anchor drug. All drugs were dosed using WHO weight-bands and children <25kg received a new paediatric TAF/FTC(15/120mg) FDC tablet. The primary endpoint was viral load(VL)<400copies/ml at week-96, analysed using logistic regression, hypothesising that TAF/FTC would be non-inferior to SOC (10% margin). Secondary endpoints included safety and immunological outcomes. Analyses were intention-to-treat. Results 919 children 3–15years, 497(54%) male, median[IQR] baseline viral load(VL) 17,573copies/ml [5549-55,700] and CD4 count 669cells/mm3[413-971], spent 99% of time on allocated NRTI backbone. At week-96, 406/454(89.4%) receiving TAF/FTC vs. 378/454(83.3%) receiving SOC had VL<400copies/mL (adjusted difference[95%CI]: 6.3%[2.0%,10.6%], p=0.004), with no evidence that this varied by ABC/3TC or ZDV/3TC SOC. CD4 count improved similarly in both arms. Growth was better with TAF/FTC vs. SOC, without evidence of excess weight-gain with any backbone/anchor drug combination (including DTG±TAF/FTC, interaction p=0.51). Bone health parameters were similar between arms, irrespective of anchor drug. One child died (treatment-unrelated); 29(3%) had serious adverse events without differences between arms. Conclusions TAF/FTC was virologically superior to SOC ZDV/3TC or ABC/3TC with a favourable safety profile, irrespective of anchor drug. Development of child-friendly TAF/FTC FDCs (±anchor drug) would increase cost-effective ART options for children and reduce drug access gaps between children and adults.(ISRCTN22964075)