Second-Line antiretroviral therapy for children iving with HIV in Africa

Journal article

Background: Children living with HIV have limited second-line antiretroviral therapy (ART) options.

Methods: Children were randomised to tenofovir alafenamide fumarate (TAF)-based or standard-of-care (SOC: abacavir (ABC) or zidovudine (ZDV) plus lamivudine (3TC)) backbone; and factorially to second-line anchor drugs: dolutegravir (DTG), ritonavir-boosted darunavir (DRV/r), atazanavir (ATV/r), or lopinavir (LPV/r). Primary endpoint was week-96 viral load (VL)<400copies/mL, analysed using logistic regression (intention-to-treat), hypothesising TAF would be non-inferior to SOC (10% margin), DTG and DRV/r superior to LPV/r and ATV/r combined, and ATV/r non-inferior to LPV/r (12% margin).

Results: Between 17/12/18 and 01/04/21, 919 children, median[IQR] 10[8-13] years, 497(54.1%) male, baseline VL 7,573copies/ml[5,549-55,700], CD4 count 669cells/mm3 [413-971], weight-for-age Zscore -1.6[-2.4,-0.9] were randomised. At week-96 TAF/FTC was superior to SOC (adjusted difference [95% CI] VL<400copies/mL +6.3% 2.0%,10.6%],p=0.004), with no evidence this varied by ABC/3TC or ZDV/3TC. Growth was better with TAF/FTC vs. SOC, without excess weight-gain with any backbone/anchor combination (including DTG+TAF/FTC). Bone health was similar between backbone arms, irrespective of anchor drug. DTG was superior (+9.7%[+4.8%,+14.5%],p<0.001) to LPV/r and ATV/r arms combined; DRV/r was not superior (+5.6%[+0.3%,+11.0%],p=0.04 vs. multiplecomparison adjusted threshold p=0.03). ATV/r was non-inferior to LPV/r (+3.4%[-3.4%, +10.2%],p=0.33). All arms except LPV/r showed age-appropriate growth. CD4 counts increased similarly in all arms for both randomisations. One child died (treatment-unrelated); 29(3%) had serious adverse events without between-arm differences.

Conclusions: Second-line ART including TAF/FTC and DTG are safe and effective for children. DRV/r is also a good option. Further development of child-friendly TAF/FTC fixed-dose-combinations (±anchor) would increase ART options, reducing the paediatric drug access gap.(ISRCTN22964075).

Authors: Musiime, V; Bwakura-Dangarembizi, M; Szubert, AJ; Mumbiro, V; Mujuri, H

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Massachusetts Medical Society
• Journal: New England Journal of Medicine
• Volume: 3921917-1932
• Pages: 1917-1932
• Publication date: 2025-05-14
• Acceptance date: 2025-03-26
• DOI: 10.1056/NEJMoa2404597
• EISSN: 1533-4406
• ISSN: 0028-4793
• Language: English