HIV treatment in African children
A new study highlights TAF-FTC and dolutegravir as the most effective and safest second-line ART regimens for children with HIV in sub-Saharan Africa.
90% of children with HIV live in sub-Saharan Africa
The global increase in the number of HIV-positive children receiving first-line antiretroviral therapy (ART) leads to a higher demand for second-line ART treatments after virological failure. Most children with HIV reside in Africa, where initial treatment regimens were often based on non-nucleoside reverse transcriptase inhibitors (NNRTIs). However, guidelines now advise transitioning to new class drugs like protease inhibitors or ritonavir-enhanced integrase inhibitors combined with two nucleoside reverse transcriptase inhibitors (NRTIs) in cases of first-line ART failure.
Determining the safest and most effective backbone and anchor drug for paediatric second-line ART remains uncertain. While a tenofovir disoproxil fumarate-based backbone is recommended for adolescents in both first and second-line ART, concerns about its adverse effects on bone and kidney health limit its paediatric use. Tenofovir alafenamide fumarate (TAF), a prodrug of tenofovir, offers improved kidney and bone safety profiles due to lower dosing requirements, but its availability and use in African children are limited.
Alternative drugs like dolutegravir and boosted protease inhibitors show promise in providing sustained viral load suppression with a high resistance barrier, but challenges like limited formulations and high costs hinder their widespread use in paediatric populations.
The CHAPAS-4 trial results
A total of 919 children (median age 10 years; 54% male) with confirmed HIV RNA >400 copies/mL despite NNRTI-based ART were enrolled across sites in Uganda, Zambia, and Zimbabwe between December 2018 and April 2021.
Backbone comparison: TAF-FTC achieved viral suppression (<400 copies/mL) at 96 weeks in 89.4% of participants compared to 83.3% in the standard-of-care group (difference +6.3 percentage points; 95% CI, 2.0–10.6; P = 0.004), demonstrating both non-inferiority and clinical superiority. Grade 3–4 adverse events occurred in 13.8% (TAF-FTC) and 13.9% (SOC), with no significant difference (P = 0.93).
Anchor drug comparison: Dolutegravir led to the highest rate of virologic suppression (92.0%), significantly outperforming the combined atazanavir/r and lopinavir/r groups (difference +9.7 pp; 95% CI, 4.8–14.5; P < 0.001). Darunavir/r did not reach the predefined superiority margin (difference +5.6 pp; 95% CI, 0.3–11.0; P = 0.04). Atazanavir/r was non-inferior to lopinavir/r (difference +3.4 pp; 95% CI, −3.4–10.2; P = 0.33). Serious adverse events were lowest with dolutegravir (5.2%) and highest with atazanavir/r (notably due to hyperbilirubinemia).
The combination of TAF-FTC and dolutegravir demonstrated superior efficacy and safety
TAF–FTC demonstrated superior virologic efficacy with additional metabolic benefits. Improvements in growth parameters were observed in the TAF–FTC arm. Importantly, renal safety was acceptable, and fixed-dose combination availability makes this backbone a strong candidate for scale-up in low-resource settings.
Dolutegravir achieved the highest suppression rates and had the lowest rate of serious adverse events among all anchors tested. Its once-daily dosing, high genetic barrier to resistance, and favourable tolerability profile support its prioritisation in second-line regimens. Given increasing use in first-line therapy, however, long-term planning for integrase-based sequencing is essential.
Darunavir/r, while effective, may pose access challenges due to limited paediatric formulations and higher costs. Atazanavir/r showed similar efficacy to lopinavir/r but was associated with increased hyperbilirubinemia and palatability issues, potentially affecting adherence. Lopinavir/r, though still widely used, had the lowest efficacy and most adverse events among the tested anchor agents.
Future directions in paediatric HIV care
The CHAPAS-4 trial provides robust evidence to guide future paediatric HIV treatment strategies. Where available, the combination of TAF-FTC and dolutegravir should be prioritised as a second-line option. However, implementation requires more than updated clinical guidance. Broader access to optimal formulations, including child-friendly fixed-dose combinations, is essential. The study supports including these combinations in the WHO Paediatric Drug Optimization Programme, which aims to prioritise the most effective drugs and formulations for rollout in low- and middle-income countries.
Further efforts are needed to address formulation gaps: several anchor agents, such as ritonavir-boosted darunavir, remain difficult to use due to high costs and lack of coformulated tablets, resulting in a high pill burden for children. Manufacturing paediatric-appropriate fixed-dose combinations could enhance adherence and efficacy.
The trial also underscores the importance of early switching before advanced immune suppression. Most participants had relatively high baseline CD4 counts, and outcomes were excellent across arms, highlighting the benefit of timely second-line initiation.
Finally, economic analysis revealed that both TAF–FTC and dolutegravir were cost-saving compared to standard care and other anchors. This adds a compelling argument for their adoption in national formularies, especially in resource-constrained settings.
As paediatric HIV care evolves, strategic priorities should include decentralisation of services, simplification of ART protocols, and exploration of long-acting therapies such as injectable cabotegravir. Tailoring treatment pathways to local realities while ensuring global coordination will be critical to close the paediatric HIV treatment gap.
- Musiime V, Bwakura-Dangarembizi M, Szubert AJ, Mumbiro V, Mujuru HA, Kityo CM, Lugemwa A, Doerholt K, Chabala C, Makumbi S, Mulenga V, McIlleron H, Burger D, Natukunda E, Shakeshaft C, Linda KJ, Nathoo K, Monkiewicz L, Yawe I, Kapasa M, Nyathi M, Lungu J, Nduna B, Ndebele W, South A, Mwamabazi M, Musoro G, Griffiths A, Zyambo K, Nazzinda R, Zimba K, Zhang Y, Walker S, Turkova A, Walker AS, Bamford A, Gibb DM; CHAPAS-4 Trial Team. Second-Line Antiretroviral Therapy for Children Living with HIV in Africa. N Engl J Med. 2025 May 15;392(19):1917-1932. doi: 10.1056/NEJMoa2404597. PMID: 40367375.