Results from the CHAPAS-4 trial published in the New England Journal of Medicine reveal that newer antiretroviral combinations containing tenofovir alafenamide (TAF) and dolutegravir (DTG) provide superior outcomes for children living with HIV who require second-line treatment.
The large-scale study, conducted across Uganda, Zambia, and Zimbabwe, enrolled 919 children aged 3-15 years who needed to switch from first-line treatments containing efavirenz or nevirapine due to treatment failure. Researchers followed participants for at least two years after initiating second-line therapy.
Superior Backbone Treatment Identified
The trial compared a newer backbone combination of TAF plus emtricitabine (FTC) against the current standard of care using abacavir (ABC) or zidovudine (ZDV) plus lamivudine (3TC). For children weighing under 25kg, researchers developed a special mini-tablet formulation of TAF plus FTC, while those over 25kg received the adult formulation.
Results showed that TAF plus FTC successfully suppressed HIV in 6% more children than the standard backbone treatments. Both options demonstrated similar side-effect profiles, but the TAF-based regimen proved more economical, saving approximately $37.68 per patient.
"These findings provide compelling evidence for updating treatment guidelines to include TAF plus FTC as a preferred backbone for second-line therapy in children," said one of the trial investigators.
Comparing Anchor Drug Performance
The CHAPAS-4 trial also evaluated four different anchor drugs that are typically combined with backbone treatments:
- Once-daily dolutegravir (DTG)
- Once-daily atazanavir/ritonavir (ATV/r)
- Once-daily darunavir/ritonavir (DRV/r)
- Twice-daily lopinavir/ritonavir (LPV/r)
DTG-based regimens demonstrated clear superiority, achieving full viral suppression in 10% more children compared to LPV/r and ATV/r-based treatments. While DRV/r showed promising results with approximately 6% better viral suppression than LPV/r and ATV/r, this difference did not reach the pre-defined threshold for statistical significance.
From a cost perspective, DTG emerged as the most economical option, saving $190.77 per patient compared to ATV/r. In contrast, DRV/r was identified as the most expensive anchor drug option.
Improved Health Outcomes Beyond Viral Suppression
Beyond viral suppression, the study revealed important health benefits for children receiving newer drug combinations. Compared to those on LPV/r-based regimens, children treated with DTG, DRV/r, or ATV/r showed measurable improvements in growth, bone health, and cholesterol levels.
"The overall clinical outcomes in CHAPAS-4 were remarkably positive," noted a trial spokesperson. "Very few children experienced disease progression or required hospitalization during the study period."
Implications for Global Treatment Guidelines
These findings reinforce the World Health Organization's current recommendation of DTG-based regimens as the preferred second-line treatment for children living with HIV. The study also provides new evidence supporting TAF's inclusion in second-line combinations for pediatric patients.
Additionally, pharmacokinetic sub-studies from CHAPAS-4 are contributing valuable data for simplified weight-band dosing of these medications. This information will facilitate the development of new formulations, including dispersible fixed-dose combination mini-pills containing TAF+FTC with or without DTG, making treatment administration easier for children.
Addressing a Critical Treatment Gap
Children living with HIV who experience first-line treatment failure have historically had limited options for second-line therapy. The CHAPAS-4 results address this critical gap by identifying more effective and tolerable treatment combinations.
The trial was funded by the EDCTP2 programme with support from the European Union, with additional funding from Janssen Pharmaceutical and Gilead Sciences Inc.
"These results represent a significant advancement in pediatric HIV care," said a senior researcher involved in the study. "By identifying more effective and cost-efficient treatment options, we can improve outcomes for children living with HIV worldwide."
