DISCUSSION
weight gain, toxicities, TAF
A dose of 15 mg TAF in children weighing 14 to <25 kg, and 25 mg TAF in children weighing ≥25 kg, in combination with FTC and 1 of 4 anchor drugs achieved GM AUC comparable to target concentrations of TAF and TFV that are safe and effective in adults. No TAF AUCWe used TAF AUCTFV AUCAs expected, and seen in earlier studies in adults, TFV AUCOur study uses TAF AUC as a proxy for efficacy and TFV AUC as a proxy for safety. It is likely that TFV AUC also correlates to the efficacy of the drug, and likewise, TAF will be indicative of safety. In our study, TAF exposure was significantly higher when it was combined with ATV/r with unknown impact on drug safety. Reassuringly, no safety signal has been raised by the independent data monitoring committee that reviews unblinded trial data regularly. For the other anchor drug combinations, TAF and TFV concentrations were comparable to adult exposure, indicating safe and effective exposure in our study. Tenofovir’s intracellular active metabolite, TFV-DP, could be used as a marker for efficacy. TFV-DP concentrations from dried blood spots as well as sparse pharmacokinetic samples of all children receiving TAF in CHAPAS-4 will be evaluated, and any correlation with viral efficacy and safety will be assessed using pharmacokinetic/pharmacodynamic analysis at the end of the CHAPAS-4 trial.Safety and efficacy data from the CHAPAS-4 trial are monitored by randomized arm, by the independent data monitoring committee, and will be released at the end of the trial. In particular, renal and bone safety linked to tenofovir use is being assessed by calcaneal ultrasound, dual energy X-ray absorptiometry, and additional biochemistry tests. No safety signal has been reported by the committee.In adults, the use of TAF has been linked to weight gain, especially when TAF is combined with DTG. Data linking TAF and weight gain are currently not available, but a trial in children receiving DTG has shown no significant increase in body weight with the use of DTG separately [A potential limitation of our study is that not all children in our study had a sample taken at 0.5 hours after dose (22 of 104), which could have impacted AUC and CTAF has the potential to reduce procurement costs of drug regimens because of the low active dose compared to the current standard-of-care backbone regimens. Furthermore, TAF treatment provides an important alternative to abacavir-containing standard-of-care regimens to children who cannot use TDF due to renal and bone toxicities. Formulations containing TAF have therefore remained in the WHO PADO5 list (Priorities for Antiretroviral Drug Optimization) [In conclusion, children aged 3–15 years, weighing ≥14 kg and taking TAF doses according to WHO-recommended weight bands with ritonavir-boosted PIs or DTG, achieved TAF and TFV concentrations that are safe and effective in adults. These data contribute to the practical use of TAF within regimens available in sub-Saharan Africa and other low- and middle-income settings.