| Summary: | <strong>Background:</strong> Nevirapine is the only non-nucleoside reverse transcriptase inhibitor currently available as a paediatric fixed-dose combination tablet and is widely used in African children. Nonetheless, the number of investigations into pharmacokinetic determinants of virological suppression in African children is limited and the predictive power of the current therapeutic range was never evaluated in this population, thereby limiting treatment optimisation. <strong>Methods:</strong> We analysed data from 322 African children (aged 0.3–13 years) treated with nevirapine, lamivudine, and either abacavir, stavudine, or zidovudine, and followed up to 144 weeks. Nevirapine trough concentration (Cmin) and other factors were tested for associations with viral load (VL)>100 copies/mL and transaminase increases >grade 1 using proportional hazard and logistic models in 219 initially antiretroviral treatment(ART)-naïve children. <strong>Results:</strong> Pre-ART VL, adherence, and nevirapine Cmin were associated with VL non-suppression (hazard-ratio [HR]=2.08 [95% CI: 1.50-2.90, p<0.001] for 10-fold higher pre-ART VL, HR=0.78 [95% CI: 0.68–0.90, p<0.001] for 10% improvement in adherence and HR=0.94 [95% CI: 0.90-0.99, p=0.014] for a 1mg/L increase in nevirapine Cmin). There were additional effects of pre-ART CD4% and clinical site. The risk of virological non-suppression decreased with increasing nevirapine Cmin and there was no clear Cmin threshold predictive of virological non-suppression. Transient transaminase elevations >grade 1 were associated with high Cmin (>12.4 mg/L), HR=5.18 (95%CI 1.95–13.80, p<0.001). <strong>Conclusions:</strong> Treatment initiation at lower pre-ART VL and higher pre-ART CD4%, increased adherence, and maintaining average Cmin higher than current target could improve virological suppression of African children treated with nevirapine without increasing toxicity.
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