title: Determinants of virological outcome and adverse events in African children treated with paediatric nevirapine fixed-dose-combination tablets.
abstract: Nevirapine is the only nonnucleoside 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 optimization.
  
  
  
  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 more than 100 copies/ml and transaminase increases more than grade 1 using proportional hazard and logistic models in 219 initially antiretroviral treatment (ART)-naive children.
  
  
  
  Pre-ART viral load, adherence, and nevirapine Cmin were associated with viral load nonsuppression [hazard ratio = 2.08 (95% confidence interval (CI): 1.50-2.90, P < 0.001) for 10-fold higher pre-ART viral load, hazard ratio = 0.78 (95% CI: 0.68-0.90, P < 0.001) for 10% improvement in adherence, and hazard ratio = 0.94 (95% CI: 0.90-0.99, P = 0.014) for a 1 mg/l increase in nevirapine Cmin]. There were additional effects of pre-ART CD4 cell percentage and clinical site. The risk of virological nonsuppression decreased with increasing nevirapine Cmin, and there was no clear Cmin threshold predictive of virological nonsuppression. Transient transaminase elevations more than grade 1 were associated with high Cmin (>12.4 mg/l), hazard ratio = 5.18 (95% CI 1.95-13.80, P < 0.001).
  
  
  
  Treatment initiation at lower pre-ART viral load and higher pre-ART CD4 cell percentage, increased adherence, and maintaining average Cmin higher than current target could improve virological suppression of African children treated with nevirapine without increasing toxicity.
authors.affiliation: aDivision of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa bMRC Clinical Trials Unit at University College London, London, United Kingdom cDepartment of Paediatrics and Child Health, University Teaching Hospital, Lusaka, Zambia dJoint Clinical Research Centre eBaylor College of Medicine Bristol Myers Squibb Children's Clinical Centre of Excellence, Kampala, Uganda fGulu Regional Centre of Excellence, Gulu, Uganda gDepartment of Pharmacy, Radboud University Medical Centre, Nijmegen, The Netherlands. *Ann S. Walker and Helen McIlleron contributed equally to the article.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Bienczak
authors.forename: Paolo
authors.initials: P
authors.lastname: Denti
authors.forename: Adrian
authors.initials: A
authors.lastname: Cook
authors.forename: Lubbe
authors.initials: L
authors.lastname: Wiesner
authors.forename: Veronica
authors.initials: V
authors.lastname: Mulenga
authors.forename: Cissy
authors.initials: C
authors.lastname: Kityo
authors.forename: Addy
authors.initials: A
authors.lastname: Kekitiinwa
authors.forename: Diana M
authors.initials: DM
authors.lastname: Gibb
authors.forename: David
authors.initials: D
authors.lastname: Burger
authors.forename: Ann S
authors.initials: AS
authors.lastname: Walker
authors.forename: Helen
authors.initials: H
authors.lastname: McIlleron
mesh_terms: D000349:Africa; D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D002648:Child; D002675:Child, Preschool; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D007223:Infant; D008297:Male; D019829:Nevirapine / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D010949:Plasma / Q000737:chemistry; D013607:Tablets / Q000627:therapeutic use; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D013607:Tablets; D019829:Nevirapine