title: Comparison of six methods to estimate adherence in an ART-naïve cohort in a resource-poor setting: which best predicts virological and resistance outcomes?
abstract: BACKGROUND
  Incomplete adherence to antiretroviral therapy (ART) results in virologic failure and resistance. It remains unclear which adherence measure best predicts these outcomes. We compared six patient-reported and objective adherence measures in one ART-naïve cohort in South Africa.
  
  
  METHODS
  We recruited 230 participants from a community ART clinic and prospectively collected demographic data, CD4 count and HIV-RNA at weeks 0, 16 and 48. We quantified adherence using 3-day self-report (SR), clinic-based pill count (CPC), average adherence by pharmacy refill (PR-average), calculation of medication-free days (PR-gaps), efavirenz therapeutic drug monitoring (TDM) and an electronic adherence monitoring device (EAMD). Associations between adherence measures and virologic and genotypic outcomes were modelled using logistic regression, with the area under the curve (AUC) from the receiver operator characteristic (ROC) analyses derived to assess performance of adherence measures in predicting outcomes.
  
  
  RESULTS
  At week 48 median (IQR) adherence was: SR 100% (100-100), CPC 100% (95-107), PR-average 103% (95-105), PR-gaps 100% (95-100) and EAMD 86% (59-94), and efavirenz concentrations were therapeutic (>1 mg/L) in 92%. EAMD, PR-average, PR-gaps and CPC best predicted virological outcome at week 48 with AUC ROC of 0.73 (95% CI 0.61-0.83), 0.73 (95% CI 0.61-0.85), 0.72 (95% CI 0.59-0.84) and 0.64 (95% CI 0.52-0.76) respectively. EAMD, PR-gaps and PR-average were highly predictive of detection of resistance mutations at week 48, with AUC ROC of 0.92 (95% CI 0.87-0.97), 0.86 (0.67-1.0) and 0.83 (95% CI 0.65-1.0) respectively. SR and TDM were poorly predictive of outcomes at week 48.
  
  
  CONCLUSIONS
  EAMD and both PR measures predicted resistance and virological failure similarly. Pharmacy refill data is a pragmatic adherence measure in resource-limited settings where electronic monitoring is unavailable. Trial registration The trial was retrospectively registered in the Pan African Clinical Trials Registry, number PACTR201311000641402, on the 13 Sep 2013 ( www.pactr.org ). The first participant was enrolled on the 12th July 2012. The last patient last visit (week 48) was 15 April 2014.
authors.affiliation: Department of Medicine, Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.|Desmond Tutu HIV Centre, Werner Beit Building North, UCT Faculty of Health Science, Anzio Road, Observatory, Cape Town, 7925 South Africa.
authors.forename: Catherine
authors.initials: C
authors.lastname: Orrell
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Karen
authors.initials: K
authors.lastname: Cohen
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Rory
authors.initials: R
authors.lastname: Leisegang
authors.affiliation: Harvard Medical School, Boston, MA USA.|Massachusetts General Hospital Center for Global Health, Boston, MA USA.|Ragon Institute of Massachusetts General Hospital, Boston, MA USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Bangsberg
authors.affiliation: Department of Medicine, Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Robin
authors.initials: R
authors.lastname: Wood
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Gary
authors.initials: G
authors.lastname: Maartens
mesh_terms: D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D048588:Benzoxazines / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D003521:Cyclopropanes; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D012367:RNA, Viral / Q000097:blood; D013019:South Africa; D011795:Surveys and Questionnaires; D017211:Treatment Failure; D019562:Viral Load / Q000187:drug effects; D016903:Drug Monitoring
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D012367:RNA, Viral; C098320:efavirenz
keywords: Adherence; Antiretroviral therapy; Electronic monitoring; Genotyping; HIV; HIV-1 resistance; Virological outcome