title: Risk factors for unstructured treatment interruptions and association with survival in low to middle income countries.
abstract: BACKGROUND
  Antiretroviral therapy (ART) treatment interruptions lead to poor clinical outcomes with unplanned or unstructured TIs (uTIs) likely to be underreported. This study describes; uTIs, their risk factors and association with survival.
  
  
  METHODS
  Analysis of ART programmatic data from 11 countries across Asia and Africa between 2003 and 2013 where an uTI was defined as a ≥90-day patient initiated break from ART calculated from the last day the previous ART prescription would have run out until the date of the next ART prescription. Factors predicting uTI were assessed with a conditional risk-set multiple failure time-to-event model to account for repeated events per subject. Association between uTI and mortality was assessed using Cox proportional hazards, with a competing risks extension to test for the influence of lost to follow-up (LTFU).
  
  
  RESULTS
  40,632 patients were included from 11 countries across 33 sites (17 Africa, 16 Asia). Median duration of follow-up was 1.61 years (IQR 0.54-3.31 years), 3386 (8.3 %) patients died, and 3453 (8.5 %) were LTFU. There were 14,817 uTIs, with 10,162 (25 %) patients having more than one uTI. In the adjusted model males were at lower risk of uTI (aHR 0.94, p < 0.01, and age 20-59 was protective compared to <20 years (20-39 years aHR 0.87, p < 0.01; 40-59 years aHR 0.86, p < 0.01). Preserved immune function, as measured by higher CD4 cell count, was associated with a reduced rate of uTI compared to CD4 <200 cells/μL (CD4 200-350 cells/μL aHR 0.89, p < 0.01; CD4 >350 cells/μL aHR 0.87, p < 0.01), whereas advanced clinical disease was associated with increased uTI rate (WHO stage 3 aHR 1.10, p < 0.01; WHO stage 4 aHR 1.21, p < 0.01). There was no relationship between uTI and mortality after adjusting for disease status and considering LTFU as a competing risk.
  
  
  CONCLUSIONS
  uTIs were frequent in people in ART programs in low-middle income countries and associated with younger age, female gender and advanced HIV. uTI did not predict survival when loss to follow-up was considered a competing risk. Further evaluation of uTI predictors and interventions to reduce their occurrence is warranted.
authors.affiliation: Infectious Diseases, Monash University and Alfred Hospital, Melbourne, Australia ; Burnet Institute, Centre for Population Health, Melbourne, Australia.
authors.forename: James H
authors.initials: JH
authors.lastname: McMahon
authors.affiliation: Burnet Institute, Centre for Population Health, Melbourne, Australia.
authors.forename: Tim
authors.initials: T
authors.lastname: Spelman
authors.affiliation: Infectious Disease Epidemiology and Research, University of Cape Town, Cape Town, South Africa ; Division of Infectious Diseases, Imperial College London, London, UK.
authors.forename: Nathan
authors.initials: N
authors.lastname: Ford
authors.affiliation: Manson Unit, Médecins Sans Frontières, London, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Greig
authors.affiliation: Public Health Department, Médecins Sans Frontières, Amsterdam, The Netherlands.
authors.forename: Anita
authors.initials: A
authors.lastname: Mesic
authors.affiliation: Manson Unit, Médecins Sans Frontières, London, UK.
authors.forename: Charles
authors.initials: C
authors.lastname: Ssonko
authors.affiliation: Public Health Department, Médecins Sans Frontières, Amsterdam, The Netherlands.
authors.forename: Esther C
authors.initials: EC
authors.lastname: Casas
authors.affiliation: Manson Unit, Médecins Sans Frontières, London, UK ; Department of Medicine and Infectious Diseases, Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: O'Brien
mesh_terms: D000328:Adult; D000349:Africa / Q000453:epidemiology; D000367:Age Factors; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001208:Asia / Q000453:epidemiology; D018791:CD4 Lymphocyte Count; D003906:Developing Countries / Q000706:statistics & numerical data; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012307:Risk Factors; D012737:Sex Factors; D013997:Time Factors; D055815:Young Adult; D016903:Drug Monitoring
chemical_list: D019380:Anti-HIV Agents
keywords: Antiretroviral therapy; Clinical outcomes; Epidemiology; Resource limited settings; Survival; Unstructured treatment interruption