title: Marginal Structural Models to Assess Delays in Second-Line HIV Treatment Initiation in South Africa.
abstract: BACKGROUND
  South African HIV treatment guidelines call for patients who fail first-line antiretroviral therapy (ART) to be switched to second-line ART, yet logistical issues, clinician decisions and patient preferences make delay in switching to second-line likely. We explore the impact of delaying second-line ART after first-line treatment failure on rates of death and virologic failure.
  
  
  METHODS
  We include patients with documented virologic failure on first-line ART from an observational cohort of 9 South African clinics. We explored predictors of delayed second-line switch and used marginal structural models to analyze rates of death following first-line failure by categorical time to switch to second-line. Cox proportional hazards models were used to examine virologic failure on second-line ART among patients who switched to second-line.
  
  
  RESULTS
  5895 patients failed first-line ART, and 63% switched to second-line. Among patients who switched, median time to switch was 3.4 months (IQR: 1.1-8.7 months). Longer time to switch was associated with higher CD4 counts, lower viral loads and more missed visits prior to first-line failure. Worse outcomes were associated with delay in second-line switch among patients with a peak CD4 count on first-line treatment ≤100 cells/mm3. Among these patients, marginal structural models showed increased risk of death (adjusted HR for switch in 6-12 months vs. 0-1.5 months = 1.47 (95% CI: 0.94-2.29), and Cox models showed increased rates of second-line virologic failure despite the presence of survivor bias (adjusted HR for switch in 3-6 months vs. 0-1.5 months = 2.13 (95% CI: 1.01-4.47)).
  
  
  CONCLUSIONS
  Even small delays in switch to second-line ART were associated with increased death and second-line failure among patients with low CD4 counts on first-line. There is opportunity for healthcare providers to switch patients to second-line more quickly.
authors.affiliation: Center for Global Health & Development, Boston University, Boston, United States of America.
authors.forename: Julia K
authors.identifier: http://orcid.org/0000-0002-1180-8764
authors.initials: JK
authors.lastname: Rohr
authors.affiliation: Clinical HIV Research Unit, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Prudence
authors.initials: P
authors.lastname: Ive
authors.affiliation: Center for Global Health & Development, Boston University, Boston, United States of America.|Department of Epidemiology, Boston University School of Public Health, Boston, United States of America.
authors.forename: C Robert
authors.initials: CR
authors.lastname: Horsburgh
authors.affiliation: Clinical HIV Research Unit, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Berhanu
authors.affiliation: Health Economics and Epidemiology Research Office, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Kate
authors.initials: K
authors.lastname: Shearer
authors.affiliation: Health Economics and Epidemiology Research Office, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Mhairi
authors.initials: M
authors.lastname: Maskew
authors.affiliation: Health Economics and Epidemiology Research Office, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Long
authors.affiliation: Health Economics and Epidemiology Research Office, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.|Right to Care, Johannesburg, South Africa.
authors.forename: Ian
authors.initials: I
authors.lastname: Sanne
authors.affiliation: Witkoppen Health and Welfare Centre, Johannesburg, South Africa.
authors.forename: Jean
authors.initials: J
authors.lastname: Bassett
authors.affiliation: Department of Medical Microbiology, University of Pretoria, Pretoria, South Africa.
authors.forename: Osman
authors.initials: O
authors.lastname: Ebrahim
authors.affiliation: Center for Global Health & Development, Boston University, Boston, United States of America.|Department of Epidemiology, Boston University School of Public Health, Boston, United States of America.|Health Economics and Epidemiology Research Office, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Fox
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D015331:Cohort Studies; D057915:Drug Substitution / Q000401:mortality / Q000706:statistics & numerical data*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000821:virology; D006801:Humans; D008297:Male; D010349:Patient Compliance / Q000523:psychology / Q000706:statistics & numerical data*; D016016:Proportional Hazards Models; D013019:South Africa; D013997:Time Factors; D017211:Treatment Failure; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents