title: Long-term consequences of the delay between virologic failure of highly active antiretroviral therapy and regimen modification.
abstract: OBJECTIVE
  Current treatment guidelines recommend immediate modification of antiretroviral therapy in HIV-infected individuals with incomplete viral suppression. These recommendations have not been tested in observational studies or large randomized trials. We evaluated the consequences of delayed modification following virologic failure.
  
  
  METHODS
  We used prospective data from two clinical cohorts to estimate the effect of time until regimen modification following first regimen failure on all-cause mortality. The impact of regimen type was also assessed. As the effect of delayed switching can be confounded if patients with a poor prognosis modify therapy earlier than those with a good prognosis, we used a statistical methodology - marginal structural models - to control for time-dependent confounding.
  
  
  RESULTS
  A total of 982 patients contributed 3414 person-years of follow-up following first regimen failure. Delay until treatment modification was associated with an elevated hazard of all-cause mortality among patients failing a reverse transcriptase inhibitor-based regimen (hazard ratio per additional 3 months delay = 1.23, 95% confidence interval: 1.08, 1.40), but appeared to have a small protective effect among patients failing a protease inhibitor-based regimen (hazard ratio per additional 3 months delay = 0.93, 95% confidence interval: 0.87, 0.99).
  
  
  CONCLUSIONS
  Delay in modification after failure of regimens that do not contain a protease inhibitor is associated with increased mortality. Protease inhibitor-based regimens are less dependent on early versus delayed switching strategies. Efforts should be made to minimize delay until treatment modification in resource-poor regions, where the majority of patients are starting reverse transcriptase inhibitor-based regimens and HIV RNA monitoring may not be available.
authors.affiliation: Division of Biostatistics, Berkeley School of Public Health, Berkeley, California 94720, USA. mayaliv@berkeley.edu
authors.forename: Maya L
authors.initials: ML
authors.lastname: Petersen
authors.forename: Mark J
authors.initials: MJ
authors.lastname: van der Laan
authors.forename: Sonia
authors.initials: S
authors.lastname: Napravnik
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Eron
authors.forename: Richard D
authors.initials: RD
authors.lastname: Moore
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D018791:CD4 Lymphocyte Count; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D017211:Treatment Failure; D016896:Treatment Outcome; D014481:United States / Q000453:epidemiology
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors