title: Emergence of drug resistance is associated with an increased risk of death among patients first starting HAART.
abstract: BACKGROUND
  The impact of the emergence of drug-resistance mutations on mortality is not well characterized in antiretroviral-naïve patients first starting highly active antiretroviral therapy (HAART). Patients may be able to sustain immunologic function with resistant virus, and there is limited evidence that reduced sensitivity to antiretrovirals leads to rapid disease progression or death. We undertook the present analysis to characterize the determinants of mortality in a prospective cohort study with a median of nearly 5 y of follow-up. The objective of this study was to determine the impact of the emergence of drug-resistance mutations on survival among persons initiating HAART.
  
  
  RESULTS
  Participants were antiretroviral therapy naïve at entry and initiated triple combination antiretroviral therapy between August 1, 1996, and September 30, 1999. Marginal structural modeling was used to address potential confounding between time-dependent variables in the Cox proportional hazard regression models. In this analysis resistance to any class of drug was considered as a binary time-dependent exposure to the risk of death, controlling for the effect of other time-dependent confounders. We also considered each separate class of mutation as a binary time-dependent exposure, while controlling for the presence/absence of other mutations. A total of 207 deaths were identified among 1,138 participants over the follow-up period, with an all cause mortality rate of 18.2%. Among the 679 patients with HIV-drug-resistance genotyping done before initiating HAART, HIV-drug resistance to any class was observed in 53 (7.8%) of the patients. During follow-up, HIV-drug resistance to any class was observed in 302 (26.5%) participants. Emergence of any resistance was associated with mortality (hazard ratio: 1.75 [95% confidence interval: 1.27, 2.43]). When we considered each class of resistance separately, persons who exhibited resistance to non-nucleoside reverse transcriptase inhibitors had the highest risk: mortality rates were 3.02 times higher (95% confidence interval: 1.99, 4.57) for these patients than for those who did not exhibit this type of resistance.
  
  
  CONCLUSIONS
  We demonstrated that emergence of resistance to non-nucleoside reverse transcriptase inhibitors was associated with a greater risk of subsequent death than was emergence of protease inhibitor resistance. Future research is needed to identify the particular subpopulations of men and women at greatest risk and to elucidate the impact of resistance over a longer follow-up period.
authors.affiliation: British Columbia Centre for Excellence in HIV/AIDS, St. Paul's Hospital, Vancouver, British Columbia, Canada. bobhogg@cfenet.ubc.ca
authors.forename: Robert S
authors.initials: RS
authors.lastname: Hogg
authors.forename: David R
authors.initials: DR
authors.lastname: Bangsberg
authors.forename: Viviane D
authors.initials: VD
authors.lastname: Lima
authors.forename: Chris
authors.initials: C
authors.lastname: Alexander
authors.forename: Simon
authors.initials: S
authors.lastname: Bonner
authors.forename: Benita
authors.initials: B
authors.lastname: Yip
authors.forename: Evan
authors.initials: E
authors.lastname: Wood
authors.forename: Winnie W Y
authors.initials: WW
authors.lastname: Dong
authors.forename: Julio S G
authors.initials: JS
authors.lastname: Montaner
authors.forename: P Richard
authors.initials: PR
authors.lastname: Harrigan
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality* / Q000821:virology; D016333:HIV Protease / Q000235:genetics / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012367:RNA, Viral / Q000097:blood / Q000235:genetics*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D016019:Survival Analysis; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D016333:HIV Protease