Emergence of Drug Resistance Is Associated with an Increased Risk of Death among Patients First Starting HAART
Open Access
- 19 September 2006
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Medicine
- Vol. 3 (9), e356
- https://doi.org/10.1371/journal.pmed.0030356
Abstract
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. 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. 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.Keywords
This publication has 23 references indexed in Scilit:
- Adherence–resistance relationships for protease and non-nucleoside reverse transcriptase inhibitors explained by virological fitnessAIDS, 2006
- Predictors of HIV Drug‐Resistance Mutations in a Large Antiretroviral‐Naive Cohort Initiating Triple Antiretroviral TherapyThe Journal of Infectious Diseases, 2005
- Antiretroviral Resistance among HIV‐Infected Persons Who Have Died in British Columbia, in the Era of Modern Antiretroviral TherapyThe Journal of Infectious Diseases, 2004
- Effect of Medication Adherence on Survival of HIV-Infected Adults Who Start Highly Active Antiretroviral Therapy When the CD4+ Cell Count Is 0.200 to 0.350 × 109 cells/LAnnals of Internal Medicine, 2003
- Six-year follow-up of HIV-1-infected adults in a clinical trial of antiretroviral therapy with indinavir, zidovudine, and lamivudineAIDS, 2003
- Continued CD4 cell count increases in HIV-infected adults experiencing 4 years of viral suppression on antiretroviral therapyAIDS, 2003
- Antiretroviral Concentrations in Untimed Plasma Samples Predict Therapy Outcome in a Population with Advanced DiseaseThe Journal of Infectious Diseases, 2003
- Is there a baseline CD4 cell count that precludes a survival response to modern antiretroviral therapy?AIDS, 2003
- Prevalence of primary HIV drug resistance among seroconverters during an explosive outbreak of HIV infection among injecting drug usersAIDS, 1999
- Quantitative detection of HIV-1 drug resistance mutations by automated DNA sequencingNature, 1993