Emergence of drug resistance is associated with an increased risk of death among patients first starting HAART

Robert S. Hogg, David Bangsberg, Viviane D. Lima, Chris Alexander, Simon Bonner, Benita Yip, Evan Wood, Winnie W Y Dong, Julio S G Montaner, P. Richard Harrigan

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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. Methods and Findings: 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 followup 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. Copyright:

Original languageEnglish (US)
Pages (from-to)1570-1578
Number of pages9
JournalPLoS Medicine
Volume3
Issue number9
DOIs
StatePublished - 2006
Externally publishedYes

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Highly Active Antiretroviral Therapy
Drug Resistance
Mortality
Mutation
Reverse Transcriptase Inhibitors
HIV
Confidence Intervals
Protease Inhibitors
Proportional Hazards Models
Disease Progression
Cohort Studies
Prospective Studies
Viruses
Survival
Therapeutics
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Medicine(all)

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Emergence of drug resistance is associated with an increased risk of death among patients first starting HAART. / Hogg, Robert S.; Bangsberg, David; Lima, Viviane D.; Alexander, Chris; Bonner, Simon; Yip, Benita; Wood, Evan; Dong, Winnie W Y; Montaner, Julio S G; Harrigan, P. Richard.

In: PLoS Medicine, Vol. 3, No. 9, 2006, p. 1570-1578.

Research output: Contribution to journalArticle

Hogg, RS, Bangsberg, D, Lima, VD, Alexander, C, Bonner, S, Yip, B, Wood, E, Dong, WWY, Montaner, JSG & Harrigan, PR 2006, 'Emergence of drug resistance is associated with an increased risk of death among patients first starting HAART', PLoS Medicine, vol. 3, no. 9, pp. 1570-1578. https://doi.org/10.1371/journal.pmed.0030356
Hogg, Robert S. ; Bangsberg, David ; Lima, Viviane D. ; Alexander, Chris ; Bonner, Simon ; Yip, Benita ; Wood, Evan ; Dong, Winnie W Y ; Montaner, Julio S G ; Harrigan, P. Richard. / Emergence of drug resistance is associated with an increased risk of death among patients first starting HAART. In: PLoS Medicine. 2006 ; Vol. 3, No. 9. pp. 1570-1578.
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abstract = "Background: The impact of the emergence of drug-resistance mutations on mortality is not well characterized in antiretroviral-na{\"i}ve 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. Methods and Findings: Participants were antiretroviral therapy na{\"i}ve 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 followup 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. Copyright:",
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AU - Hogg, Robert S.

AU - Bangsberg, David

AU - Lima, Viviane D.

AU - Alexander, Chris

AU - Bonner, Simon

AU - Yip, Benita

AU - Wood, Evan

AU - Dong, Winnie W Y

AU - Montaner, Julio S G

AU - Harrigan, P. Richard

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N2 - 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. Methods and Findings: 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 followup 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. Copyright:

AB - 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. Methods and Findings: 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 followup 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. Copyright:

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