Long-term consequences of the delay between virologic failure of highly active antiretroviral therapy and regimen modification

Maya L. Petersen, Mark J. Van Der Laan, Sonia Napravnik, Joseph J. Eron, Richard D Moore, Steven G. Deeks

Research output: Contribution to journalArticle

Abstract

Objectives: Current treatment guidelines recommend immediate modification of anti-retroviral 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. Design/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). Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)2097-2106
Number of pages10
JournalAIDS
Volume22
Issue number16
DOIs
StatePublished - 2008

Fingerprint

Highly Active Antiretroviral Therapy
Protease Inhibitors
Reverse Transcriptase Inhibitors
Mortality
HIV
Confidence Intervals
Therapeutics
Structural Models
Observational Studies
Guidelines
RNA

Keywords

  • Antiretroviral resistance
  • Highly active antiretroviral therapy
  • HIV RNA level monitoring
  • Incomplete viral suppression
  • Inverse probability of treatment weighting
  • Marginal structural models
  • Time-dependent confounding

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Long-term consequences of the delay between virologic failure of highly active antiretroviral therapy and regimen modification. / Petersen, Maya L.; Van Der Laan, Mark J.; Napravnik, Sonia; Eron, Joseph J.; Moore, Richard D; Deeks, Steven G.

In: AIDS, Vol. 22, No. 16, 2008, p. 2097-2106.

Research output: Contribution to journalArticle

Petersen, Maya L. ; Van Der Laan, Mark J. ; Napravnik, Sonia ; Eron, Joseph J. ; Moore, Richard D ; Deeks, Steven G. / Long-term consequences of the delay between virologic failure of highly active antiretroviral therapy and regimen modification. In: AIDS. 2008 ; Vol. 22, No. 16. pp. 2097-2106.
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abstract = "Objectives: Current treatment guidelines recommend immediate modification of anti-retroviral 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. Design/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). Conclusion: 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.",
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AU - Napravnik, Sonia

AU - Eron, Joseph J.

AU - Moore, Richard D

AU - Deeks, Steven G.

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N2 - Objectives: Current treatment guidelines recommend immediate modification of anti-retroviral 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. Design/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). Conclusion: 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.

AB - Objectives: Current treatment guidelines recommend immediate modification of anti-retroviral 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. Design/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). Conclusion: 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.

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