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

Abstract

Objectives: 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.

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.

Figure 1

Conditional hazard ratios estimated using weighted pooled logistic regression, with weights used to control for confounding of time until treatment modification, baseline differences between subjects failing a protease inhibitor vs. reverse transcriptase inhibitor regimen, and potentially informative censoring. Hazard ratios for reverse transcriptase inhibitor regimens in the UNCHCC following 2^nd HAART failure not reported due to small sample size (N=31). PI: failing regimen contains protease inhibitor; Non-PI: failing regimen does not contain protease inhibitor; Death: endpoint is all-cause mortality; CD4 failure: endpoint is composite of all-cause mortality and immunologic failure; JHHCC 1^st failure/JHHCC 2^nd failure: among subjects in JHHCC experiencing first and second HAART failures, respectively; UNC 1^st failure/UNC 2^nd failure: among subjects in UNCHCC experiencing first and second HAART failures, respectively.

Figure 2

Conditional hazard of mortality over time, plotted for a range of delay times until treatment modification. Estimates based on weighted pooled logistic regression, with weights used to control for confounding of time until treatment modification, baseline differences between subjects failing a protease inhibitor vs. reverse transcriptase inhibitor regimen, and potentially informative censoring. The Deletion/Substitution/Addition algorithm was used to model the conditional hazard of all-cause mortality as a function of time since failure occurred and months spent on failing regimen, making minimal parametric assumptions. A. Among subjects failing a protease inhibitor regimen. B. Among subjects failing a reverse transcriptase inhibitor regimen.