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

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.