Background:  Since the introduction of HAART, a growing number of patients have had virologic failure. Although the risk of death appears to increase when effective ART is no longer available, no study has been sufficiently large to quantify the clinical factors that predict time to death after multiple-HAART failure. In a collaboration of U.S. and Canadian cohorts, we investigated the calendar trend of multiple HAART failure and factors associated with mortality after virologic failure of at least 2 distinct HAART regimens.

Methods:  Representing more than 60 sites, 16 cohorts contributed data on 30,768 HIV-infected individuals who initiated HAART. Among this group, we identified those who demonstrated virologic failure (HIV-1 RNA >1000 copies/mL), modified therapy (change in non-NRTI ART), and subsequently had a second virologic failure. From the cohort of second virologic failures, multivariate Cox regression was used to assess demographic and clinical factors associated with mortality.

Results:  Of the 30,768 individuals who received HAART, 12,938 progressed to first virologic failure, 7552 had a regimen change, and 3162 had a second virologic failure. The risk of second virologic failure declined over time from 1996 to 1997 (95/100 person-years) to 2004to 2005 (13/100 person-years, adjusted RR = 0.42, p <0.001). There were 10,885 preson-years of follow-up and 865 (27%) deaths after the second virologic failure; median time from second virologic failure to death was 6.5 years. Cumulative mortality was 3.7% at 1 year and 35.6% at 5 years. Factors that were associated with mortality after second virologic failure are shown. ARV experience prior to first HAART, number of distinct HAART regimens prior to second virologic failure, time from first HAART, and pre-HAART CD4 and HIV-1 RNA were not associated with mortality.   

                        * p < 0.05, ** p <0.01, ***p <0.001 

Conclusions:  The risk of progressing to a second episode of VF on HAART has declined dramatically over the past decade.  Patients at highest risk for death after 2^nd VF according to these factors should be managed as quickly as possible during VF.