Mortality among HIV+ participants randomized to omit NRTIs vs. Add NRTIs in options (ACTG A5241)

Background: OPTIONS enrolled treatment experienced participants with virologic failure who then started a new regimen after randomization to omit or add NRTIs. In the primary week 48 analysis, we found that omitting NRTIs was not inferior to adding NRTIs (CROI 2013, 153LB). In this analysis, we examined all-cause mortality. Methodology: A5241 enrolled 360 subjects who had PI, NNRTI and NRTI experience and/or viral resistance. Personalized regimens with 3-4 ARVs (excluding NRTIs) having >2 active drugs, and NRTI combinations were selected; subjects were then randomized to add or omit NRTIs with the new regimen. All subjects were followed for 96 weeks for outcomes including mortality. Since mortality events were rare, exact logistic regression models using one covariate estimated exact odds ratios (eOR). Results: During the screening process, when all subjects continued the failing NRTI-containing regimen (median duration 51 days), the mortality rate was 4.15/100 patient-years [p-y] (3 deaths). Following study entry and initiation of study treatment, there was only 1 death (0.31/100 p-y) among those omitting NRTIs (n=177); this participant died of trauma and pneumonia. Among those adding NRTIs (n=180), there were 10 deaths (3.1/100 p-y); these occurred at <24 wks (3), 24-48 wks (2), 48-72 wks (2), 72-96 wks (3) after study entry. Causes of death (with contributing factors) included heart failure (lymphoma) (1), cardiac disease (2), E. coli sepsis (liver failure, acute renal failure, HCV+) (1), cirrhosis (intra-abdominal bleed, HCV+) (1), listeria meningitis (1), pneumonia (2), PML (1) and renal failure (IRIS, hepatitis, autoimmune enteropathy) (1). All 10 add NRTI participants had initial virologic response to treatment. Ability to identify factors associated with death is limited due to the rarity of events, especially by arm. VACS mortality index using baseline values was a significant predictor of mortality (eOR=1.9 per 10 unit increase, 95% CI = 1.3-2.8), whereas individual components of the index were not significantly associated: age (p=.17), hemoglobin (p=0.25), creatinine clearance (p=0.11), CD4 (0.91), HIV RNA (p=0.18), Hepatitis C (p=0.12). Conclusions: In a randomized study that omitted vs. added NRTIs to new regimens, an unexplained imbalance in mortality was observed with only one death in the omit NRTI arm. Interpretation of the mortality difference is difficult because of the small number of events (11) and the potential for unmeasured confounders. The VACS mortality index was useful in predicting mortality in this treatment experienced population.