| Dose-limiting adverse events associated with anti-retroviral therapy (ART) generally include gastro-intestinal (GI) issues such as vomiting and nausea. However, serious adverse events (SAEs) do occur, the most frequent of which include liver toxicities and renal impairment as well as recent evidence of cardio-vascular disease (CVD) risk. This safety evaluation of tipranavir, a protease inhibitor, focused on the following three primary endpoints: (1) Single instance of hepatotoxicity (2) Recurrent hepatotoxicity (3) Risk of CVD among those with concomitant abacavir (ABC) drug use For the first endpoint, results indicate that underlying presence of liver disease (+LD) is associated with the development of severe transaminase elevations and clinical hepatic SAEs in treatment-experienced HIV-positive patients receiving ART with TPV/r 500/200 mg BID. The Kaplan-Meier (K-M) cumulative risk estimate of patients with severe transaminase elevations by Week 96 was higher among those with LD (20.6%), compared to those without (12.5%). Many patients who developed severe transaminase elevations on TPV/r therapy were able to continue treatment uninterrupted or resume treatment after temporary discontinuation, with ALT/AST levels returning to DAIDS Grade 2 or less during the treatment period.Recurrent hepatic abnormality events suggested a declining risk of hepatotoxicity associated with TPV/r therapy after the first two instances. Using the Prentice, Williams and Peterson - Counting Process (PWP-CP) model for recurrent events, the hazard ratio (HR) following treatment onset is significant for the first two occurrences of severe transaminase elevations but not for those beyond these first two events. This finding is supported by the Prentice, Williams and Peterson - Gap time model (PWP-GP) model of recurrent events: the increased risk associated with TPV/r was limited to the first occurrence.The analysis of CVD risk associated with exposure to abacavir indicates a significant association for myocardial infarction (MI) but not other CVD events this risk remained significant after controlling for potential confounding variables and other conventional risk factors. Current ABC users, when compared to controls, had a three-fold higher risk of developing an MI. Multivariate analyses revealed glucose level at baseline and current ABC exposure were independently associated with this increased risk of MI. |
