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Higher Tipranavir Levels in People With Liver Fibrosis
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8th International Workshop on Pharmacology of HIV Therapy
April 16-18, 2007, Budapest
Mark Mascolini
People with "significant" liver fibrosis (a FibroScan-predicted Metavir score at or above 2) were 17 times more likely to have high tipranavir levels than people with less advanced liver disease [1]. Only tipranavir concentrations independently predicted short-term liver toxicity in this single-center retrospective analysis.
The RESIST trials recorded grade 3 or 4 elevated alanine aminotransferase (ALT) in 10% of people taking tipranavir/ritonavir versus 3% of those taking other PIs for 48 weeks, a highly significant difference (P < 0.0001) [2]. To investigate potential interactions between tipranavir/ritonavir, liver toxicity, and liver fibrosis in practice, clinicians at Madrid's Carlos III Hospital measured liver disease markers and tipranavir levels when 66 people started a tipranavir/ritonavir-based salvage regimen and again 12 weeks later.
The study group's age averaged 44 years, and 58 (88%) were men. Average CD4 count stood at 342, viral load at 3.8 log copies/mL (under 10,000 copies), ALT at 43 IU/L, and aspartate aminotransferase (AST) at 39 IU/L. Nineteen people (29%) coinfected with hepatitis C virus (HCV) had an average HCV load of 6.35 log IU/mL, but nobody had a positive hepatitis B surface antigen test.
ALT rose after 12 weeks (P = 0.08) and significantly after 24 weeks of tipranavir therapy (P = 0.03), but AST did not. Univariate analysis (considering one variable at a time) correlated week 0 AST, week 0 ALT, significant fibrosis, HCV coinfection, and tipranavir trough concentrations with AST or ALT elevations at week 12. But in multivariate analysis only tipranavir troughs remained an independent predictor of liver enzyme jumps at 12 weeks, upping the risk 12% for every higher 10-microgram/mL plasma level (P = 0.07). Still, only 3 people in this cohort had grade 3 or 4 liver enzyme elevations in 12 weeks.
Tipranavir levels proved significantly higher in people with versus without significant liver fibrosis, as defined above (P = 0.011). Multivariate statistical analysis singled out only significant fibrosis as an independent predictor of higher tipranavir levels: Significant fibrosis raised that risk 17.38 times (95% confidence interval 1.76 to 32.9, P = 0.03).
The Carlos III team cautioned that, although FibroScan "may be a useful tool to identify patients at risk for tipranavir overexposure, longer follow-up is needed to ascertain whether there is a relationship between greater tipranavir plasma levels and increased risk of liver toxicity."
References
1. Morello J, P. Garcia-Gasco P, Blanco F, et al. Higher plasma levels of tipranavir in patients with more significant liver fibrosis and risk of liver toxicity. 8th International Workshop on Pharmacology of HIV Therapy. April 16-18, 2007. Budapest. Abstract 35.
2. Hicks CB, Cahn P, Cooper DA, et al. Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials. Lancet. 2006;368:466-475.
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