Risk of Liver Toxicity in HIV Patients Treated with Tipranavir (Aptivus) is Related to Hepatitis C Coinfection, Liver Fibrosis, and Drug Levels

Liver toxicity is a potential side effect of certain antiretroviral drugs, and the risk is higher in people with pre-existing liver disease. However, there is less data available for newer agents such as the second-generation protease inhibitor tipranavir (Aptivus).

As reported at the recent 4th International AIDS Society Conference on HIV Treatment, Pathogenesis, and Prevention in Sydney, Australia (July 22-25, 2007), Spanish researchers performed a study to assess the safety and pharmacokinetics of tipranavir in patients with different stages of liver fibrosis.

The retrospective analysis included all 66 patients who started ritonavir-boosted tipranavir as part of a salvage regimen at Hospital Carlos III in Madrid. Most (88%) were men, the mean age was 44 years, the mean CD4 count was 292 cells/mm3, and the mean HIV viral load was 3.8 log copies/mL. The mean AST and ALT levels were both 43 IU/L. While 19 patients were HCV RNA positive, none was hepatitis B surface antigen positive. Advanced liver fibrosis was seen in 14 patients (29%) patients (9 with stage F3 and 5 with F4).

Liver enzymes levels, liver fibrosis (by FibroScan), and tipranavir plasma levels were recorded at baseline and every 12 weeks during tipranavir/ritonavir therapy.

Results

• The mean tipranavir level at 12 weeks was 36 mcg/mL.

• ALT increased significantly during follow-up, especially in patients with stage F4 fibrosis.

• Tipranavir levels significantly correlated with ALT elevations at week 24 (P=0.02).

• Grade 3/4 ALT elevations were seen in 4 patients, all of whom had high tipranavir levels.

• 2 patients with liver cirrhosis experienced variceal bleeding.

• Tipranavir levels were greater in patients with liver fibrosis scores of F3/F4 compared with the rest (51 vs 30 mcg/mL; P=0.02).

• Overall, HIV-HCV coinfected patients had higher tipranavir levels than HCV-uninfected subjects.

• In a multivariate analysis, only liver fibrosis was associated with greater tipranavir levels (P=0.04).

Conclusion

"Liver enzyme elevations in patients treated with tipranavir are more common in patients with advanced liver fibrosis and/or in patients with high tipranavir plasma levels," the researchers concluded.

They recommended that, "Since plasma concentrations of tipranavir are increased in patients with advanced liver fibrosis, assessment of liver fibrosis stage in coinfected patients with non-invasive tools such as Fibroscan and therapeutic drug monitoring may be helpful to identify patients at risk for tipranavir overexposure."

08/10/07

Reference
P Garcia-Gasco, J Morello, P Barreiro, and others. The risk of liver toxicity in HIV patients treated with tipranavir is related to hepatitis C, liver fibrosis stage and plasma drug levels. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Sydney, Australia, July 22-25, 2007. Abstract MOPEB058.