Liver Toxicity Associated with Ritonavir-boosted Tipranavir

The RESIST 1 and 2 trials showed the superior efficacy of ritonavir-boosted tipranavir (Aptivus) over comparator boosted protease inhibitors in treatment-experienced patients.

However, some concern remains with regard to liver toxicity in patients taking tipranavir/ritonavir, prompting a data analysis presented at the 46th ICAAC conference, held last week in San Francisco.

The RESIST trials enrolled a total of 1485 participants. The present analysis included 1206 patients who had completed at least 24 weeks of treatment; approximately 50% had completed 48 weeks.

Study participants had advanced HIV disease. About 10% in the tipranavir arms and 15% in the comparator PI arms were co-infected with hepatitis C and/or hepatitis B virus (HCV or HBV).

Throughout the studies, researchers monitored patients' liver function tests (LFTs), including measurement of the liver enzymes ALT and AST.

Results

Emergent Grade 3 or 4 LFT abnormalities were more common with tipranavir/ritonavir (74 patients; 9.9%) than with comparator PIs (26 patients; 3.5%).

Cox analyses identified HCV and/or HBV coinfection as a risk factor for Grade 3-4 LFT elevations with tipranavir/ritonavir (RR = 2.1) and with comparator PIs (RR = 2.5).

In the tipranavir/ritonavir arm, coinfected patients were at increased risk compared with subjects without coinfection.

Elevated baseline LFTs were also a risk factor in both arms.

Of the 74 patients in the tipranavir/ritonavir arm who developed Grade 3-4 LFT elevations, 4 experienced serious liver-related adverse events.

57 patients (77%) remained on their assigned treatment (47 uninterrupted and 10 after temporary interruption).

32 out of the 47 patients on uninterrupted treatment had their LFT elevations decrease to Grade 2 or less.

14 of the 47 had stable LFTs, and only 1 patient experience elevation by 1 grade.

Of the 10 patients who temporarily interrupted tipranavir/ritonavir, LFT elevations decreased to Grade 2 or lower in half and remained at Grade 3 in 1; 4 patients did not have prior LFT elevations before re-challenge.

17 patients with Grade 3-4 LFT elevations (out of 748 total patients in the tipranavir arms; 2.3%) discontinued tipranavir/ritonavir.

Among these 17 patients, 5 (0.7%) developed serious liver-related adverse events.

4 patients had their liver enzyme elevations resolve after discontinuing tipranavir/ritonavir.

1 patient with elevated bilirubin died of multi-organ failure.

Conclusion

In conclusion, the authors wrote, "While LFT elevations were observed in the RESIST studies, only 2.3% of patients who received tipranavir/ritonavir discontinued therapy due to emergent Grade 3-4 [elevations]. Among these patients, hepatic serious adverse events were rare."

They added that, "Hepatic monitoring should occur frequently throughout the course of therapy with tipranavir/ritonavir. The majority of patients (77%) who developed Grade 3-4 LFT [elevations] were able to continue therapy."

Johns Hopkins University School of Medicine, Baltimore, MD; University of Bonn, Bonn, Germany; Hospital Carlos III, Madrid, Spain; Boehringer Ingelheim, Ridgefield, CT.

10/03/06

Reference
M Sulkowski, J Rockstroh, V Soriano, and others. Clinical Course of Increased LFTs and Hepatic Events Associated with Ritonavir (RTV)-Boosted Tipranavir (TPV/r) Based Therapy in RESIST Trials. 46th ICAAC. San Francisco, CA. September 27-30, 2006. Abstract H-1899.

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