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  11th International Workshop on Clinical Pharmacology of HIV Therapy
Sorrento, Italy
April 7-9, 2010
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Higher Darunavir and Raltegravir Levels in
Small Study of People With Liver Disease

  11th International Workshop on Clinical Pharmacology and HIV Therapy, April 7-9, 2010, Sorrento
Mark Mascolini
Levels of darunavir and raltegravir, both mainly metabolized by the liver, were higher in HIV-infected people with moderate to severe liver disease than in a comparison group of HIV-positive people without liver problems [1]. Darunavir troughs were substantially higher in people with cirrhosis than in people with more moderate liver impairment.
This small case-control study involved 5 Caucasian men coinfected with HIV and hepatitis C virus (HCV) who started a regimen containing both the integrase inhibitor raltegravir and the protease inhibitor darunavir. Researchers at Rome's INMI Lazzaro Spallanzani Infectious Diseases Department collected blood samples from these 5 men 14 and 30 days after their started their raltegravir/darunavir-based regimen. They compared raltegravir and darunavir levels in these men with levels in 24 people without HCV who were taking these two drugs for HIV.
The 5 HIV/HCV-coinfected men averaged 48 years in age (+/- 5 standard deviation). They had been infected with HIV for an average 16 years and had an average lowest-ever CD4 count of 58 and an average body mass index of 23 kg/m(2) (+/- 1.3). Along with raltegravir and darunavir, 2 men were taking a second protease inhibitor, 2 were taking two nucleosides, and 1 was taking a nonnucleoside. Ultrasonography indicated that 3 men had cirrhosis (Child Pugh stage B) and 2 had chronic active HCV-related hepatitis.
Raltegravir trough concentrations averaged 637 ng/mL in the men with liver impairment versus 221 ng/mL in the HCV-negative controls. The 3 men with cirrhosis had a raltegravir trough of 665 ng/mL, compared with 581 ng/mL in the 2 HIV/HCV-coinfected men without cirrhosis.
Darunavir troughs in coinfected men averaged 8519 ng/mL, compared with 3236 ng/mL in the control group. Darunavir troughs averaged 9820 ng/mL in the 3 men with cirrhosis versus 2016 ng/mL in the 2 coinfected men without cirrhosis.
Virologic and immunologic results were similar in the 3 men with cirrhosis and the 2 without cirrhosis, and antiretroviral safety over the course of this study did not differ between these two groups. One of the men with cirrhosis died 1 month after starting the raltegravir/darunavir regimen because of acute liver and kidney disease.
On the basis of this small case-control comparison, the investigators suggest "special caution in the use of raltegravir, and especially of darunavir, in patients with moderate to severe liver impairment because of the risk of additive toxicity."
US prescribing information already advises clinicians to "monitor liver function before and during therapy [with darunavir/ritonavir], especially in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases." For raltegravir, US prescribing information cites "no clinically important pharmacokinetic differences between subjects with moderate hepatic impairment and healthy subjects" but cautions that "the effect of severe hepatic impairment on the pharmacokinetics of raltegravir has not been studied."
1. Tommasi C, Nicastri E, Gallo AL, et al. Raltegravir and darunavir plasma pharmacokinetic in HIV-1 infected patients with advanced liver disease. 11th International Workshop on Clinical Pharmacology and HIV Therapy. April 7-9, 2010. Sorrento. Abstract 10.