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Indinavir/RTV 400/100mg in Co-infection
Reported by Jules Levin
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INDINAVIR-RITONAVIR REGIMEN (400 MG/100 MG BID) IN HIV/HCV CO-INFECTED PATIENTS IN THE HEPADOSE STUDY: THE RELATIONSHIP BETWEEN PROTEASE INHIBITORS PLASMA CONCENTRATIONS AND LIVER LESIONS
S Dominguez1, Y Benhamou1, G Peytavin2, M Astriti1, A Simon1, R Agher1,
V Calvez1, and C Katlama1 1 Pitie-Salptrire Hospital; and 2 Bichat-Claude Bernard Hospital, Paris, France
Comments from Jules Levin: This study comes from a well known group of French HIV and HCV researchers. The study is a start in understanding the effect of HIV on hepatitis in co-infected patients. The results suggest implications regarding indinavir dosing in co-infected patients, but the study does not distinguish IDV blood levels between patients with earlier hepatitis syage disease F0/1 vs F2 vs F3/F4. All HCV stages are lumped together so we don't know if perhaps IDV dosing might be different for F1 vs F4. All HIV drug companies should however be doing these types of studies. The EMEA and the FDA have recently issued guidelines to HIV drug companies requesting that they study the effect of all HIV drugs on the liver of HCV/HIV co-infected patients. We need appropriately designed studies that will yield good answers to the key questions. Based on the data below I'm not convinced this study yields good and adequate answers to all the questions raised by the study.
Antiretroviral drugs hepatotoxicity is frequent in HIV patients particularly in HIV/HCV co-infected patients (pts). Whether this toxicity could be related to impaired drug metabolism remains to be determined.
The objective of the study is to compare plasma antiretroviral drug concentrations in HIV-HCV and in HIV infected pts in order to analyse the relationship between drug concentrations and liver lesions.
The Hepadose study is an ongoing study where plasma ARV concentrations were measured in HIV/HCV pts with a documented liver biopsy and a stable ARV regimen. Co-infected pts will be matched to a control group of HIV pts. Plasma HIV-1 RNA, HCV RNA levels, CD4 cell count, fibrosis markers, routine chemistry
and Cmin and Cmax serum IDV and RTV using HPLC methods were
measured and drug adverse effects were recorded.
Among the 63 co-infected pts already included, we report here results of the 19 pts receiving an IDV/RTV (400/100 mg bid) containing regimen. They were 16 males, 16 IVDU, with a median age of 39 years. Median duration of HVC infection before liver biopsy was 17.2 years. HCV genotype (G) distribution G2/3 (0/7 pts) and G1/4 (11/1 pts), liver fibrosis scores F0 (2 pts), F1 and F2 (9 pts), F3 and F4 (8 pts), activity scores A0 (1 pt), A1 and A2 (16 pts), A3 (1 pt) and median percentage of steatosis was 19.2%. They have been for a median time of 208 days on this regimen.
Twelve pts (63.15%) had an HIV RNA below 200 copies/ml, median CD4 cell count was 283/µl.
Median Cmin and Cmax were 229 and 2073 ng/ml for IDV and 454 and 1217 ng/ml for RTV. IDV Cmin was below 150 ng/ml in 3 non- adherent pts and >625
ng/ml in 1 pt (3346 ng/ml). No significant relationship between IDV plasma concentrations and fibrosis or inflammatory scores and no severe adverse effects were found.
According to my reading of the new PHHS Guidelines issued in July 2003 at the IAS Conference, indinavir Cmin should be at least 100ng/ml.
The authors conclude that these interim results shows that 80% of pts using an IDV/RTV containing regimen had adequate, non toxic and effective IDV and RTV Cmin despite HIV/HCV co-infection and fibrosis.
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