Background:
The objectives of this study were to determine nelfinavir (NFV) and its metabolite M8 (similar activity in vitro as NFV) pharmacokinetic parameters and their variability in HIV/HCV co-infected patients and in HIV-positive controls with negative hepatitis serology, and to evaluate the opportunity of developing individualised dosing strategies for HIV/HCV-positive subjects with liver dysfunction.
 

Methods:
42 HIV+/HCV- patients (mean/SD ALT levels:34.3/27.2 UL), 24 HIV+/HCV+ patients without cirrhosis (mean/SD ALT levels:61.5/51.6 UL) and 14 HIV+/HCV+ patients with cirrhosis confirmed by biopsy (mean/SD ALT levels:110.0/60.6 UL; Child-Pugh grade A: 10 pts,  grade B: 3pts and grade C: 1pt)  were enrolled into the study. All patients were in steady-state treatment with NFV as part of their antiretroviral regimen, at the dosage of 1250mg bid or 750mg tid. For the determination of plasma NFV and M8 concentrations, blood samples (³7 samples per patient) were obtained during the dosing interval. Concentrations of NFV and M8 in plasma were measured simultaneously by a validated high-performance liquid chromatographic method (HPLC) with UV detection. Pharmacokinetic parameters were calculated by model independent analysis. ANOVA was used for statistical analysis of the results.
 

Results:
Compared with HIV+/HCV- patients,  HIV/HCV co-infected patients without and with cirrhosis had significantly (p<0.05) lower “oral” clearance (CL/F) values by  35% and 65%, respectively. This was manifested as 58% and 155% higher AUC_0-24 of NFV, respectively. The mean/SD NFV+M8 AUC0-24 value, normalized to a dosage of 2500 mg/day,  was 90.55/33.44 mg.h/mL in HIV+/HCV- pts, 122.68/41.92 mg.h/mL in HIV+/HCV+ pts without cirrhosis and 198.20/110.84 mg.h/mL in HIV+/HCV+ pts with cirrhosis; the differences between all three studied groups were statistically significant. The metabolic M8/NFV ratio in HIV+/HCV- pts was 0.27 and decreased by 25% and 80% in HIV/HCV+ pts without  and with cirrhosis, respectively.
 

Conclusions:
An average NFV dose reduction of 25% in HIV/HCV coinfected pts without cirrhosis and of 50% in HIV/HCV coinfected pts with cirrhosis , ensuring the same systemic exposure to NFV + M8 as in HIV+/HCV- pts, should be useful to maintain antiviral efficacy and possibly to improve tolerance.