Background:  Ribavirin (RBV) plays an important role in the achievement of sustained virological response to hepatitis C virus (HCV) therapy when combined with pegylated interferon (pegIFN). The critical role of RBV exposure seems to be particularly relevant in HIV/HCV-co-infected patients. Inter-individual and intra-individual variations in RBV plasma concentrations during the administration of HCV therapy could influence its efficacy.

Methods:  RBV plasma concentrations were measured at weeks 4, 12, 24, 36, and 48 by high-performance liquid chromatography (HPLC) in all co-infected patients who initiated HCV therapy with pegIFN plus RBV (800 mg if <65 kg; 1000 mg if 65 to 75 kg; 1200 mg if >75 kg) in 2003 in Madrid. Sustained virological response was defined as undetectable HCV RNA 24 weeks after the end of treatment.

Results:  A total of 98 co-infected patients were analyzed. At baseline, median body weight was 67.2 kg; RBV dose, 1000 mg/day. HCV genotype distribution was:  1 (64%), 2 (1%), 3 (33%), 4 (2%). As a consequence of RBV-associated anemia, 15% of patients underwent RBV dose reductions during the treatment period. A significant body weight loss was noticed during anti-HCV treatment (3.4 kg on average at week 48). Mean RBV plasma concentrations throughout the course of treatment was 2.88 mg/mL. While wide inter-individual variability was found, RBV plasma concentrations were relatively stable for each patient during the first 12 weeks of treatment (p = 0.08). However, at weeks 24, 36, and 48, significant increases in median RBV plasma concentrations were observed over values obtained at week 4 (+0.32 µg/mL, p = 0.02; +0.55 µg/mL, p <0.001; and +0.55 µg/mL, p = 0.003, respectively). At week 24, this intra-individual variation significantly correlated with a loss in body weight (p = 0.03). Overall, higher RBV plasma concentrations (p = 0.006) and genotypes 2 and 3 (p = 0.03) were independent predictors of sustained virological response. In genotypes 1 and 4, RBV plasma concentration was the only variable associated with sustained virological response (p = 0.02). In contrast, neither RBV plasma concentrations nor RBV daily dose could predict sustained virological response in genotypes 2 and 3.

Conclusions:  RBV plasma concentrations show a wide inter-individual variability. A higher exposure to RBV as a consequence of significant body weight loss throughout HCV treatment, could determine a significant increase in RBV plasma concentrations for each patient. While continuous exposure to RBV is necessary for achieving sustained virological response in patients infected with genotypes 1 and 4, this is not the case for genotypes 2 and 3.