Early Monitoring of Ribavirin Plasma Concentrations May Predict Anemia and Early Virologic Response in HIV/Hepatitis C Virus-Coinfected Patients

Abstract

Ribavirin (RBV) in combination with pegylated interferon alpha (pegIFN) is currently the standard treatment of hepatitis C virus (HCV) infection. The development of anemia requires a reduction in RBV doses in a substantial proportion of patients, limiting their chances of treatment response. The primary goal of this study was to assess if early monitoring of RBV plasma levels could help to predict anemia as well as early HCV RNA response in HIV/HCV-coinfected individuals. The secondary goal was to evaluate if antiretroviral drugs might influence RBV plasma levels. Plasma RBV concentrations were measured at weeks 4 and 12 in 98 HIV/HCV-coinfected individuals who initiated therapy with pegIFN-2a (180 microg/wk) plus RBV (800-1200 mg/d). RBV plasma levels correlated with RBV dose per kilogram of body weight (P = 0.02). Larger drops in hemoglobin levels were independently associated with higher RBV plasma levels and zidovudine (ZDV) use (P < 0.001). Likewise, higher RBV levels (P = 0.007) and HCV genotype 3 (P < 0.001) were found to be independent predictors of virologic response at week 4. Similar findings were obtained at week 12. Patients receiving ZDV concomitantly showed significantly higher RBV plasma concentrations compared with those who did not (3.28 mug/mL vs. 2.51 mug/mL; P = 0.002). RBV levels were not significantly altered by the coadministration of other nucleoside/nucleotide analogues. In summary, RBV plasma levels correlate with the development of anemia and with the achievement of an early virologic response. Therefore, early therapeutic drug monitoring might help to tailor RBV dosages, improving the efficacy and safety of anti-HCV treatment.

Association of ITPA polymorphisms rs6051702/rs1127354 instead of rs7270101/rs1127354 as predictor of ribavirin-associated anemia in chronic hepatitis C treated patients

“…Otherwise, it has been demonstrated that anemia is related to the intra-erythrocytic and plasma concentrations of RBV (Caviglia et al, 2012;D'Avolio et al, 2012a;D'Avolio et al, 2013;D'Avolio et al, 2012c;De Franceschi et al, 2000;De Nicolò et al, 2013;Kubota et al, 2010;Loustaud-Ratti et al, 2008;Loustaud-Ratti et al, 2011;Morello et al, 2008;Rendon et al, 2005), moreover RBV plasma and intra-erythrocytic concentrations are correlated with the RBV doses taken by patients. Otherwise, RBV concentration is not only dependent on the administered dose, but also on body weight, absorption (nucleoside transporters and food effect) and excretion.…”

“…Among these, the only modifiable feature is RBV pharmacokinetic exposure, which shows a remarkable variability among HCV-infected patients (Tsubota et al, 2003). In fact, early assessment of RBV concentration is suggested by some studies (Caviglia et al, 2012;D'Avolio et al, 2012a;Loustaud-Ratti et al, 2008;Morello et al, 2008;Rendon et al, 2005) in order to adjust individual RBV dose.…”

“…Beside ITPA polymorphisms, a series of individual features such as RBV concentration, age, platelet count, haemoglobin concentration and haptoglobin phenotype were found to have some degree of association with the risk of anemia (Caviglia et al, 2012;D'Avolio et al, 2012a;Lindahl et al, 2004;Nomura et al, 2004;Rendon et al, 2005;van Vlerken et al, 2011;Van Vlierbergh et al, 2001). Among these, the only modifiable feature is RBV pharmacokinetic exposure, which shows a remarkable variability among HCV-infected patients (Tsubota et al, 2003).…”

Population Pharmacokinetic Modeling of Plasma and Intracellular Ribavirin Concentrations in Patients with Chronic Hepatitis C Virus Infection

“…It is difficult to predict which patients will develop hemolytic anemia from ribavirin treatment. Prior studies have found an association between hemoglobin decline and increased ribavirin concentrations in plasma (15,16) and RBCs (17). Another study found that total intracellular ribavirin concentrations in RBCs, but not plasma levels, were significantly correlated with hemoglobin decline, which suggested that ribavirin levels in RBC would be a preferable parameter for assessing ribavirin-induced hemolytic anemia (18).…”

Plasma Ribavirin Trough Concentrations at Week 4 Predict Hepatitis C Virus (HCV) Relapse in HIV-HCV-Coinfected Patients Treated for Chronic Hepatitis C

“…The association between RBV C trough and relapse supports the essential role of RBV exposure in the clearance of HCV and highlights the idea that besides influencing the early decay of HCV clearance (18,19), it may influence as well the risk of HCV relapse independently of any effect on RVR, as recently shown in trials testing HCV protease inhibitors (9,10). This observation is important since monitoring of RBV C trough at week 4 might allow adaptation strategies to maximize the chances of cure with standard HCV therapy.…”