Inosine triphosphatase polymorphisms and ribavirin pharmacokinetics as determinants of ribavirin-associate anemia in patients receiving standard anti-HCV treatment.

BACKGROUND: Functional variants of inosine triphosphatase (ITPA) were recently found to protect against ribavirin (RBV)-induced hemolytic anemia. However, no definitive data are yet available on the role of plasma RBV concentrations on hemoglobin (Hb) decrement. Moreover, no data have been published on the possible interplay between these 2 factors. METHODS: A retrospective analysis included 167 patients. The ITPA variants rs7270101 and rs1127354 were genotyped and tested using the χ test for association with Hb reduction at week 4. We also investigated, using multivariate logistic regression, the impact of RBV plasma exposure on Hb concentrations. RESULTS: Both single nucleotide polymorphisms were associated with Hb decrease. The carrier of at least 1 variant allele in the functional ITPA single nucleotide polymorphisms was associated with a lower decrement of Hb (-1.1 g/dL), as compared with patients without a variant allele (-2.75 g/dL; P = 4.09 × 10). RBV concentrations were not influenced by ITPA genotypes. A cut-off of 2.3 µg/mL of RBV was found to be associated with anemia (area-under-receiver operating characteristic = 0.630, sensitivity = 50.0%, and specificity = 69.5%, P = 0.008). In multivariate logistic regression analyses, the carrier of a variant allele (P = 0.005) and plasma RBV concentrations <2.3 µg/mL (P = 0.016) were independently associated with protection against clinically significant anemia at week 4. CONCLUSIONS: Although no direct relationship was found between ITPA polymorphisms and plasma RBV concentrations, both factors were shown to be significantly associated with anemia. A multivariate regression model based on ITPA genetic polymorphisms and RBV trough concentration was developed for predicting the risk of anemia. By relying upon these 2 variables, an individualized management of anemia seems to be feasible in recipients of pegylated interferon-RBV therapy.

Pharmacokinetic and pharmacodynamic determinants of early virological response to enfuvirtide-based regimens in HIV-positive patients.

BACKGROUND: Early virological response (VR) to enfuvirtide-based salvage regimens at week 12 has been described as a predictor of long-term therapeutic success. The relationship between enfuvirtide plasma exposure and VR has not yet been investigated in the clinical setting. Our aim was to investigate the role of enfuvirtide plasma exposure as a determinant of early VR in the clinical setting. METHODS: Forty-two multidrug-experienced patients starting a salvage enfuvirtide-based regimen were prospectively evaluated over a 12 week period. HIV-RNA levels and enfuvirtide C(trough) were regularly measured. VR was considered as achievement of viral load (VL) undetectability and/or a decrease of more than 1 log at week 12. RESULTS: Optimized background score (OBS) and enfuvirtide C(trough) concentrations were associated with VL decrease at week 12. An OBS > or =2 and enfuvirtide C(trough) >2100 ng/mL were associated with VR. The pharmacokinetic/pharmacodynamic (PK/PD) analysis confirmed this exposure-response relationship both in the total population and in different groups according to OBS <2 or > or =2. Higher estimates of IC(50) were calculated for the OBS <2 group when compared with the OBS > or =2 group (7551 versus 2330 ng/mL, respectively), without a marked difference in I(0) (0.31 versus 0.21 log) and I(max) (-2.64 versus -3.33 log). CONCLUSIONS: Enfuvirtide plasma exposure and OBS were found to significantly influence the magnitude and rate of early VR. The PK/PD modelling of enfuvirtide concentrations was different in our clinical setting, compared with previous data obtained under trial conditions. Therefore, optimization of enfuvirtide plasma exposure could deserve further evaluation as a determinant of therapeutic response in HIV-positive patients.