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Background: Sofosbuvir is a potent nucleotide HCV NS5B polymerase inhibitor that is also a P-glycoprotein (encoded by the ABCB1 gene) and breast cancer resistance protein (encoded by the ABCG2 gene) substrate. Concerning previous anti-HCV therapies, pharmacogenetics had a significant impact, particularly considering the association of interleukin28B polymorphisms with dual-therapy (ribavirin + pegylated IFN) outcomes., Objectives: In this work, we investigated the association between sofosbuvir and its prevalent metabolite (GS-331007) plasma concentrations at 1 month of therapy and genetic variants (SNPs) in genes encoding transporters and nuclear factors (ABCB1, ABCG2 and HNF4α) related to sofosbuvir transport., Patients and Methods: Allelic discrimination was performed through real-time PCR, whereas plasma concentrations were evaluated through liquid chromatography. One hundred and thirteen patients were enrolled., Results: Sofosbuvir concentrations were below the limit of quantification since the drug was converted into its GS-331007 metabolite. ABCB1 2677 G>T (P = 0.044) and HNF4α 975 C>G (P = 0.049) SNPs were associated with GS-331007 metabolite plasma concentrations. In linear multivariate analysis, liver stiffness, insulin resistance, baseline haemoglobin and haematocrit and SNPs in the ABCB1 gene (3435 CT/TT and 1236 TT genotypes) were significant predictors of GS-331007 concentrations. Furthermore, we performed sub-analyses considering the anti-HCV concomitant drug and HCV genotype, identifying specific polymorphisms associated with GS-331007 plasma concentrations: ABCB1 3435 C>T and HNF4α975 C>G in patients treated with daclatasvir, ABCB1 2677 G>T with ledipasvir and ABCB1 3435 C>T, ABCB1 2677 G>T, ABCG2 421 C>A and ABCG2 1194 + 928 C>A with ribavirin., Conclusions: In this study we suggested sofosbuvir GS-331007 metabolite plasma levels were affected by variants in the ABCB1 and HNFα genes.

Background: Daclatasvir is an inhibitor of HCV non-structural 5A protein and is a P-glycoprotein substrate. Pharmacogenetics has had a great impact on previous anti-HCV therapies, particularly considering the association of IL-28B polymorphisms with dual therapy outcome., Objectives: We investigated the association between daclatasvir plasma concentrations at 2 weeks and 1 month of therapy and genetic variants (SNPs) in genes encoding transporters and nuclear factors (ABCB1, ABCB11 and HNF4α)., Patients and Methods: Allelic discrimination was achieved through real-time PCR, whereas plasma concentrations were evaluated through LC-MS/MS., Results: Fifty-two patients were analysed, all enrolled in the Kineti-C study. HNF4α 975 C > G polymorphism was found to be associated with the daclatasvir plasma concentrations at 2 weeks (P = 0.009) and 1 month of therapy (P = 0.006). Linear regression analysis suggested that, at 2 weeks of therapy, age, baseline BMI and haematocrit were significant predictors of daclatasvir concentrations, whereas at 1 month of therapy ABCB111131 CC and HNF4α CG/GG genotypes were significant predictors of daclatasvir concentrations., Conclusions: These are the first and preliminary results from our clinical study focusing on daclatasvir pharmacogenetics, showing that this approach could have a role in the era of new anti-HCV therapies., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: To study the association between trough ribavirin concentration (C(trough)) with sustained virological response (SVR) and haemoglobin (Hb) decrease in HIV/hepatitis C virus (HCV)-co-infected (HIV+/HCV+) patients treated with anti-HCV therapy., Methods: HIV+/HCV+ patients treated with ribavirin and pegylated interferon were prospectively evaluated. Qualitative and quantitative HCV-RNA, Hb levels and ribavirin C(trough) were measured at baseline and weeks 2, 4, 12, 24, 36 and 48 during therapy. HCV-RNA was also measured at 24 weeks after the end of therapy. Efficacy analysis was performed on patients with a definitive virological outcome (SVR, relapser and non-responder), whereas for toxicity analysis, dropouts were considered until the last available observation., Results: Fifty-two patients (54.7% with genotype 1 or 4) were included. Overall, no correlation between ribavirin C(trough) and early virological response (EVR) nor SVR was found. However, in patients with genotype 1 or 4, ribavirin C(trough) was independently associated with EVR (P = 0.036) and SVR (P = 0.046). A ribavirin C(trough) cut-off of 1600 ng/mL was found to be associated with both EVR (chi(2) = 5.69, P = 0.028) and SVR (chi(2)=4.2, P = 0.04). Higher ribavirin C(trough) correlated with Hb decrease (R = -0.361, P = 0.009) and was independently associated with an Hb decrease of >4 g/dL (P = 0.009). Receiver operating characteristic (ROC) analysis indicated that a ribavirin C(trough) of >2300 ng/mL was associated with an Hb decrease of >4 g/dL (chi(2) = 8.08, P = 0.01)., Conclusions: Our study confirmed a relationship between ribavirin exposure and both efficacy and toxicity. Moreover, we found ribavirin C(trough) cut-offs for both SVR in genotypes 1 and 4 and overall haematological toxicity. These findings deserve further clinical evaluation.

Objectives: To evaluate the early anti-HIV activity of pegylated interferon (PEG-IFN) alfa-2a and ribavirin in HIV/hepatitis C virus (HCV) co-infected patients not receiving antiretroviral therapy., Patients and Methods: In 19 patients with baseline plasma HIV load (HIV-RNA) >1000 copies/mL treated with PEG-IFN alfa-2a and ribavirin, HIV-RNA and T-cell subsets were measured at baseline and 2, 4 and 12 weeks after initiation of anti-HCV therapy., Results: We observed a significant HIV-RNA decrease (>1 log(10) copies/mL) through week 12 of anti-HCV treatment. The magnitude of HIV-RNA decline was associated with baseline HIV-RNA, CD4 count and PEG-IFN weight-adjusted dose., Conclusions: A significant early anti-HIV activity of PEG-IFN alfa-2a was observed. Such an effect warrants further clinical evaluation in the management of co-infected patients.

Objectives: The optimal regimen for acute hepatitis C (AHC) is considered to be a 24 week treatment with interferon (IFN) alpha-2b. A 24 week treatment with pegylated IFN (PEG-IFN) alpha-2b is also effective. This study was designed to assess response rates to a 12 week regimen of PEG-IFN alpha-2b., Patients and Methods: Patients with AHC were treated with PEG-IFN alpha-2b for 12 weeks in an open, non-randomized, prospective cohort study. Diagnosis of AHC was made with positive serum HCV RNA and elevated alanine aminotransferase (ALT) levels with a documented seroconversion or a known risk factor in the preceding 6 months. Treatment was administered within a median of 31 days (range 0-116) of the ALT level peak at a dosage varying from 1.06 to 1.66 microg/kg/week. The primary end-point was a sustained virological response (SVR)., Results: Nineteen patients were treated, of whom 11 patients (57.9%) had HCV genotype 1. Fourteen patients were asymptomatic. An SVR was achieved in 74% of patients and the SVR rate was 100 and 83.3%, respectively, in genotype 1 and non-1 infected patients treated with a dosage>or=1.33 microg/kg, compared with 40 and 50%, respectively, in those who received a lower dosage. An SVR was significantly associated by multivariate analysis only with PEG-IFN dosage>or=1.33 microg/kg/week. No significant association was found with any viral genotype., Conclusions: The rate of SVR was independent of the HCV genotype and was significantly associated by multivariate analysis only with the higher PEG-IFN dosage. Early identification and treatment of AHC is likely to decrease the burden of chronic hepatitis, especially when caused by HCV genotype 1.