Simone Mornese Pinna

Treatment with daclatasvir and sofosbuvir for 24 weeks without ribavirin in cirrhotic patients who failed first-generation protease inhibitors

BackgroundTreatment of patients with chronic hepatitis C who failed the triple therapy with first generation of protease inhibitors is not still defined. The combined use of sofosbuvir (SOF) and daclatasvir (DCV) seems to be promising due to higher genetic barrier, good tolerance and effectiveness.MethodsWe described the treatment with this drug combination in a real-life cohort of 20 cirrhotic patients with genotype 1 who failed the triple therapy.Results18 of them (90%) with Child–Pugh A, 11 (55%) with genotype 1a, 17 (85%) with more than 1 and 8 (40%) with more than 2 previous failed treatment; all patients had at baseline NS3 resistance-associated variants related to triple therapy failure. RBV was not administered due to anemia in previous treatments. The sustained virological response was 100%.ConclusionTreatment with SOF + DCV without RBV for 24 weeks is safe and effective in cirrhotic patients who failed triple therapy with the first generation of protease inhibitors.

Influence of ABCB11 and HNF4α genes on daclatasvir plasma concentration: preliminary pharmacogenetic data from the Kineti-C study

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.

Vitamin D pathway genetic variants are able to influence sofosbuvir and its main metabolite pharmacokinetics in HCV mono-infected patients

Vitamin D levels and genetic variants were associated with drug outcome/toxicity and concentrations. The plasma exposure of GS-331007, the main sofosbuvir metabolite, has been related to SVR. We evaluated the impact of polymorphisms in genes (CYP27B1, CYP24A1, VDBP and VDR) related to vitamin D pathway on sofosbuvir and GS-331007 plasma levels in HCV mono-infected patients at one month of treatment. Polymorphisms were investigated through real-time PCR; drug plasma quantification was performed through a UHPLC-MS/MS method. GS-331007 levels were associated with CYP24A1rs2248359 and VDRCdx2 variants in all the analyzed patients and linear regression analysis showed that sex, body mass index, HCV genotype, baseline estimated glomerular filtration rate, VDRCdx2AG/GG and CYP27B1-1260TT genotypes significantly predict concentrations. We performed sub-analyses considering the HCV genotype and the concomitant drug, identifying polymorphisms associated with GS-331007 concentrations. This is the first study focusing on vitamin D pathway gene variants and DAAs concentrations, but further studies are required.

Pharmacogenetics of the anti-HCV drug sofosbuvir: a preliminary study

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.

Role of simeprevir plasma concentrations in HCV treated patients with dermatological manifestations

BACKGROUND AND AIMS Up till now the role of simeprevir plasma concentrations has not been described in treated patients affected by chronic hepatitis C and with dermatological side-effects. In this study, we have evaluated a possible relationship between plasma levels and the onset of skin complaints for the first time. METHODS We report a clinical and pharmacokinetic analysis of 56 patients treated with simeprevir-based therapies. RESULTS Simeprevir plasma concentrations were significantly related to dermatological side-effects at early time-points (P<0.001). In logistic regression, simeprevir concentrations at 1 week was the best predictive factor forskin symptoms (OR=1.901, 95%IC: 1.001-2.304; P=0.007). CONCLUSION Simeprevir plasma measurements could be a useful tool in a real-life clinical setting for prevention of dermatological symptoms.

Daclatasvir Plasma Levels in a Cohort of Patients with Hepatitis C Virus Infection Taking Methadone: A Prospective Analysis

Backround: The effect of methadone (MET) during therapy with novel direct-acting antiviral agents is still not fully understood. Currently, no data are available about the influence of MET on daclatasvir (DCV) plasma levels in patients affected by chronic hepatitis C (CHC). The aim of this study was to assess the DCV plasma concentrations in patients treated with sofosbuvir (SOF) plus DCV, with or without ribavirin (RBV) and with or without MET. Methods: In this analysis, 47 patients were included, treated consecutively with SOF + DCV ± RBV for 24 weeks, from May to October 2015; 22 (46.8%) received MET substitutive therapy. Results and Conclusion: We found a significant difference in DCV levels at 2 weeks and 1 month: 150 ng/mL in patients without MET and 313 ng/mL with MET at 2 weeks (p < 0.001), 149 and 279 ng/mL at 1 month (p = 0.006). DCV levels were lower in cirrhotic patients (p < 0.001); among cirrhotic patients we also evidenced higher DCV concentrations in patients receiving MET at 2 weeks, 1 and 2 months (p < 0.001, p = 0.005, and p = 0.031, respectively). In multivariate analysis, the only predictive factor associated with DCV plasma levels was the presence of MET. The reason for this increased DCV exposure is unclear; on the clinical side, we have not observed significant adverse events related to the reduction or increase of MET plasma levels. The administration of MET in patients with advanced fibrosis or cirrhosis leads to an early increase of DCV plasma level without significant clinical effects or toxicity.