Daclatasvir plus sofosbuvir, with or without ribavirin, for hepatitis C virus genotype 3 in a French early access programme.

BACKGROUND & AIMS: Optimally effective treatment for hepatitis C virus genotype 3 (GT3) is urgently needed, particularly in advanced liver disease. Daclatasvir plus sofosbuvir was efficacious in phase 3 studies. Real-world data for daclatasvir+sofosbuvir in advanced GT3 infection are presented from the French Temporary Authorisation for Use programme, which allowed patients in need without other treatment options access to daclatasvir ahead of its market authorization. METHODS: Patients with F3/F4 fibrosis and/or extrahepatic hepatitis C virus manifestations, post-liver transplant hepatitis C virus recurrence and/or indication for liver/kidney transplant, were treated with daclatasvir+sofosbuvir (60+400 mg daily) for a recommended duration of 24 weeks. Addition of ribavirin and/or shorter treatment was at physician's discretion. The primary efficacy analysis was sustained virological response at post-treatment week 12 (SVR12; modified intention-to-treat). Safety was assessed by spontaneous adverse event reporting. RESULTS: The efficacy population comprised 333 patients, mostly cirrhotic (77%, of whom 18% were decompensated) and treatment experienced (72%). After 24 weeks of daclatasvir+sofosbuvir, SVR12 was 89% (174/196) overall (95% CI 83.6-92.5%), 98% (43/44) without cirrhosis (95% CI 88.2-99.6%) and 86% (129/150) with any degree of cirrhosis (95% CI 79.5-90.7%), without SVR12 increase in those who received additional ribavirin for 24 weeks (SVR12 82% [50/61; 95% CI 70.5-89.6%]). Among 516 GT3-infected patients with safety data, 5 discontinued for adverse events and 11 died. CONCLUSIONS: Daclatasvir+sofosbuvir achieved high SVR12 rates and was well tolerated in this large real-world cohort of GT3-infected patients with advanced liver disease, without benefit of ribavirin in those treated 24 weeks.

[Regional differences in hospitalisations for complications of chronic hepatitis C in 2012]. / Disparités régionales des hospitalisations pour complication de l'hépatite chronique C en 2012.

Objective: Only limited recent information is available concerning the regional incidence and prevalence of chronic hepatitis C (CHC), but this information is critical for optimal definition of public health policies for the management of hepatitis C. The objective of this study was to evaluate the feasibility of mapping potential regional differences in the prevalence of CHC and its complications using data from a health administrative database. Methods: The 2012 PMSI MCO hospital database contains information on diagnosis and healthcare resource use, essentially related to all hospitalisations in France. Hospital stays related to CHC were identified on the basis of ICD-10 disease codes. Hospital stays were classified according to stage of liver disease: non-cirrhotic liver disease, compensated cirrhosis, decompensated cirrhosis or hepatocellular carcinoma (HCC). All study variables were documented for each French administrative region in 2012. Results: In 2012, 12,040 patients were hospitalised in France for a reason related to CHC, corresponding to a standardised age- and gender- adjusted prevalence rate of 19.3/100,000 persons. The highest prevalences of CHC and HCC were observed in the Ile de France, Alsace and Provence-Alpes-Côte-d'Azur regions. Conclusions: This study demonstrates the feasibility of using the PMSI database to identify regional differences in the prevalence of CHC. This information may be useful for planning regional healthcare resource provision for CHC.

Real-World Efficacy of Daclatasvir and Sofosbuvir, With and Without Ribavirin, in HIV/HCV Coinfected Patients With Advanced Liver Disease in a French Early Access Cohort.

BACKGROUND: Efficacious, well-tolerated, direct antiviral agents have drastically changed the prognosis of hepatitis C virus (HCV) disease, but real-world data for oral treatments are limited in key populations such as HIV/HCV coinfection with advanced liver disease. Daclatasvir (DCV) efficacy and safety was assessed in the French "Autorisation Temporaire d'Utilisation" (ATU) program, providing DCV ahead of market authorization to patients with advanced HCV disease without other treatment options. METHODS: This was a subanalysis of HIV/HCV coinfected ATU patients treated with DCV plus sofosbuvir (SOF). Recommended duration was 24 weeks; addition of ribavirin (RBV) and/or shorter treatment was at the physician's discretion. The primary efficacy analysis was sustained virologic response at posttreatment week 12 (SVR12; modified intention-to-treat). Safety was assessed by spontaneous adverse event reporting. RESULTS: The efficacy population (N = 407) was mostly cirrhotic (72%, of whom 18% were decompensated), HCV treatment-experienced (82%), and infected with genotypes 1 (69%), 3 (12%), or 4 (19%). Median CD4 was 555 cells/mm; 95% had HIV RNA <50 copies/mL. Most (74%) were treated for 24 weeks; 14% received RBV. SVR12 was 92% overall (95% confidence interval: 88.6% to 94.0%); 90% (86.4% to 93.2%) in patients with cirrhosis; 95% (88.9% to 97.5%) in patients without cirrhosis. SVR12 was consistent across HCV genotypes and antiretroviral regimens. Among 617 patients with safety data, 7 discontinued for an adverse event and 10 died. CONCLUSIONS: DCV+SOF±RBV achieved high SVR12 and was well tolerated in this large real-world cohort of HIV/HCV coinfected patients with advanced liver disease.

Chronic hepatitis C: Burden of disease and cost associated with hospitalisations in France in 2012 (The HEPC-LONE study).

BACKGROUND AND OBJECTIVE: This retrospective hospital database analysis aimed to determine the burden and cost of hospitalisations related to chronic hepatitis C (CHC) infections in France in 2012. METHODS: All hospital stays with CHC (ICD-10 code B18.2) coded as the principal, related or significantly associated diagnosis were extracted from the French National Hospital database 2012 (PMSI). Hospitalisations not directly related to CHC were excluded. Patients were assigned to a liver disease stage, namely non-cirrhotic liver disease, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma or post-liver transplantation. Costing was performed using French national tariffs and expressed in 2013 Euros. We documented 22,056 hospital stays involving 12,040 patients who were considered to be directly related to CHC. Of these stays, 11,779 (53.4%) were documented in patients with severe complications (decompensated cirrhosis, hepatocellular carcinoma or liver transplantation). RESULTS AND CONCLUSIONS: The mean number and duration of hospital stays increased with disease severity. Overall, 1181 patients (9.8%) died during hospitalisation. The total cost of hospital stays for CHC was estimated to be € 61 million, of which 26.4% were attributable to hepatocellular carcinoma, 32.5% to post-liver transplantation and 21.0% to decompensated cirrhosis. Compared with a previous analysis in 2009, the number of patients hospitalised fell by 22%, although the patients hospitalised were overall more severely ill. The total cost of hospitalisation decreased by 8%, with a notably marked reduction in the number of biopsies performed (32%). This study illustrates the persistently high burden of CHC infections in France.

Role of cytokines in the assessment of the severity of chronic hepatitis C and the prediction of response to therapy.

AIMS: (i) To characterize serum levels of pro/anti-inflammatory cytokines in non-cirrhotics with hepatitis C; (ii) to correlate levels of these cytokines with degree of disease at baseline; and (iii) to characterize the immuno-modulatory effects of therapy with response. METHODS: We studied 103 patients that were part of randomized, controlled, clinical trials. Serum cytokines were measured using enzyme-linked immunosorbent assay. RESULTS: Using standard therapy in the presence and absence of ribavirin, the sustained responders had lower baseline tumor necrosis alpha (TNF-alpha) levels as compared to relapsed responders and non-responders. In patients receiving pegylated therapy, the degree of inflammation as determined by histology was paralleled by high TNF-alpha levels at baseline. In pegylated combination therapy with high dose ribavirin, lower levels of TNF-alpha, transforming growth factor beta (TGF-beta) and fibrosis scores were seen when comparing baseline with follow up. In sustained responders, regardless of therapy, the histological activity scores were lower at follow up as compared to baseline. CONCLUSIONS: Pegylated combination therapy reduces and sustains TNF-alpha levels and liver inflammation as shown by the histological activity index. In addition, it is able to reduce fibrosis as judged both by TGF-beta levels and fibrosis scores as compared to standard therapy.

Serum tumour necrosis factor-alpha and transforming growth factor-beta levels in chronic hepatitis C patients are immunomodulated by therapy.

Our aims were: (i) to characterize serum levels of tumour necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta) in non-cirrhotics with hepatitis C; (ii) to correlate levels of theses cytokines with degree of disease at baseline; (iii) to characterize the immunomodulatory effects of therapy with response and (iv) to compare profiles of cytokines in patients treated with pegylated-interferon alpha-2b monotherapy (PMT) vs its combination with ribavirin (PCT1-low dose ribavirin and PCT2-high dose ribavirin). We studied 56 patients that were part of two randomized, controlled, clinical trials. At baseline, high TNF-alpha levels paralleled the degree of inflammation as determined by histology. In PCT2, a significant reduction was seen in levels of TNF-alpha, TGF-beta and fibrosis scores when comparing baseline with follow-up. In sustained responders, regardless of therapy, the histological activity scores were lower at follow-up as compared to baseline. In conclusion, PCT2 is able to constantly reduce and sustain TNF-alpha levels, which is responsible for the sustained decline in liver inflammation as shown by the histological activity index and it is also able to reduce fibrosis as judged both by TGF-beta levels and fibrosis scores.