C. Dorival

Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) – NCT01514890

BACKGROUND & AIMSnIn phase III trials, the safety profile of triple therapy (pegylated interferon/ribavirin with boceprevir or telaprevir) seems to be similar in HCV treatment-experienced cirrhotic and non-cirrhotic patients, but few cirrhotics were included. We report the week 16 safety and efficacy analysis in a cohort of compensated cirrhotics treated in the French Early Access Programme.nnnMETHODSn674 genotype 1 patients, prospectively included, received 48 weeks of triple therapy. The analysis is restricted to 497 patients reaching week 16.nnnRESULTSnA high incidence of serious adverse events (40.0%), and of death and severe complications (severe infection or hepatic decompensation) (6.4%), and a difficult management of anaemia (erythropoietin and transfusion use in 50.7% and 12.1%) were observed. Independent predictors of anaemia < 8 g/dl or blood transfusion were: female gender (OR 2.19, 95% CI 1.11-4.33, p=0.024), no lead-in phase (OR 2.25, 95% CI 1.15-4.39, p=0.018), age ≥ 65 years (OR 3.04, 95% CI 1.54-6.02, p=0.0014), haemoglobin level (≤ 12 g/dl for females, ≤ 13 g/dl for males) (OR 5.30, 95% CI 2.49-11.5, p=0.0001). Death or severe complications were related to platelets count ≤ 100,000/mm(3) (OR 3.11, 95% CI 1.30-7.41, p=0.0105) and albumin <35 g/dl (OR 6.33, 95% CI 2.66-15.07, p=0.0001), with a risk of 44.1% in patients with both. However, the on-treatment virological response was high.nnnCONCLUSIONSnThe safety profile was poor and patients with platelet count ≤ 100,000/mm(3) and serum albumin <35 g/L should not be treated with the triple therapy.

Effectiveness of telaprevir or boceprevir in treatment-experienced patients with HCV genotype 1 infection and cirrhosis.

BACKGROUND & AIMSnWe investigated the effectiveness of the protease inhibitors peginterferon and ribavirin in treatment-experienced patients with hepatitis C virus (HCV) genotype 1 infection and cirrhosis.nnnMETHODSnIn the Compassionate Use of Protease Inhibitors in Viral C Cirrhosis study, 511 patients with HCV genotype 1 infection and compensated cirrhosis who did not respond to a prior course of peginterferon and ribavirin (44.3% relapsers or patients with viral breakthrough, 44.8% partial responders, and 8.0% null responders) were given either telaprevir (nxa0= 299) or boceprevir (nxa0= 212) for 48 weeks. We assessed percentages of patients with sustained viral responses 12 weeks after therapy and safety. This observational study did not allow for direct comparison of the 2 regimens.nnnRESULTSnAmong patients given telaprevir, 74.2% of relapsers, 40.0% of partial responders, and 19.4% of null responders achieved SVR12. Among those given boceprevir, 53.9% of relapsers, 38.3% of partial responders, and none of the null responders achieved SVR12. In multivariate analysis, factors associated with SVR12 included prior response to treatment response, no lead-in phase, HCV subtype 1b (vs 1a), and baseline platelet count greater than 100,000/mm(3). Severe adverse events occurred in 49.9% of cases, including liver decompensation, severe infections in 10.4%, and death in 2.2%. In multivariate analysis, baseline serum albumin level less than 35 g/L and baseline platelet counts of 100,000/mm(3) or less predicted severe side effects or death.nnnCONCLUSIONSnRelatively high percentages of real-life, treatment-experienced patients with HCV genotype 1 infection and cirrhosis respond to the combination of peginterferon and ribavirin with telaprevir or boceprevir. However, side effects are frequent and often severe. Baseline levels of albumin and platelet counts can be used to guide treatment decisions. ClinicalTrials.gov number: NCT01514890.

Safety and efficacy of daclatasvir-sofosbuvir in HCV genotype 1-mono-infected patients

BACKGROUND & AIMSnWe report the first real-life results of the sofosbuvir+daclatasvir combination in hepatitis C virus (HCV) genotype 1 infected patients.nnnMETHODSnThe France REcherche Nord&Sud Sida-hiv Hépatites (ANRS) CO22 HEPATHER Therapeutic options for hepatitis B and C: A French cohort is a multicentre observational cohort which aims to include 15,000 HCV- and 10,000 HBV-infected patients. We selected all participants (n=768) with a HCV genotype 1 who initiated sofosbuvir (400mg/day) and daclatasvir (60mg/day) before October 1st 2014, with or without ribavirin (1-1.2g/day) for a duration of 12weeks or 24weeks. The main endpoint criterion was sustained virological response at 12weeks (SVR12), defined by the absence of detectable HCV-RNA 12weeks after the last treatment intake. Missing SVR12 measurements were imputed using SVR24 measurements (n=45), otherwise considered as virological failure (n=18).nnnRESULTSnA SVR12 was obtained in 729/768 (95%) patients, ranging from 92% (12-week sofosbuvir+daclatasvir) to 99% (24-week sofosbuvir+daclatasvir+ribavirin). The SVR12 rates did not significantly differ between the 24-week (550/574 (96%)) and the 12-week (179/194 (92%); p=0.0688) durations or between regimens with (165/169 (98%)) or without ribavirin (564/599 (94%); p=0.0850). The SVR12 rate was greater than 97% in non-cirrhotic patients irrespective of the treatment duration or the addition of ribavirin. Among cirrhotic patients, the SVR12 rate was higher with 24 than 12-week regimen (423/444 (95%) vs. 105/119 (88%); p=0.0054).nnnCONCLUSIONnThe sofosbuvir+daclatasvir combination is associated with a high rate of SVR12 in patients infected by genotype 1, with an optimal duration of 12weeks in non-cirrhotic and 24weeks in cirrhotic patients. The number of patients receiving ribavirin was too low to adequately assess its impact.nnnLAY SUMMARYnThe sofosbuvir+daclatasvir combination of antiviral drugs is associated with a high rate (95%) of viral eradication in patients infected by HCV genotype 1. The best duration of a ribavirin-free sofosbuvir+daclatasvir combination seems to be 12weeks in non-cirrhotic patients and 24weeks for those with cirrhosis. Clinical trial number: NCT01953458.

Using Pharmacokinetic and Viral Kinetic Modeling To Estimate the Antiviral Effectiveness of Telaprevir, Boceprevir, and Pegylated Interferon during Triple Therapy in Treatment-Experienced Hepatitis C Virus-Infected Cirrhotic Patients

ABSTRACT Triple therapy combining a protease inhibitor (PI) (telaprevir or boceprevir), pegylated interferon (PEG-IFN), and ribavirin (RBV) has dramatically increased the chance of eradicating hepatitis C virus (HCV). However, the efficacy of this treatment remains suboptimal in cirrhotic treatment-experienced patients. Here, we aimed to better understand the origin of this impaired response by estimating the antiviral effectiveness of each drug. Fifteen HCV genotype 1-infected patients with compensated cirrhosis, who were nonresponders to prior PEG-IFN/RBV therapy, were enrolled in a nonrandomized study. HCV RNA and concentrations of PIs, PEG-IFN, and RBV were frequently assessed in the first 12 weeks of treatment and were analyzed using a pharmacokinetic/viral kinetic model. The two PIs achieved similar levels of molar concentrations (P = 0.5), but there was a significant difference in the 50% effective concentrations (EC50) (P = 0.008), leading to greater effectiveness for telaprevir than for boceprevir in blocking viral production (99.8% versus 99.0%, respectively, P = 0.002). In all patients, the antiviral effectiveness of PEG-IFN was modest (43.4%), and there was no significant contribution of RBV exposure to the total antiviral effectiveness. The second phase of viral decline, which is attributed to the loss rate of infected cells, was slow (0.19 day−1) and was higher in patients who subsequently eradicated HCV (P = 0.03). The two PIs achieved high levels of antiviral effectiveness. However, the suboptimal antiviral effectiveness of PEG-IFN/RBV and the low loss of infected cells suggest that a longer treatment duration might be needed in cirrhotic treatment-experienced patients and that a future IFN-free regimen may be particularly beneficial in these patients.

The negative impact of HBV/HCV coinfection on cirrhosis and its consequences

Hepatitis B virus (HBV)/hepatitis C virus (HCV) confection has been rarely studied in nonasian series.

Plasma apolipoprotein H limits HCV replication and associates with response to NS3 protease inhibitors‐based therapy

Chronic infection with HCV remains a public health problem with approximately 150 million people infected worldwide. HCV intersects with lipid metabolism for replication and entry; and plasma concentrations of apolipoproteins have been identified as predictors for response to therapy. Herein, we conducted a screen of plasma proteins, including all apolipoproteins, to identify correlates of response to pegylated‐interferon/ribavirin (PR) and HCV non‐structural protein 3 (NS3) inhibitors (i.e., telaprevir/boceprevir) therapy in treatment‐experienced cirrhotic patients from the ANRS CUPIC cohort.

Signal detection on a patient cohort: A disproportionality analysis of the ANRS CO22 HEPATHER cohort to identify associations between direct acting antivirals and adverse events in patients with hepatitis C virus chronic infection

Our aim was to explore a signal detection method for early identification of potential adverse drug reactions (ADRs) in a patient cohort.

Letter: more studies are needed to elucidate the impact of HBV/HCV coinfection on cirrhosis and its consequences-Authors’ reply

1. Pol S, Haour G, Fontaine H, et al. The negative impact of HBV/HCV coinfection on cirrhosis and its consequences. Aliment Pharmacol Ther. 2017;46:1054-1060. 2. WHO Guidelines Approved by the Guidelines Review Committee. Guidelines for the Prevention, Care and Treatment of Persons with Chronic Hepatitis B Infection. Geneva: World Health Organization; 2015. 3. Shiha G, Ibrahim A, Helmy A, et al. Asian-pacific association for the study of the liver (APASL) consensus guidelines on invasive and noninvasive assessment of hepatic fibrosis: a 2016 update. Hepatol Int. 2017;11:1-30. 4. Singh S, Muir AJ, Dieterich DT, Falck-Ytter YT. American gastroenterological association institute technical review on the role of elastography in chronic liver diseases. Gastroenterology. 2017;152:15441577. 5. Seto WK, Hui RW, Mak LY, et al. Association between hepatic steatosis, measured by controlled attenuation parameter, and fibrosis burden in chronic hepatitis B. Clin Gastroenterol Hepatol. 2017. https://doi.org/10.1016/j.cgh.2017.09.044 [Epub ahead of print]. 6. Hui RWH, Seto WK, Cheung KS, et al. Inverse relationship between hepatic steatosis and hepatitis B viremia: results of a large case-control study. J Viral Hepat. 2017. https://doi.org/10.1111/jvh.12766 [Epub ahead of print]. 7. Rafiq N, Younossi ZM. Interaction of metabolic syndrome, nonalcoholic fatty liver disease and chronic hepatitis C. Expert Rev Gastroenterol Hepatol. 2008;2:207-215. 8. Dev A, Patel K, Conrad A, Blatt LM, McHutchison JG. Relationship of smoking and fibrosis in patients with chronic hepatitis C. Clin Gastroenterol Hepatol. 2006;4:797-801. 9. Chang FM, Wang YP, Lang HC, et al. Statins decrease the risk of decompensation in hepatitis B virusand hepatitis C virus-related cirrhosis: a population-based study. Hepatology. 2017;66:896-907. 10. Hodge A, Lim S, Goh E, et al. Coffee intake is associated with a lower liver stiffness in patients with non-alcoholic fatty liver disease, hepatitis C, and hepatitis B. Nutrients. 2017;9. https://doi.org/10. 3390/nu9010056 [Epub ahead of print].