April 10, 2015

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By Will Boggs MD

April 02, 2015

NEW YORK (Reuters Health) - Fibroblast growth factor-2 (FGF-2) and other non-interferon mediators contribute to hepatitis C virus (HCV) reinfection after liver transplantation, researchers from Germany report.

"We have identified FGF-2 and the signaling cascade triggered by it as an unexpected novel driver of HCV replication," Dr. Sandra Ciesek from Medizinische Hochschule Hannover told Reuters Health by email. "Hence, it is important to be aware that modulation of host signaling cascades (e.g., certain novel anti-cancer drugs, such as brivanib, that block FGF signaling) may have unexpected effects on viral replication."

While orthotopic liver transplantation is the only treatment for end-stage liver disease due to HCV infection, it is not a cure, and nearly all patients develop graft reinfection.

Dr. Ciesek and colleagues set out to determine how the inflammatory response that occurs in the peritransplantation period modulates the HCV replication cycle and whether it contributes to the poor outcome of HCV-positive individuals after liver transplant.

All 13 transplant recipients (three of whom had HCV) showed marked rises in C-reactive protein levels between pre-transplant and post-transplant sera, but there was heterogeneity in the changes of serum chemokines and no apparent association with the etiology of liver disease.

Among 27 non-interferon inflammatory mediators examined by the researchers, FGF-2 alone enhanced HCV RNA replication and release of infectious particles, they report in Gut, online March 23.

In contrast, FGF-1, a close relative of FGF-2, did not enhance HCV RNA replication.

The effects of FGF-2 appeared to be mediated by signaling through FGF receptor 3 (FGFR3).

In 70 individuals with chronic HCV infection, serum FGF-2 levels were significantly higher in those with high viral load than in those with low viral load.

The investigators are now studying which exact downstream events triggered by FGF-2 and FGFR3 are required for HCV replication.

"Right now there is an enormous opportunity to prevent the majority of post-transplant HCV reinfection events by using direct antiviral agent combinations that have reached the market during the past 15 months," Dr. Ciesek said. "We do not anticipate that modulation of the host serum milieu (or FGF2 signaling) will play a major role here."

"There remains a minority of patients -- those with very advanced liver disease and concomitant renal failure -- that cannot be treated with the currently available regimens," she added. "Thus, new approaches may be needed for this subgroup of patients. It is conceivable that modulation of host factors or host signaling pathways might play a role here."

SOURCE: http://bit.ly/1GgGAwe

Gut 2015.

Source

Lancet. 2015 Mar 21;385(9973):1075-86. doi: 10.1016/S0140-6736(14)61795-5. Epub 2014 Nov 11.

Lawitz E1, Gane E2, Pearlman B3, Tam E4, Ghesquiere W5, Guyader D6, Alric L7, Bronowicki JP8, Lester L9, Sievert W10, Ghalib R11, Balart L12, Sund F13, Lagging M14, Dutko F15, Shaughnessy M15, Hwang P15, Howe AY15, Wahl J15, Robertson M15, Barr E15, Haber B15.

Erratum in Lancet. 2015 Mar 21;385(9973):1074.

Abstract

BACKGROUND: There is a high medical need for an interferon-free, all-oral, short-duration therapy for hepatitis C virus (HCV) that is highly effective across diverse patient populations, including patients with cirrhosis or previous null response to pegylated interferon (peginterferon) plus ribavirin (PR-null responders). We aimed to assess the efficacy, safety, and effective treatment duration of grazoprevir (an HCV NS3/4A protease inhibitor) combined with elbasvir (an HCV NS5A inhibitor) with or without ribavirin in patients with HCV genotype 1 infection with baseline characteristics of poor response.

METHODS: The C-WORTHY trial is a randomised, open-label phase 2 trial of grazoprevir plus elbasvir with or without ribavirin; here we report findings for two cohorts of previously untreated patients with cirrhosis (cohort 1) and those with previous PR-null response with or without cirrhosis (cohort 2) enrolled in part B of the study. Eligible patients were adults aged 18 years or older with chronic HCV genotype 1 infection and HCV RNA concentrations of 10 000 IU/mL or higher in peripheral blood. We randomly assigned patients to receive grazoprevir (100 mg daily) and elbasvir (50 mg daily) with or without ribavirin for 12 or 18 weeks. Randomisation was done centrally with an interactive voice response system; patients and study investigators were masked to treatment duration up to week 12 but not to treatment allocation. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL at 12 weeks after end of treatment (SVR12), assessed by COBAS TaqMan version 2.0. This study is registered with ClinicalTrials.gov, number NCT01717326.

FINDINGS: We describe findings for 253 patients enrolled in cohort 1 (n=123) or cohort 2 (n=130). In cohort 1, we randomly assigned 60 patients to the 12-week regimen (31 with ribavirin and 29 with no ribavirin) and 63 to the 18-week regimen (32 with ribavirin and 31 with no ribavirin); in cohort 2, we randomly assigned 65 patients to the 12-week regimen (32 with ribavirin and 33 with no ribavirin) and 65 to the 18-week regimen (33 with ribavirin and 32 with no ribavirin. High SVR12 rates were achieved irrespective of the use of ribavirin or extension of the treatment duration from 12 to 18 weeks; SVR12 rates ranged from 90% (95% CI 74-98; 28/31; cohort 1, 12 weeks, ribavirin-containing) to 100% (95% CI 89-100; 33/33; cohort 2, 18 weeks, ribavirin-containing). Among patients treated for 12 weeks with grazoprevir plus elbasvir without ribavirin, 97% (95% CI 82-100, 28/29) of patients in cohort 1 and 91% (76-98, 30/33) of patients in cohort 2 achieved SVR12. Adverse events reported in more than 10% of patients were fatigue (66 patients, 26% [95% CI 21-32]), headache (58 patients, 23% [95% CI 18-29]), and asthenia (35 patients, 14% [95% CI 10-19]).

INTERPRETATION: Treatment with grazoprevir plus elbasvir, both with and without ribavirin and for both 12 and 18 weeks' treatment duration, showed high rates of efficacy in previously untreated patients with cirrhosis and previous PR-null responders with and without cirrhosis. These results support the phase 3 development of grazoprevir plus elbasvir.

FUNDING:

Merck & Co, Inc.

Copyright © 2015 Elsevier Ltd. All rights reserved.

PMID: 25467591 [PubMed - indexed for MEDLINE]

Source

Hepatology. 2015 Apr;61(4):1127-35. doi: 10.1002/hep.27726. Epub 2015 Mar 10

Nelson DR1, Cooper JN, Lalezari JP, Lawitz E, Pockros PJ, Gitlin N, Freilich BF, Younes ZH, Harlan W, Ghalib R, Oguchi G, Thuluvath PJ, Ortiz-Lasanta G, Rabinovitz M, Bernstein D, Bennett M, Hawkins T, Ravendhran N, Sheikh AM, Varunok P, Kowdley KV, Hennicken D, McPhee F, Rana K, Hughes EA; ALLY-3 Study Team.

Author information

1University of Florida, Gainesville, FL.

Abstract

Treatment options for patients with hepatitis C virus (HCV) genotype 3 infection are limited, with the currently approved all-oral regimens requiring 24-week treatment and the addition of ribavirin (RBV). This phase III study (ALLY-3; ClinicalTrials.gov: NCT02032901) evaluated the 12-week regimen of daclatasvir (DCV; pangenotypic nonstructural protein [NS]5A inhibitor) plus sofosbuvir (SOF; pangenotypic NS5B inhibitor) in patients infected with genotype 3. Patients were either treatment naïve (n = 101) or treatment experienced (n = 51) and received DCV 60 mg plus SOF 400 mg once-daily for 12 weeks. Coprimary endpoints were the proportions of treatment-naïve and treatment-experienced patients achieving a sustained virological response (SVR) at post-treatment week 12 (SVR12). SVR12 rates were 90% (91 of 101) and 86% (44 of 51) in treatment-naïve and treatment-experienced patients, respectively; no virological breakthrough was observed, and ≥99% of patients had a virological response (VR) at the end of treatment. SVR12 rates were higher in patients without cirrhosis (96%; 105 of 109) than in those with cirrhosis (63%; 20 of 32). Five of seven patients who previously failed treatment with an SOF-containing regimen and 2 of 2 who previously failed treatment with an alisporivir-containing regimen achieved SVR12. Baseline characteristics, including gender, age, HCV-RNA levels, and interleukin-28B genotype, did not impact virological outcome. DCV plus SOF was well tolerated; there were no adverse events (AEs) leading to discontinuation and only 1 serious AE on-treatment, which was unrelated to study medications. The few treatment-emergent grade 3/4 laboratory abnormalities that were observed were transient.

CONCLUSION: A 12-week regimen of DCV plus SOF achieved SVR12 in 96% of patients with genotype 3 infection without cirrhosis and was well tolerated. Additional evaluation to optimize efficacy in genotype 3-infected patients with cirrhosis is underway. (Hepatology 2015;61:1127-1135).

© 2015 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.

PMID: 25614962 [PubMed - in process]

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