Showing posts with label geno2. Show all posts
Showing posts with label geno2. Show all posts

Monday, May 14, 2018

Elbasvir and grazoprevir with or without ribavirin, treatment–naive participants HCV genotype 2, 4, 5 or 6

Patients with non-genotype 1 HCV infection differ with regard to response to DAAs. This study evaluated the efficacy and safety of EBR/GZR, with or without RBV, in HCV genotype 2, 4, 5, or 6 infection.

A. Brown C. Hézode E. Zuckerman G. R. Foster A. Zekry S. K. Roberts F. Lahser C. Durkan C. Badshah B. Zhang M. Robertson J. Wahl E. Barr B. Haber on behalf of the C‐SCAPE Study Investigators

J Viral Hepat. 2018;25(5):457-464. 

Introduction
People with hepatitis C virus (HCV) infection other than genotype 1 represent a heterogeneous group of individuals who differ with regard to their profile of response to all–oral, direct–acting antiviral regimens.[1,2] The recent approval of sofosbuvir/velpatasvir for people infected with HCV genotypes 1–6 now provides a single treatment option across genotypes. However, prior to the introduction of sofosbuvir/velpatasvir, treatment recommendations for genotype 2, 3, 5 and 6 were based on small studies with limited numbers of participants, or on subgroup analyses where small numbers of participants were enrolled alongside participants with genotype 1 or 4 infection.

The fixed–dose combination of elbasvir (EBR, MK–8742), an NS5A inhibitor, and grazoprevir (GZR, MK–5172), an NS3/4A protease inhibitor, is approved in the US, Europe and Canada as a treatment for HCV genotype 1 and 4 infection.[12] In those with HCV genotype 1 or 4 infection, EBR/GZR has shown efficacy in the subpopulations of treatment–naive people,[13] HIV/HCV co–infected people,[14] people who have previously failed treatment[15,16] and people with chronic kidney disease.[17] In vitro, EBR and GZR have shown pangenotypic potency in HCV replicons;[18,19] however, less has been reported about the clinical efficacy and safety of EBR/GZR in people with HCV nongenotype 1/4 infection. The phase 2 C–SCAPE study evaluated the efficacy and safety of EBR/GZR, with or without ribavirin (RBV), in treatment–naive participants with HCV genotype 2, 4, 5 or 6 infection...

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Tuesday, April 10, 2018

Sweden-Introduction of second-generation direct-acting antivirals in HCV:Register-based Study

Introduction of the second-generation direct-acting antivirals (DAAs) in chronic hepatitis C: a register-based study in Sweden
P. Frisk, K. Aggefors T. Cars N. Feltelius S. A. LoovB. Wettermark O. Weiland

First Online: 09 April 2018

The conditions for introducing the first six of the second-generation direct-acting antivirals for chronic hepatitis C infection in Sweden were outlined in a national introduction protocol. The overall cure rate was estimated to 96%, with some variation between genotypes. Despite regional variation in other cost containment strategies, the high level of adherence to recommendations among prescribers and similar introduction rates in the regions indicate that the protocol contributed considerably to a rapid uptake and equal distribution of DAAs in Sweden.

Full-Text

Abstract
Purpose Introduction of the direct-acting antivirals (DAAs) for treatment of chronic hepatitis C (CHC) infection has been challenging in all health systems. In Sweden, a national protocol for managed introduction was developed. It was optional, but all county councils agreed to implement and follow it. The purpose of this study was to study (a) cure rates among all patients initiated on treatment in 2014–2015, (b) prescribers’ adherence to the drug recommendations and treatment eligibility criteria in the protocol, and (c) introduction rate in the six Swedish healthcare regions.

Method
A cross-sectional study where national data from the Prescribed Drug Register and the quality register InfCare Hepatitis defined the study population, and clinical data from the Patient Register and InfCare Hepatitis were used to monitor outcomes. Descriptive statistics were used.

Results
A total of 3447 patients were initiated on treatment during 2014–2015. The overall cure rate, based on data from 85% of the cohort, was 96%, with variation between genotypes. Adherence to drug recommendations increased over time and varied between 43.2 and 94.2%. Adherence to the treatment eligibility criteria was initially 80% and increased to 87% when treatment restrictions were widened. The introduction rate differed initially between the regions and reached stable levels 15–18 months after the launch of the first DAA.

Conclusion
The estimated overall cure rate was 96%, with some variations between genotypes. A high level of adherence to the introduction protocol as well as similar introduction rates in the health care regions indicate that the introduction protocol, alongside with other measures taken, contributed considerably to a rapid uptake and equal distribution of DAAs in Sweden.

Continuer reading online: https://link.springer.com/article/10.1007%2Fs00228-018-2456-y

Friday, February 9, 2018

HCV infection and liver cirrhosis - Predictors of functional benefit of hepatitis C therapy in a ‘real-life’ cohort

World J Gastroenterol. Feb 21, 2018; 24(7): 852-861
Published online Feb 21, 2018. doi: 10.3748/wjg.v24.i7.852

Retrospective Study
Predictors of functional benefit of hepatitis C therapy in a ‘real-life’ cohort
Niels Steinebrunner, Kerstin Stein, Catharina Sandig, Thomas Bruckner, Wolfgang Stremmel, Anita Pathil

Therapeutic regimens for patients with chronic hepatitis C virus (HCV) infection have substantially improved over the last few years. However real-life data in patients with cirrhosis are still limited, and predictors of functional benefit of direct-acting antivirals are not well defined. We analysed data from patients with HCV infection and liver cirrhosis to evaluate predictors of functional benefit for identifying patients profiting most from antiviral therapy beyond HCV eradication.


Abstract
AIM
To define predictors of functional benefit of direct-acting antivirals (DAAs) in patients with chronic hepatitis C virus (HCV) infection and liver cirrhosis.

METHODS
We analysed a cohort of 199 patients with chronic HCV genotype 1, 2, 3 and 4 infection involving previously treated and untreated patients with compensated (76%) and decompensated (24%) liver cirrhosis at two tertiary centres in Germany. Patients were included with treatment initiation between February 2014 and August 2016. All patients received a combination regimen of one or more DAAs for either 12 or 24 wk. Predictors of functional benefit were assessed in a univariable as well as multivariable model by binary logistic regression analysis.

RESULTS
Viral clearance was achieved in 88% (175/199) of patients. Sustained virological response (SVR) 12 rates were as follows: among 156 patients with genotype 1 infection the SVR 12 rate was 90% (n = 141); among 7 patients with genotype 2 infection the SVR 12 rate was 57% (n = 4); among 30 patients with genotype 3 infection the SVR 12 rate was 87% (n = 26); and among 6 patients with genotype 4 infection the SVR 12 rate was 67% (n = 4). Follow-up MELD scores were available for 179 patients. A MELD score improvement was observed in 37% (65/179) of patients, no change of MELD score in 41% (74/179) of patients, and an aggravation was observed in 22% (40/179) of patients. We analysed predictors of functional benefit from antiviral therapy in our patients beyond viral eradication. We identified the Child-Pugh score, the MELD score, the number of platelets and the levels of albumin and bilirubin as significant factors for functional benefit.

CONCLUSION
Our data may contribute to the discussion of potential risks and benefits of antiviral therapy with individual patients infected with HCV and with advanced liver disease.

Full Text

Sunday, January 28, 2018

Efficacy of direct-acting antiviral treatment for chronic hepatitis C: A single hospital experience

World J Hepatol. Jan 27, 2018; 10(1): 88-94
Published online Jan 27, 2018. doi: 10.4254/wjh.v10.i1.88

Efficacy of direct-acting antiviral treatment for chronic hepatitis C: A single hospital experience

Rena Kaneko, Natsuko Nakazaki, Risa Omori, Yuichiro Yano, Masazumi Ogawa, Yuzuru Sato

Abstract
AIM
To evaluate the efficacy of direct-acting antivirals (DAAs) in Kanto Rosai Hospital.

METHODS
All patients with hepatitis C virus (HCV) who underwent DAA prescription were enrolled in this study. The present study was a single center retrospective analysis using patients infected with HCV genotype 1 or 2. Resistance analysis was performed by using direct sequencing and cycleave PCR in genotype 1 patients treated with interferon (IFN)-free DAA. The primary endpoint was sustained virologic response at 12 wk after therapy (SVR12).

RESULTS
A total of 117 patients participated in the study, including 135 with genotype 1 and 42 with genotype 2. Of the 135 patients with genotype 1, 16 received protease inhibitor + IFN + ribavirin and all achieved SVR. Of the 119 patients who received IFN-free DAA (in different combinations), 102 achieved SVR and 9 failed (7/9 were on daclatasvir/asunaprevir and 2/9 on ledipasvir/sofosbuvir). Efficacy analysis was done only for 43 patients who received daclatasvir/asunaprevir. From this analysis, Y93 resistance-associated substitutions were significantly correlated with SVR.

CONCLUSION
The SVR rate was 98% for genotype 1 and 100% for genotype 2. However, caution is needed for HCV NS5A resistance-associated substitutions that are selected by HCV NS5A inhibitors because cerebrovascular adverse events are induced by some DAA drugs.

Key Words: Resistance-associated substitutions, Direct-acting antivirals, Sustained viral response, Hepatitis C

Core tip:
Direct-acting antivirals have been approved for the treatment of hepatitis C virus (HCV) genotype 1 and 2 infections in Japan since 2011. In the new era of DAA therapy, predictors who fail to respond to DAA might be compromised by resistance-associated substitutions. There have been few reports of daclatasvir/asunaprevir failure because daclatasvir/asunaprevir is limited in Japan. Therefore, it might be important to report these cases for future research and treatment of HCV.

Tuesday, September 26, 2017

Most patients with HCV genotypes 2, 4, 5, 6 achieve SVR with Mavyret

Most patients with HCV genotypes 2, 4, 5, 6 achieve SVR with Mavyret
Asselah T, et al. Clin Gastroenterol Hepatol. 2017;doi:10.1016/j.cgh.2017.09.027.
September 26, 2017
Most patients with hepatitis C genotype 2, 4, 5 or 6 who received Mavyret for 8 weeks achieved sustained virologic response with a high safety profile, according to results from three phase 3 studies. The rate of virologic failure was less than 1%.

Sunday, September 24, 2017

Sofosbuvir plus ribavirin treatment of HCV genotype 2: results of the real-world, clinical practice HCV-TARGET study

Effectiveness and safety of sofosbuvir plus ribavirin for the treatment of HCV genotype 2 infection: results of the real-world, clinical practice HCV-TARGET study
Tania M Welzel1, David R Nelson2, Giuseppe Morelli2, Adrian Di Bisceglie3, Rajender K Reddy4, Alexander Kuo5, Joseph K Lim6, Jama Darling7, Paul Pockros8, Joseph S Galati9, Lynn M Frazier10, Saleh Alqahtani11, Mark S Sulkowski11, Monika Vainorius7, Lucy Akushevich7, Michael W Fried7, Stefan Zeuzem1 for the HCV-TARGET Study Group

Full Text

In summary, in this large, international cohort study, the all-oral combination of SOF and RBV was safe and effective for treatment of HCV GT2. While response rates in patients without cirrhosis were high and comparable with those reported in clinical trials, the presence of lower albumin levels and liver cirrhosis was associated with lower SVR12 rates. Larger, randomised trials in patients with cirrhosis are required to determine the benefit of extended treatment durations of SOF and RBV in this patient group. Recent studies showed that combined SOF and valpatasvir (ASTRAL-1, ASTRAL-2) yielded SVR12 rates of up to 100% in patients with GT2 and cirrhosis, so that the combination of SOF and a GT2-active NS5A inhibitor for 12 weeks may be preferable to SOF and RBV for more than 12 weeks in patients with GT2 and liver cirrhosis.

Abstract
Objective Due to a high efficacy in clinical trials, sofosbuvir (SOF) and ribavirin (RBV) for 12 or 16 weeks is recommended for treatment of patients with HCV genotype (GT) 2 infection. We investigated safety and effectiveness of these regimens for GT2 in HCV-TARGET participants.

Design HCV-TARGET, an international, prospective observational study evaluates clinical practice data on novel antiviral therapies at 44 academic and 17 community medical centres in North America and Europe. Clinical data were centrally abstracted from medical records. Selection of treatment regimen and duration was the investigator's choice. The primary efficacy outcome was sustained virological response 12 weeks after therapy (SVR12).

Results Between December 2013 and April 2015, 321 patients completed 12 weeks (n=283) or 16 weeks (n=38) of treatment with SOF and RBV. Prior treatment experience and cirrhosis was more frequent among patients in the 16-week regimen compared with 12 weeks (52.6% vs 27.6% and 63.2% vs 21.9%, respectively). Overall, SVR12 was 88.2%. The SVR12 in patients without cirrhosis was 91.0% and 92.9% for 12 or 16 weeks of therapy, respectively. In patients with cirrhosis treated for 12 or 16 weeks, SVR12 was 79.0% and 83%. In the multivariate analysis, liver cirrhosis, lower serum albumin and RBV dose at baseline were significantly associated with SVR12. Common adverse events (AEs) included fatigue, anaemia, nausea, headache, insomnia, rash and flu-like symptoms. Discontinuation due to AEs occurred in 2.8%.

Conclusions In this clinical practice setting, SOF and RBV was safe and effective for treatment of patients with HCV GT2 infection

Tuesday, August 29, 2017

Treatment Of HCV Infection with New Drugs: Real World Experience in Southern Brazil

2017 Sep-Oct;16(5):727-733. doi: 10.5604/01.3001.0010.2717.

Treatment of Chronic HCV Infection with the New Direct Acting Antivirals (DAA): First Report of a Real World Experience in Southern Brazil.
Cheinquer H1, Sette-Jr H2, Wolff FH1, de Araujo A1, Coelho-Borges S1, Soares SRP2, Barros MFA2.

Full Text 

Abstract
INTRODUCTION AND AIM:
There is almost no data regarding the efficacy of direct acting antivirals (DAAs) therapy in Brazil. The aim of this historical cohort study is to describe the sustained virologic response (SVR) rate among real-world compensated chronic hepatitis C patients in three hepatology centers from Southern Brazil.

MATERIALS AND METHODS:
Patients were included if they had at least 12 weeks follow-up after the end of therapy. Patients that were lost to follow-up or had treatment prematurely interrupted for any reason were considered treatment failure in this intention to treat analysis.

RESULTS:
219 patients were analyzed. Mean age was 57.4 ± 10.9 years and 142/219 (64.8%) were male. Genotype 1 was present in 166 patients (75.8%; 1a 29.2%, 1b 46.6%); Genotypes 2, 3 and 4 in 8 (3.7%), 43 (19.6%) and 2 (0.9%), respectively. 96 (43.8%) were cirrhotic. 134 (59.5%) were treatment experienced. DAA therapies were: sofosbuvir (SOF) + ribavirin (RBV) in 10 patients; SOF + simeprevir (SMV) ± RBV in 73; SOF + pegylated interferon (PEG-IFN) + RBV in 6; SOF + daclatasvir (DCV) ± RBV in 51, SOF + ledipasvir (LDV) ± RBV in 61, and paritaprevir/ ritonavir + ombitasvir + dasabuvir (PTVr/OBV/DSV) ± RBV in 18 patients. SVR-12 was achieved in 208/219 (95%). Ten patients had virologic failure: 6 cirrhotic, 7 treatment experienced, and 6 either genotype 3 or 1a. No adverse event was attributed to the DAA therapy.

CONCLUSIONS:
Real world experience with DAA therapy in Southern Brazil showed a high rate of SVR and excellent tolerability. Failure to achieve SVR was mainly observed among patients with at least one negative predictor of response: cirrhosis and/or genotypes 1a or 3.

Full text

Sunday, August 20, 2017

(grazoprevir-ruzasvir-uprifosbuvir) Shorter anti-HCV regimen effective in patients with or without cirrhosis

In Case You Missed It

Full Text
Shortening the duration of therapy for chronic HCV
Lancet Published online August 9, 2017
PDF provided by @HenryEChang via Twitter


Shorter anti-HCV regimen effective in patients with or without cirrhosis
Last Updated: 2017-08-18
By Will Boggs MD
NEW YORK (Reuters Health) - An eight-week regimen containing grazoprevir-ruzasvir-uprifosbuvir appears to be effective for treating hepatitis C virus (HCV) infection in patients with or without cirrhosis, according to findings from a pair of randomized phase 2 open-label trials.

Dr. Edward J. Gane from Auckland Clinical Studies, in Auckland, New Zealand, and colleagues - in part A of the C-CREST-1 and C-CREST-2 trials - randomly assigned 240 patients with HCV genotype 1, 2 or 3 and without cirrhosis to receive an eight-week course of a daily three-drug combination:

- grazoprevir 100 mg, plus

- either elbasvir 50 mg or ruzasvir 60 mg, plus

- either 300 mg or 450 mg of uprifosbuvir.

The studies were funded by Merck and Co.

Sustained virologic response rates 12 weeks after the end of therapy (SVR12) were 92% with both doses of the grazoprevir-ruzasvir-uprifosbuvir regimen and ranged from 85% to 88% (depending on uprifosbuvir dose) with grazoprevir-elbasvir-uprifosbuvir, according to one of the reports, both online August 9 in The Lancet Gastroenterology and Hepatology.

All four regimens were well-tolerated.

"These results support the selection of grazoprevir plus ruzasvir plus uprifosbuvir 450 mg as the regimen for further clinical investigation in broader populations," the researchers conclude.

Dr. Eric Lawitz from Texas Liver Institute at the University of Texas Health San Antonio and colleagues extended these findings in part B of C-CREST-1 and C-CREST-2. In this trial, 675 patients with HCV-1, -2, -3, -4 or -6, with or without cirrhosis, received eight, 12, or 16 weeks of grazoprevir-ruzasvir-uprifosbuvir 450 mg, with or without ribavirin.

SVR12 rates with eight weeks of therapy were 93% in individuals with genotype 1a, 98% with genotype 1b, 86% with genotype 2 (without cirrhosis; patients with HCV-2 and cirrhosis received a longer course), 95% with genotype 3 (treatment naive, without cirrhosis) and 100% with genotypes 4 and 6.

"We were surprised by the relatively lower efficacy of an 8-week duration of this regimen among those with genotype 2 infection," Dr. Lawitz told Reuters Health by email. "However, extending therapy to 12 weeks overcame this effect."

SVR12 rates were generally higher among participants with or without cirrhosis who received 12 or 16 weeks of therapy.

There were no documented virologic failures after week 12 of follow-up, although 10 participants who achieved SVR12 were lost to follow-up.

As in part A of the study, treatment with this fixed-dose combination with or without ribavirin was generally well tolerated.

"Results from the current studies support further investigation of grazoprevir, ruzasvir, and uprifosbuvir as a pan-genotypic regimen in individuals infected with HCV with and without cirrhosis, and suggest that this combination has the potential to provide a safe, single-duration regimen in most populations, including individuals with cirrhosis infected with genotype 3 who had previously received treatment with pegylated interferon and ribavirin," the researchers conclude.

"We await data from phase 3 to know how this regimen might impact the current treatment landscape," Dr. Lawitz said. "We hope that this regimen will be able to give providers more options with regard to pan-genotypic regimens for the treatment of HCV."

Dr. Eleanor M. Wilson from the University of Maryland School of Medicine, Baltimore, who coauthored an accompanying comment in the journal, told Reuters Health by email, "The safety and efficacy data seem promising, but it's still investigational, so not sure about its impact on the field of hepatitis C treatment yet."

"With the recent approvals of Vosevi and Mavyret, in addition to the previously available options, I think the overall take-away is that it's fantastic that there are more hepatitis C treatment options for patients and providers," she said. "It's tremendous that previously so-called 'difficult-to-treat patients' including those with previous treatment experience, comorbid conditions like HIV or renal disease, and those with advanced fibrosis and cirrhosis now have a variety of safe and highly effective options to treat their hepatitis C."

"My area of expertise is in novel treatment approaches, including strategies to reduce the treatment duration in order to increase access and decrease treatment cost, as well as options for patients who haven't successfully cleared HCV with first-line therapy (due to problems of adherence or viral resistance), and from that standpoint, it's an exciting time to be a hepatitis C provider," Dr. Wilson said.

Dr. Mark Sulkowski, who directs the viral hepatitis center at Johns Hopkins University in Baltimore, told Reuters Health by email, "We currently have multiple outstanding HCV regimens for the treatment of all genotypes of hepatitis C, which typically include combinations of direct-acting antiviral inhibitors of HCV protein targets NS3 (protease), NS5A and NS5B (polymerase). While we have seen the regulatory approval of multiple inhibitors of the NS3 and NS5A proteins, to date, only one (nucleotide) inhibitor of the NS5B polymerase active site has been approved, sofosbuvir."

"The C-CREST-1 and -2 studies provide a phase 2 evaluation of another (nucleotide) analogue inhibitor of NS5B, uprifosbuvir," said Dr. Sulkowski, who was not involved in the research. "Based on the results of these studies, uprifosbuvir appears to be poised to move to phase 3 studies, and if successful in phase 3 trials, this agent could become a valuable addition to the available drugs to treat hepatitis C."

Dr. Gane did not respond to a request for comment.
Merck funded the trials and employed most of the authors.

SOURCE: Lancet Gastroenterol Hepatol 2017.
Abstract 
Abstract 
Abstract 

Friday, August 18, 2017

Hepatitis C - Newly Approved Mavyret Has High Response Rates

The Lancet
Download Full Text Article - PDF provided by Henry E. Chang‏ via Twitter:

Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial
Xavier Forns, Samuel S Lee, Joaquin Valdes, Sabela Lens, Reem Ghalib, Humberto Aguilar, Franco Felizarta, Tarek Hassanein, Holger Hinrichsen, Diego Rincon, Rosa Morillas, Stefan Zeuzem, Yves Horsmans, David R Nelson, Yao Yu, Preethi Krishnan, Chih-Wei Lin, Jens J Kort, Federico J Mensa

Summary Background
The once-daily, ribavirin-free, pangenotypic, direct-acting antiviral regimen, glecaprevir coformulated with pibrentasvir, has shown high rates of sustained virological response in phase 2 and 3 studies. We aimed to assess the efficacy and safety of 12 weeks of coformulated glecaprevir and pibrentasvir in patients with hepatitis C virus (HCV) infection and compensated cirrhosis......
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The Lancet
Download Full Text Article - PDF provided by Henry E. Chang‏ via Twitter:

Comment 
New anti-HCV drug combinations: who will benefit?
Publication stage: In Press Corrected Proof
DOI: http://dx.doi.org/10.1016/S1473-3099(17)30486-3
In The Lancet Infectious Diseases1 Xavier Forns and colleagues present the results of a phase 3 trial assessing the efficacy and safety of 12 weeks of treatment with glecaprevir (300 mg) coformulated with pibrentasvir (120 mg) in patients with chronic hepatitis C virus (HCV) genotype 1, 2, 4, 5, or 6 infection and compensated cirrhosis. Of 146 enrolled patients, 145 (99%, 95% CI 98–100) achieved a sustained virological response. The study did not include patients with decompensated cirrhosis; the same is true for studies of sofosbuvir, velpatasvir, and voxilaprevir.2....
Continue reading......

Newly Approved Hepatitis C Drug Has High Response Rates
By Amy Orciari Herman
Edited by David G. Fairchild, MD, MPH, and Lorenzo Di Francesco, MD, FACP, FHM
Nearly all patients with chronic hepatitis C virus (HCV) infection treated with glecaprevir-pibrentasvir achieved sustained virologic response after 12 weeks of therapy, according to results of an industry-funded, phase 3 trial in the Lancet Infectious Diseases. The once-daily combination drug (brand name, Mavyret) was approved by the FDA earlier this month to treat all HCV genotypes.

The trial enrolled 146 adults with HCV genotype 1a, 1b, 2, 4, 5, or 6 and compensated cirrhosis who either had not been previously treated, or had not responded to interferon-based treatment or to treatment with sofosbuvir plus ribavirin (with or without pegylated interferon). At 12 weeks after treatment ended, all but one patient had sustained virologic response. A patient with HCV genotype 1a and a history of treatment with pegylated interferon plus ribavirin relapsed at week 8.

Nearly 70% of patients had adverse events, most of which were mild (e.g., fatigue). No serious events were related to the study drug.

Link(s):
The Lancet
Lancet Infectious Diseases article (Free abstract)
Lancet Infectious Diseases comment (Subscription required)
Background: Physician's First Watch coverage of glecaprevir-pibrentasvir (Free)
Source-

Thursday, June 1, 2017

Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection

New England Journal of Medicine

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Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection
Marc Bourlière, M.D., Stuart C. Gordon, M.D., Steven L. Flamm, M.D., Curtis L. Cooper, M.D., Alnoor Ramji, M.D., Myron Tong, M.D., Natarajan Ravendhran, M.D., John M. Vierling, M.D., Tram T. Tran, M.D., Stephen Pianko, M.D., Meena B. Bansal, M.D., Victor de Lédinghen, M.D., Robert H. Hyland, D.Phil., Luisa M. Stamm, M.D., Ph.D., Hadas Dvory-Sobol, Ph.D., Evguenia Svarovskaia, Ph.D., Jie Zhang, Ph.D., K.C. Huang, Ph.D., G. Mani Subramanian, M.D., Diana M. Brainard, M.D., John G. McHutchison, M.D., Elizabeth C. Verna, M.D., Peter Buggisch, M.D., Charles S. Landis, M.D., Ph.D., Ziad H. Younes, M.D, Michael P. Curry, M.D., Simone I. Strasser, M.D., Eugene R. Schiff, M.D., K. Rajender Reddy, M.D., Michael P. Manns, M.D., Kris V. Kowdley, M.D., and Stefan Zeuzem, M.D., for the POLARIS-1 and POLARIS-4 Investigators*

N Engl J Med 2017; 376:2134-2146
June 1, 2017 DOI: 10.1056/NEJMoa1613512

Background
Patients who are chronically infected with hepatitis C virus (HCV) and who do not have a sustained virologic response after treatment with regimens containing direct-acting antiviral agents (DAAs) have limited retreatment options.

Methods
We conducted two phase 3 trials involving patients who had been previously treated with a DAA-containing regimen. In POLARIS-1, patients with HCV genotype 1 infection who had previously received a regimen containing an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive either the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the protease inhibitor voxilaprevir (150 patients) or matching placebo (150 patients) once daily for 12 weeks. Patients who were infected with HCV of other genotypes (114 patients) were enrolled in the sofosbuvir–velpatasvir–voxilaprevir group. In POLARIS-4, patients with HCV genotype 1, 2, or 3 infection who had previously received a DAA regimen but not an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive sofosbuvir–velpatasvir–voxilaprevir (163 patients) or sofosbuvir–velpatasvir (151 patients) for 12 weeks. An additional 19 patients with HCV genotype 4 infection were enrolled in the sofosbuvir–velpatasvir–voxilaprevir group.

Results
In the three active-treatment groups, 46% of the patients had compensated cirrhosis. In POLARIS-1, the rate of sustained virologic response was 96% with sofosbuvir–velpatasvir–voxilaprevir, as compared with 0% with placebo. In POLARIS-4, the rate of response was 98% with sofosbuvir–velpatasvir–voxilaprevir and 90% with sofosbuvir–velpatasvir. The most common adverse events were headache, fatigue, diarrhea, and nausea. In the active-treatment groups in both trials, the percentage of patients who discontinued treatment owing to adverse events was 1% or lower.

Conclusions
Sofosbuvir–velpatasvir–voxilaprevir taken for 12 weeks provided high rates of sustained virologic response among patients across HCV genotypes in whom treatment with a DAA regimen had previously failed. (Funded by Gilead Sciences; POLARIS-1 and POLARIS-4 ClinicalTrials.gov numbers, NCT02607735 and NCT02639247.)

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Abstract Source
http://www.nejm.org/doi/full/10.1056/NEJMoa1613512?query=featured_home

NEJM Journal Watch - Commentary On The Article
When DAA Treatment for Hepatitis C Fails, 3-Drug Regimen "Highly Effective"
By Kelly Young
Edited by Susan Sadoughi, MD, and Richard Saitz, MD, MPH, FACP, DFASAM
The combination of sofosbuvir, velpatasvir, and voxilaprevir is effective for hepatitis C in patients with virologic failure after direct-acting antiviral agent (DAA) treatment, according to two phase 3, industry-funded trials in the New England Journal of Medicine.

For POLARIS-1, roughly 300 patients with genotype-1 hepatitis C infection whose prior NS5A-inhibitor treatment had failed were randomized to either daily sofosbuvir-velpatasvir-voxilaprevir or placebo for 12 weeks. An additional 100 patients with non-genotype 1 infection were enrolled in the treatment group.

For POLARIS-4, over 300 patients with hepatitis C who had taken a direct-acting antiviral other than an NS5A inhibitor were randomized to receive sofosbuvir-velpatasvir with or without voxilaprevir.

Sustained virologic response 12 weeks after treatment ended was 96% for the POLARIS-1 treatment group (vs. 0% with placebo).

In POLARIS-4, the three-drug regimen had a 98% response rate, compared with 90% for sofosbuvir-velpatasvir. Sustained response rates were high for all genotypes.

Infectious disease expert Dr. Paul Sax comments: "This triple-therapy treatment strategy provides a highly effective option for that small proportion of patients who failed prior treatment for hepatitis C with non-interferon-based regimens. Although few in number, candidates for this treatment (and their clinicians) will welcome this treatment when it is FDA approved."
http://www.jwatch.org/fw112944/2017/06/01/when-daa-treatment-hepatitis-c-fails-3-drug-regimen

MEDPAGE TODAY
Triple-DAA Pill Offers HCV Retreatment Option
Most patients, all unsuccessful on previous DAA regimens, cleared the virus
combination of three drugs that act directly to block hepatitis C (HCV) replication successfully cured most patients who had previously failed therapy with such agents, researchers reported.

In two phase III trials, the investigational combination of sofosbuvir, velpatasvir, and voxilaprevir cleared the virus in 96% and 98% of patients, regardless of whether they had compensated cirrhosis or not, according to Marc Bourlière, MD, of Hôpital Saint-Joseph in Marseille, France, and colleagues.
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Media Coverage Of This Article

New Combo Pill Offers Hope to Hepatitis C Patients Who Fail Other Treatment
Updated: May 31, 2017 — 7:00 PM EDT
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WEDNESDAY, May 31, 2017 (HealthDay News) -- A pill that contains three powerful antiviral drugs might offer a cure for many hepatitis C patients who have failed other treatments, researchers report.

The pill -- which contains the antiviral drugs sofosbuvir (Sovaldi), velpatasvir and voxilaprevir -- was nearly 100 percent effective in curing hepatitis C in patients whose disease returned after treatment with other antiviral drugs, the researchers said.

"Currently, we have very good treatments for hepatitis C, and we are able to achieve a cure in over 90 percent of patients. So globally, although only a few patients relapse, it still is a significant number," said lead researcher Dr. Marc Bourliere, from the Hospital Saint Joseph in Marseilles, France.

This new pill is being developed as a rescue treatment for patients who have failed other therapy, he said. When it was used as an initial treatment in another study, the combination pill fared no better than the usual treatment, he added.

The data from these and other trials, funded by Gilead Sciences, the maker of the combination pill, is in the hands of the U.S. Food and Drug Administration, where it is undergoing the approval process, Bourliere said.

The bottom line, according to Bourliere, is: "We have other options even if you fail the first treatments."

The new combination pill is likely to be expensive. In 2014, Gilead introduced a combination drug for hepatitis C called Harvoni, which was priced at more than $1,000 a dose with a 12-week course of treatment running $94,500, the Associated Press reported.

Hepatitis is an inflammation of the liver that can be caused by several viruses, including hepatitis C. Hepatitis C is usually spread when blood from an infected person enters the body of someone not infected. Most people become infected with hepatitis C by sharing needles or other equipment to inject drugs, the U.S. Centers for Disease Control and Prevention says.

Approximately 75 percent to 85 percent of people who have hepatitis C will develop chronic infection. In the United States, as many as 4 million people have chronic hepatitis C, according to the CDC.

Many people infected with hepatitis C don't know they have it because they don't look or feel sick.
Chronic hepatitis C is serious and can result in long-term health problems, including liver damage, liver failure, liver cancer or death. Hepatitis C is the leading cause of cirrhosis and liver cancer, and the most common reason for liver transplantation in the United States.
In two, phase 3 trials, Bourliere and his colleagues treated patients with the combination pill or a placebo or other antiviral drugs.

In the first trial, 300 patients were randomly assigned to the combination pill or a placebo. These patients all had hepatitis C genotype 1. In addition, 114 patients with other genotypes of hepatitis C were given the combination pill. Patients took the pill daily for 12 weeks.

Among patients taking the combination pill, 96 percent responded to treatment. None on the placebo showed a response, the researchers found.

The second trial included 314 patients with hepatitis C genotypes 1, 2 or 3. All had failed other treatments, but hadn't been given a NS5A inhibitor, such as velpatasvir or daclatasvir. This group received either the combination pill (163 patients) or sofosbuvir-velpatasvir (151 patients).
In addition, 19 patients with genotype 4 hepatitis C were given the combination pill.

In this trial, 98 percent of the patients taking the combination pill responded to 12 weeks of treatment. And 90 percent of those who received sofosbuvir-velpatasvir responded to treatment, the findings showed.

The most common side effects were headache, fatigue, diarrhea and nausea, Bourliere said. Only 1 percent or fewer patients stopped treatment because of the side effects, he said.

Dr. David Bernstein is chief of hepatology at Northwell Health in Manhasset, N.Y. He called the new drug "a very important advance. This is really for salvage therapy. I don't think this is first-line therapy, but it gives hope to the people who fail the current therapies we have."
The report was published June 1 in the New England Journal of Medicine.

https://consumer.healthday.com/infectious-disease-information-21/hepatitis-news-373/new-combo-pill-offers-hope-to-hepatitis-c-patients-who-fail-other-treatment-723205.html

Wednesday, May 24, 2017

Interferon-free treatments in patients with hepatitis C genotype 1-4 infections in a real-world setting

. 2017 May 6; 8(2): 137–146.
Published online 2017 May 6. doi:  10.4292/wjgpt.v8.i2.137

Interferon-free treatments in patients with hepatitis C genotype 1-4 infections in a real-world setting
Huascar Ramos, Pedro Linares, Ester Badia, Isabel Martín, Judith Gómez, Carolina Almohalla, Francisco Jorquera, Sara Calvo, Isidro García, Pilar Conde, Begoña Álvarez, Guillermo Karpman, Sara Lorenzo, Visitación Gozalo, Mónica Vásquez, Diana Joao, Marina de Benito, Lourdes Ruiz, Felipe Jiménez, Federico Sáez-Royuela, and Asociación Castellano y Leonesa de Hepatología (ACyLHE)

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Abstract
AIM
To investigated the real-world effectiveness and safety of various regimens of interferon-free treatments in patients infected with hepatitis C virus (HCV).

METHODS
We performed an observational study to analyze different antiviral treatments administered to 462 HCV-infected patients, of which 56.7% had liver cirrhosis. HCV RNA after 4 wk of treatment and at 12 wk after treatment sustained virologic response (SVR) as well as serious adverse events (SAEs) was analyzed first for the whole cohort and then separately in patients who met or did not meet the inclusion criteria of a clinical trial (CT-met and CT-unmet, respectively).

RESULTS
The most frequently prescribed treatment was simeprevir/sofosbuvir (36.4%), followed by sofosbuvir/ledipasvir (24.9%) and ombitasvir/paritaprevir/ritonavir (r)/dasabuvir (19.9%). Ribavirin (RBV) was administered in 198 patients (42.9%). SVRs occurred in 437/462 patients (94.6%). The SVRs ranged between 93.3% and 100% for genotypes 1-4. SVRs were achieved in 96.2% patients in the CT-met group vs 91.9% patients in the CT-unmet group (P = 0.049). Undetectable HCV RNA at week 4 occurred in 72.9% of the patients. In the univariate analysis, the factors associated with SVRs were lower liver stiffness, absence of cirrhosis, higher platelet count, higher albumin levels, no RBV dose reduction, undetectable HCV RNA at week 4 and CT-met group. In the multivariate analysis, only albumin was an independent predictor of treatment failure (P = 0.04). Eleven patients (2.4%) developed SAEs; 5.2% and 0.7% of the patients in the CT-unmet and CT-met groups, respectively (P = 0.003).

CONCLUSION
A high proportion of patients with HCV infection achieved SVRs. For patients who did not meet the CT criteria, treatment regimens must be optimized.

Keywords: Hepatitis C virus infection, Genotype 1-4, Real world treatment, Direct-acting antiviral agents

Core tip: Our study analyzes the hepatitis C virus (HCV) most common genotypes treatment and all the possible combinations with direct-acting antiviral agents which are nowadays available in our country. We have found sustained virological response rates up to 90%, even in genotypes 1 and 3. The current study analyzes HCV RNA after 4 wk of treatment and 12 and 24 wk after the end of the treatment, as well as the adverse events. We analyze, separately, the patients who meet or do not meet the inclusion criteria of a clinical trial, finding that in this last group the response is lower.


DISCUSSION ONLY
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Our real-world study is representative of monoinfected, non-transplanted patients and the treatment regimens available in Spain in 2015. Because the decision to treat and the choice of treatment were entirely at the discretion of the treating physician and randomization was not possible, this study could not directly compare the effectiveness and safety of the treatment regimens.

In the general cohort, the global efficacy was high (94.6% SVR) and the results were similar to those achieved in the CTs, although almost 60% of the patients had received previous HCV antiviral treatment and more than half had liver cirrhosis.

We found that 0.4% of the subjects who achieved a SVR at week 12 subsequently relapsed at week 24 (did not achieve SVR24), and this percentage was a similar to or even lower than those found in other studies[16,17]. Therefore, this finding confirmed previous results in a real-world setting and showed good concordance between SVRs at week 12 and week 24 based on different new AAD-based regimens, including those with shorter durations and/or with drugs with lower barriers to resistance. However, in our opinion, to definitively determine a “cure” in every patient in clinical practice, a SVR must be confirmed at week 24.

Until now, few real-world setting studies have included results that consider the most frequent genotypes (1 to 4). The most significant study is the US retrospective analysis of data from 17487 patients with genotypes 1 to 4 from the Veterans Affairs (VA) National Healthcare System[18], in which a global SVR of 90.7% was found, which was lower than that in our study. This difference may be linked to early discontinuation of treatment in 4.4% of patients with available SVR data[18].

In our study, albumin was the only independent predictor of a SVR. Other studies[14,18] have also shown that albumin and other variables associated with cirrhosis or worse liver function were related to a lower SVR, thus confirming these findings in a real-world setting and with a wide number of patients and supporting the results of CTs in which patients with a more advanced liver disease have a worse response to treatment.

Most real-world studies reported results in genotype 1 HCV patients[14,19,20]. The SVR rate in our study, which included 362 genotype 1 patients, was 94.5% of the overall genotype 1 patients, which was somewhat higher than previously reported rates (SVRs over 91%), although limited differences were observed among the different DAA combinations, treatment durations and use of RBV. SMV and SOF with or without RBV was the most used treatment in our genotype 1 patients, which was likely because it was the best combination available at the beginning of the study. This treatment was used in 149 of the total genotype 1 patients. Most of these patients had liver cirrhosis and were included in the CT-unmet group because the most severe patients were prioritized. However, these patients achieved a SVR of 93.3%. In other studies with thousands of patients with genotype 1 HCV treated with this regimen, the SVR rates were lower at between 75% and 84%[14,15,21]. The main cause of the differences between our cohort and the others was likely the lower rate of subtype 1a (31.2%) and Q80K variants in our genotype 1 patients. Although these variants were not analyzed in the current study, they appeared in only 2.7% of Spanish genotype 1 patients[22].

Other treatment combinations also showed high rates of SVR in our study; i.e., 95.0% with SOF/LDV and 94.5% with OBV/PTV/r/DSV. These rates were similar to the 92.9% or 92% SVR rates derived from the first regimen presented in two US VA National Healthcare System studies[18,19] and the 94.9% or 95.1% SVR rates achieved with the second regimen in other studies in clinical practice[18,20].

In our cohort, only eleven genotype 2 patients were treated, and all of them achieved a SVR regardless of the treatment regimen used. High rates of SVR with the combination SOF + RBV were more similar to those described in Asian CTs[23] than the SVR of 79.0% or 86.2% achieved in clinical practice in the two VA studies[14,18] or the SVR of 88.2% from the recent analysis of 321 genotype 2 HCV infected HCV-TARGET participants[24]. However, the low number of genotype 2 patients in our study indicate that several of the currently recommended combinations in clinical guidelines, such as SOF and DCV[25] should be favored because they presented 100% SVR rates in all patients.

Patients with HCV genotype 3 are at a higher risk of liver disease progression and hepatocellular carcinoma development[26,27]. However, compared with other HCV genotypes, DAA combinations have lower efficacy against genotype 3 in patients with liver cirrhosis in CTs.

In the current study, the global SVR in patients with genotype 3 HCV infection was 93.3%. In our cohort, 82.2% of patients with this genotype were treated with SOF and DCV, with a global SRV rate of 90.3%-91.9% in patients with liver cirrhosis and 100% without. In others studies in real-world settings, a global SVR of 60%-70% was achieved in genotype 3 infection with SOF plus RBV[18,28]. All these studies had remarkably low rates, which was likely related to the use of combinations that are currently not recommended because of their low efficacy[25].

Patients with HCV genotype 4 infection are poorly represented in pivotal CTs of second-generation DAAs[25] and in most real-world studies. In the VA study, a SVR of 87.6% with SOF and LDV and 96.4% with OBV and PTV/r was achieved in patients with this genotype[18]. In the current study, 44 patients who were HCV genotype 4-infected were treated and the SVR rate was 95% (100% with SOF and LDV, 92.3% with OBV and PTV/r and 94.7% with SMV and SOF).

The week 4 response data were available for almost all patients in the current study. We found that 72.9% of patients had an undetectable HCV RNA at week 4, similar to another analysis[19,29]. In this last real-world setting study, significant SVR rate reductions of 7.1% to 10.5% according to the addition of RBV or not, respectively, were observed in patients who did not have an undetectable HCV RNA at week 4 compared with those with undetectable HCV RNA at week 4, which was similar to the 6% observed in the current study[19]. The clinical implications of this finding on treatment decisions, such as potentially adding RBV or extending the treatment duration based on 4 wk of on-treatment HCV RNA, warrants further study.

Despite the real-world nature of our cohort, which included a higher proportion of elderly patients and many patients with liver cirrhosis, the safety and tolerability of all regimens were good. Discontinuation rates were low (< 1%), which is similar to that of CTs, and there were no deaths during treatment or follow up. In Backus et al[20] higher early discontinuation rates of 5.3% to 15.2% according to the treatment combination were found. In contrast, of the 802 patients in the genotype 1 group from the HCV-TARGET cohort treated with SMV and SOF, the rate of discontinuation for adverse events was only 2%[15].

In patients from the genotype 1 and genotype 3 groups from the HCV-TARGET cohort, the most commonly reported AEs were fatigue and headache, which is consistent with the results presented here[15,28]. However, anemia associated with RBV was less frequent in our study.

Overall, the reported rates of SAEs (2.4%) were similar to those reported in the pivotal CTs and lower than the 5.3% or the 7.3% described in other studies in “real-world”[15,28]. Again, in the three studies, the most frequent SAEs were the same decompensating events. However, in the current study, only seven of 262 cirrhotic patients experienced decompensation.

Because the real-world population is heterogeneous, it is important to investigate the treatment outcomes in patients excluded from CTs. Thus, we divided patients into two groups: Patients who met the requirements to take part in a CT and patients who did not meet these requirements. We found that the CT-unmet patients had lower rates of SVR and higher rates of SAEs, liver decompensation and treatment interruptions than the CT-met patients. Thus, in this group of patients, it might be advisable to conduct a more rigorous follow-up investigation to closely monitor tolerability and optimize treatment regimens.

This study has the usual limitations related to its observational, real-world design and electronic data collection. Resistance testing was not performed; thus, we were unable to assess the impact of this factor. The lack of randomization limited the ability to directly compare treatment groups, which is further compounded by the small number of patients in certain subgroups.

In conclusion, our study confirmed the efficacy and safety data reported in CTs in a cohort of patients with genotypes 1-4 and a wide range of basal characteristics, including a high proportion of patients with advanced fibrosis and treatment experience. Our results confirmed and occasionally improved upon the efficacy and safety results reported in other recently published real-world setting studies with a large number of patients[8,19], and these results are in sharp contrast to the lower SVR rates reported in certain early real-world studies on interferon-free therapy with second generation DAAs[14,15]. Moreover, our results indicate that treatment regimens should be optimized in patients that do not fulfill classical CT inclusion criteria because of their lower rates of SVR and higher rates of SAEs.

Thursday, April 20, 2017

ILC 2017: SOF/VEL with or without VOX- High efficacy with investigational direct-acting antiviral treatment combination is accompanied with substantial gains in patient-reported outcomes

ILC 2017: High efficacy with investigational direct-acting antiviral treatment combination is accompanied with substantial gains in patient-reported outcomes

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Patients with Hepatitis C and cirrhosis experience the greatest improvements in patient-reported outcomes with sofosbuvir/velpatasvir with or without voxilaprevir compared to those without cirrhosis 

April 20, 2017, Amsterdam, The Netherlands:  Analysis of patient outcome data from the POLARIS-1, 2, 3 and 4 studies presented today demonstrate that patients with Hepatitis C virus (HCV) and cirrhosis experience the greatest improvement of patient-reported outcome (PRO) scores when taking treatment with sofosbuvir (SOF) + velpatasvir (VEL), with or without voxilaprevir (VOX), an anti-HCV regimen that has been shown to be safe and effective against all HCV genotypes in different populations. The analysis of the four studies, presented at The International Liver Congress™ 2017 in Amsterdam, The Netherlands, showed that achievement of sustained virologic response at 12 weeks (SVR12) was associated with significant improvements in PROs, which were more prominent in patients with cirrhosis than those without.

Hepatitis C is one of the most widespread transmissible diseases.1 HCV is a leading cause of chronic liver disease, end-stage cirrhosis and liver cancer.2 It is estimated to infect over 185 million people worldwide, of whom 350,000 die each year, with 84,000 of those being in Europe.3 In Europe, liver cirrhosis is responsible for 1–2% of all deaths,4 and was the leading cause of adult liver transplants between 1988 and 2013.5 Until the approval of direct-acting antiviral (DAA) drugs, HCV was treated with pegylated interferon alpha and ribavirin, which caused serious adverse effects in many patients, often leading to premature termination of therapy.1 DAAs have revolutionised treatment, as they are well tolerated and highly efficacious.6 

“This analysis showed that although patients with HCV and cirrhosis have significantly impaired patient-reported outcomes, they experience the greatest improvement during treatment with SOF/VEL with or without VOX, when compared to those without cirrhosis,” said Dr Zobair Younossi, Center for Liver Diseases, Washington, United States, and lead author of the study. “We also found that achieving a sustained virologic response with the drugs was associated with substantial gains in outcomes.”

This analysis combined data from 1,908 patients with chronic HCV who were enrolled in four Phase 3 studies (POLARIS 1 to 4) that assessed the efficacy and safety of SOF/VEL/VOX in the treatment of HCV-infected patients. Outcomes from 26 PRO domain scores relating to quality of life, fatigue, work productivity and activity impairment were assessed using questionnaires.     

The overall cure rate (SVR12) was 94% for patients with and without cirrhosis in both the SOF/VEL/VOX and SOF/VEL treatment groups. Patients with cirrhosis experienced significant improvements in their PRO scores compared to the start of treatment, which were similar or greater than those in patients without cirrhosis. Individuals with cirrhosis treated with placebo did not have any PRO improvements.    “Successful treatment of HCV-related cirrhosis with DAA therapy improves patient-reported outcomes, and this will certainly impact not only the direct but also the significant indirect costs linked to this progressive disease,” said Prof Francesco Negro, Divisions of Gastroenterology and Hepatology of Clinical Pathology, University Hospital of Geneva, Switzerland and EASL Governing Board Member.

POLARIS 1, 2, 3 and 4 POLARIS-1 was a double-blind, placebo-controlled study of SOF/VEL/VOX for 12 weeks in adults with chronic HCV infection who had been treated previously with DAA therapy.7 POLARIS-2 was an open-label study that randomised patients with chronic HCV infection who had not previously received DAA therapy to treatment with SOF/VEL/VOX for eight weeks or SOF/VEL for 12 weeks.8 POLARIS-3 was an open-label study that randomised patients with genotype 3 HCV infection and cirrhosis to receive SOF/VEL/VOX daily for eight weeks or SOF/VEL for 12 weeks.9 The open-label POLARIS-4 study randomised patients with chronic HCV infection who had previously received DAAs, but not an NS5A inhibitor (a DAA that is a protease inhibitor), to treatment with either SOF/VEL/VOX or SOF/VEL for 12 weeks.10

About The International Liver Congress™ This annual congress is the biggest event in the EASL calendar, attracting scientific and medical experts from around the world to learn about the latest in liver research. Attending specialists present, share, debate and conclude on the latest science and research in hepatology, working to enhance the treatment and management of liver disease in clinical practice. This year, the congress is expected to attract approximately 10,000 delegates from all corners of the globe. The International Liver Congress™ 2017 will take place from April 19 – 23, at the RAI Amsterdam, Amsterdam, The Netherlands.

About The European Association for the Study of the Liver (EASL) (www.easl.eu) Since its foundation in 1966, this not-for-profit organisation has grown to over 4,000 members from all over the world, including many of the leading hepatologists in Europe and beyond. EASL is the leading liver association in Europe, having evolved into a major European Association with international influence, with an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.

Onsite location reference  
Session title: Late breaker posters Time, date and location of session: 08:00 – 18:00, Thursday 20 April – Saturday 22 April, Hall 1 Presenter: Zobair Younossi, United States of America Abstract: High efficacy is accompanied with substantial gains in patient reported outcomes in cirrhotic patients with chronic hepatitis C treated with sofosbuvir (SOF), velpatasvir with or without voxilaprevir (VOX): data from POLARIS 1, 2, 3 and 4 (LBP-544)

Author disclosures Research funds or consultation fees from BMS, Gilead Sciences, Intercept, Allergan and GSK.

References 1 World Health Organization. Access to new medicines in Europe: technical review of policy initiatives and opportunities for collaboration and research. March 2015. Available from: http://apps.who.int/medicinedocs/documents/s21793en/s21793en.pdf. Last accessed: April 2017.  2 Mühlberger N et al. HCV-related burden of disease in Europe: a systematic assessment of incidence, prevalence, morbidity, and mortality. BMC Public Health 2009;9:34. 3 World Health Organization. Hepatitis C in the WHO European Region Fact Sheet. July 2015. Available from: http://www.euro.who.int/__data/assets/pdf_file/0010/283357/factsheet-en-hep-c.pdf?ua=1. Last accessed: April 2017.  4 European Association for the Study of Liver. The burden of liver disease in Europe. A review of epidemiological data. Available from: http://www.easl.eu/medias/EASLimg/Discover/EU/54ae845caec619f_file.pdf. Last accessed: April 2017.  5 European Liver Transplant Registry. Specific results by disease. Available from: http://www.eltr.org/Specific-results-by-disease.html. Last accessed: April 2017.  6 Liang T, Ghany M. Current and future therapies for hepatitis C virus infection. N Engl Med 2013;369(7):679–680. 7 ClinicalTrials.gov. NCT02607735. Safety and efficacy of sofosbuvir/velpatasvir/voxilaprevir in adults with chronic HCV infection who have previously received treatment with directacting antiviral therapy (POLARIS-1). Available from: https://clinicaltrials.gov/ct2/show/NCT02607735. Last accessed: April 2017.  8 ClinicalTrials.gov. NCT02607800. Safety and efficacy of sofosbuvir/velpatasvir/voxilaprevir and sofosbuvir/velpatasvir in adults with chronic HCV infection who have not previously received treatment with direct-acting antiviral therapy (POLARIS-2). Available from: https://clinicaltrials.gov/ct2/show/NCT02607800. Last accessed: April 2017.  9 ClinicalTrials.gov. NCT02639338. Safety and efficacy of SOF/VEL/VOX FDC for 8 weeks and SOF/VEL for 12 weeks in adults chronic genotype 3 HCV infection and cirrhosis. Available from: https://clinicaltrials.gov/ct2/show/NCT02639338. Last accessed: April 2017.  10 ClinicalTrials.gov. NCT02639247. Safety and efficacy of SOF/VEL/VOX FDC for 12 weeks and SOF/VEL for 12 weeks in DAA-experienced adults with chronic genotype HCV infection who have not received an NS5A inhibitor. Available from: https://clinicaltrials.gov/ct2/show/NCT02639247. Last accessed: April 2017.

Recommended reading @ Healio - International Liver Congress- Three HCV drugs may not be better than two

International Liver Congress
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Friday, March 31, 2017

High Cure Rates for HCV Patients Undergoing Liver Transplant with New DAAs

AGA Reading Room
High Cure Rates for HCV Patients Undergoing Liver Transplant with New DAAs
Indications that post-transplant treatment should start sooner rather than later
by Liz Highleyman
Contributing Writer, MedPage Today

For hepatitis C patients who receive liver transplants, a population that is challenging to treat with interferon-based therapy, treatment with new direct-acting antivirals (DAAs) leads to high cure rates.

The choice of which DAA to use depends on the hepatitis C virus (HCV) genotype and the severity of liver damage. Outcomes are better in people who have not yet developed severe damage in the new liver, suggesting that post-transplant treatment should be started sooner rather than later.
Continue reading....

Sunday, November 13, 2016

AASLD 2016 Glecaprevir/Pibrentasvir: High SVR Rates in HCV GT 2, 4, 5, 6 Without Cirrhosis

Nov 13
Glecaprevir/Pibrentasvir: High SVR Rates in HCV GT 2, 4, 5, 6 Without Cirrhosis
By Debra Hughes, MS
Patients with chronic hepatitis C virus (HCV) genotypes (GT) 2, 4, 5, or 6 infection without cirrhosis had SVR12 rates of 97% after 8 weeks of treatment with co-formulated glecaprevir/pibrentasvir, investigators from the SURVEYOR-II, Part 4, concluded at The Liver Meeting® 2016.​

Press Release
Nov 11
Update AbbVie's Glecaprevir/Pibrentasvir (G/P) Acheive High SVR12 Rates at 8 Wks Genotypes 1-6
- 97.5 percent of chronic HCV infected patients without cirrhosis and new to treatment across all major genotypes (GT1-6) achieved SVR12 with 8 weeks of G/P
- Across the 8-week arms of three registrational studies, no patients discontinued treatment due to adverse events
- G/P is an investigational, pan-genotypic, once-daily, ribavirin-free regimen for the treatment of chronic HCV

Additional updates @ MPR
Current updates: Conference Reports
Updates On This Blog: AASLD 2016

Friday, August 26, 2016

Hepatitis C/Effectiveness of Sofosbuvir, Ledipasvir/Sofosbuvir, or Paritaprevir/Ritonavir/Ombitasvir and Dasabuvir

September 2016 Gastroenterology.
Volume 151, Issue 3, Pages 457–471.e5

Effectiveness of Sofosbuvir, Ledipasvir/Sofosbuvir, or Paritaprevir/Ritonavir/Ombitasvir and Dasabuvir Regimens for Treatment of Patients With Hepatitis C in the Veterans Affairs National Health Care System

George N. Ioannou, Lauren A. Beste, Michael F. Chang, Pamela K. Green, Elliott Lowy, Judith I. Tsui, Feng Su, Kristin Berry

DOI: http://dx.doi.org/10.1053/j.gastro.2016.05.049

Background & Aims
We investigated the real-world effectiveness of sofosbuvir, ledipasvir/sofosbuvir, and paritaprevir/ritonavir/ombitasvir and dasabuvir (PrOD) in treatment of different subgroups of patients infected with hepatitis C virus (HCV) genotypes 1, 2, 3, or 4.

Methods
We performed a retrospective analysis of data from 17,487 patients with HCV infection (13,974 with HCV genotype 1; 2131 with genotype 2; 1237 with genotype 3; and 135 with genotype 4) who began treatment with sofosbuvir (n = 2986), ledipasvir/sofosbuvir (n = 11,327), or PrOD (n = 3174), with or without ribavirin, from January 1, 2014 through June 20, 2015 in the Veterans Affairs health care system. Data through April 15, 2016 were analyzed to assess completion of treatments and sustained virologic response 12 weeks after treatment (SVR12). Mean age of patients was 61 ± 7 years, 97% were male, 52% were non-Hispanic white, 29% were non-Hispanic black, 32% had a diagnosis of cirrhosis (9.9% with decompensated cirrhosis), 36% had a Fibrosis-4 index score >3.25 (indicator of cirrhosis), and 29% had received prior antiviral treatment.

Results
An SVR12 was achieved by 92.8% (95% confidence interval [CI], 92.3%–93.2%) of subjects with HCV genotype 1 infection (no significant difference between ledipasvir/sofosbuvir and PrOD regimens), 86.2% (95% CI, 84.6%–87.7%) of those with genotype 2 infection (treated with sofosbuvir and ribavirin), 74.8% (95% CI, 72.2%–77.3%) of those with genotype 3 infection (77.9% in patients given ledipasvir/sofosbuvir plus ribavirin, 87.0% in patients given sofosbuvir and pegylated-interferon plus ribavirin, and 70.6% of patients given sofosbuvir plus ribavirin), and 89.6% (95% CI 82.8%–93.9%) of those with genotype 4 infection. Among patients with cirrhosis, 90.6% of patients with HCV genotype 1, 77.3% with HCV genotype 2, 65.7% with HCV genotype 3, and 83.9% with HCV genotype 4 achieved an SVR12. Among previously treated patients, 92.6% with genotype 1; 80.2% with genotype 2; 69.2% with genotype 3; and 93.5% with genotype 4 achieved SVR12. Among treatment-naive patients, 92.8% with genotype 1; 88.0% with genotype 2; 77.5% with genotype 3; and 88.3% with genotype 4 achieved SVR12. Eight-week regimens of ledipasvir/sofosbuvir produced an SVR12 in 94.3% of eligible patients with HCV genotype 1 infection; this regimen was underused.

Conclusions
High proportions of patients with HCV infections genotypes 1–4 (ranging from 75% to 93%) in the Veterans Affairs national health care system achieved SVR12, approaching the results reported in clinical trials, especially in patients with genotype 1 infection. An 8-week regimen of ledipasvir/sofosbuvir is effective for eligible patients with HCV genotype 1 infection and could reduce costs. There is substantial room for improvement in SVRs among persons with cirrhosis and genotype 2 or 3 infections.

Discussion Only
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LDV/SOF, PrOD, and SOF-based antiviral regimens resulted in remarkably high SVR rates in the VA national health care system, approaching the rates reported in clinical trials. This is in contrast to previous interferon-based regimens, which consistently resulted in much lower SVR rates in real-world clinical practice than in clinical trials.12, 13, 14, 15, 16, 17 SVR rates were higher in genotype 1– (SVR 92.8%) and genotype 4–infected patients (SVR 89.6%) than genotype 2– (SVR 86.2%) or 3–infected patients (SVR 74.8%), and these differences were even greater among cirrhotic and treatment-experienced patients. Among genotype 1–infected patients, there was no significant difference in SVR rates between LDV/SOF and PrOD regimens in either unadjusted or multivariable, propensity-score-adjusted analyses, and SVR rates >90% were achieved even in subgroups such as treatment-experienced or cirrhotic patients. The short, 8-week LDV/SOF monotherapy regimen resulted in excellent SVR rate (94.3%), but was used in only 48.6% of genotype 1–infected patients eligible for 8-week therapy (ie, treatment-naïve patients with viral load <6 million IU/mL, without cirrhosis). Long, 24-week regimens did not result in higher SVR rates and were rarely used, despite being FDA-approved and American Association for the Study of Liver Diseases/Infectious Diseases Society of America–recommended32 for certain genotype 1 patients with cirrhosis.

Among a total of 17,487 patients, our study included 5250 patients with a diagnosis of cirrhosis and 5960 with a FIB-4 score >3.25 (which is highly suggestive of cirrhosis), who achieved surprisingly high overall SVR rates of 86.8% and 87.4%, respectively. These high SVR rates were driven by genotype 1–infected cirrhotic patients who had much higher SVR (90.6%; 95% CI, 89.7%–91.5%) than genotype 2 (77.3%; 95% CI 73.3%–80.9%) or genotype 3 (65.7%; 95% CI, 61.2%–69.8%). To our knowledge, this is the largest study of DAAs in cirrhotic patients and the SVR rates in genotype 1–infected patients are the highest reported in real-world clinical practice. LDV/SOF, PrOD, and SOF regimens have allowed patients with cirrhosis to be cured of HCV in substantial numbers and proportions for the first time ever. Longer follow-up of these patients is necessary to determine whether patients with cirrhosis who achieve SVR by DAAs are protected from developing progressive liver dysfunction, liver failure, or HCC and, whether they are capable of liver remodeling and regression of cirrhosis.

American Association for the Study of Liver Diseases/Infectious Diseases Society of America guidelines during the time period of our study,32 as well as the LDV/SOF package insert,33 recommend that LDV/SOF regimens should extend for 12 or 24 weeks, with the single exception of a short, 8-week LDV/SOF monotherapy regimen that “can be considered,”33 “with caution and at the discretion of the practitioner”32 in treatment-naïve, genotype 1–infected patients without cirrhosis with an HCV viral load <6 million IU/mL. This is based on a post-hoc analysis of the ION-3 clinical trial showing higher relapse rates in those treated for 8 weeks who had a viral load ≥6 million (9 of 92 [10%]) compared with those with a viral load <6 million IU/mL (2 of 123 [2%]).3 VA treatment guidelines explicitly recommended 8 weeks of treatment for this subgroup of patients.34 Indeed, our study confirmed that 8 weeks of LDV/SOF monotherapy had similarly high SVR rates (94.8%) as 12 weeks (95.3%) in this favorable subgroup. However, our results also showed that treatment was unnecessarily extended beyond 8 weeks in 1833 of 4066 patients in this subgroup, dramatically increasing the cost of treatment without increasing SVR. Our results should offer reassurance to treatment providers that 8 weeks of LDV/SOF monotherapy is sufficient duration in this subgroup.

VA treatment guidelines during the study period designated PrOD as the preferred regimen in genotype 1–infected patients except for prior null responders, those previously treated with protease inhibitors, and patients with Child’s B or C cirrhosis (in whom the preferred regimen was LDV/SOF and ribavirin for 12 weeks) and except for treatment naïve, non-cirrhotics with a viral load <6 million (in whom 8-week LDV/SOF and 12-week PrOD regimens were equally preferred). This was due to the lower cost of 12 weeks of PrOD ($22,850) compared with 12 weeks of LDV/SOF ($37,157) in the VA system during the study period and the absence of evidence that one is more effective than the other in the subgroups for which PrOD was preferred. Our data support the VA treatment recommendations because we found no difference in SVR between PrOD and LDV/SOF regimens in either adjusted or unadjusted analyses, in the entire population or in clinically relevant subgroups (cirrhosis or not, treatment-experienced or naïve). Despite these recommendations and the higher cost, LDV/SOF regimens constituted 77% and PrOD only 23% of regimens in genotype-1–infected patients. This could be due to higher prevalence of drug–drug interactions, higher pill burden, and more frequent requirement for co-prescription of ribavirin in PrOD regimens compared with LDV/SOF regimens.

After the end of the study period, and after FDA approval of elbasvir/grazoprevir as an additional regimen for genotype 1 HCV on January 28, 2016, regimen costs in the VA were further reduced dramatically, to approximately $17,000 per 12-week course for LDV/SOF, PrOD, and elbasvir/grazoprevir and treatment recommendations changed to “equally recommend” all 3 agents as of March 2016.

Genotype 3–infected patients had the lowest SVR rates in our study, just as in clinical trials. We found that the non-FDA–approved regimen of LDV/SOF and ribavirin had a higher SVR rate (77.9%; 95% CI, 73.1%–82.0%) than the longer and more expensive FDA-approved regimen of SOF and ribavirin for 24 weeks (70.6%; 95% CI, 66.9%–74.1%). However, the highest SVR rate in genotype 3–infected patients was observed in the regimen that included PEG together with SOF and ribavirin (87.0%; 95% CI, 80.0%–91.8%), the only interferon-containing regimen that is still recommended.32
Few large real-world studies of interferon-free regimens are currently available for comparison with ours. The HCV-TARGET, a prospective cohort study of patients undergoing HCV treatment in routine clinical care in academic centers, reported SVR rate to SOF and simeprevir in genotype 1–infected patients of 88% among 151 transplant recipients and 84% among 836 non-transplant recipients.35, 36 This regimen has been superseded by LDV/SOF and PrOD-based regimens. Among 487 patients with decompensated cirrhosis treated in the United Kingdom under an Expanded Access Programme with SOF, LDV/SOF, or daclatasvir, SVR was achieved in 90.5% of genotype 1– and 68.8% of genotype 3–infected patients37—very similar to our findings. A smaller VA study looked at only treatment-naïve, genotype 1–infected patients treated with LDV/SOF and reported SVR rates almost identical to ours among this subgroup.38 The TRIO Network, which compiles data from participating “real-world” academic and community HCV treatment clinics in the United States, reported in an abstract an SVR rate of 94% among 1521 genotype 1–infected patients treated with LDV/SOF monotherapy.39
The main limitation of our study was that SVR data were unavailable in 9% of patients, which can lead to overestimated SVR rates among those with available SVR data. We think this is unlikely for 2 reasons. First, patients with missing SVR data were similar to those with available SVR data (Supplementary Table 2). Although early discontinuation of treatment in <8 weeks was more common in patients with missing SVR data (25% vs 4.4%), the majority of patients with missing SVR completed 8 or more weeks of treatment, demonstrating that patients with missing SVR data were not patients who “dropped out” of treatment or were “lost to follow-up,” but rather patients (or physicians) who were simply delinquent in getting their SVR viral load measured after the end of their treatment—not an uncommon phenomenon outside of clinical trials. Second, we used comprehensive multiple imputation models that included duration of treatment in addition to baseline, pretreatment characteristics to impute the missing SVR data and found only a non-substantial reduction in SVR after imputation (Table 5), suggesting that it is unlikely that our results of observed SVR are biased toward overestimation due to the missing SVR data. Important strengths of the study include the complete ascertainment of filled pharmacy prescriptions and the utilization of complete electronic medical records since 1999 from a national health care system that treats the greatest number of HCV-infected patients in the United States.

Our results demonstrate that LDV/SOF, PrOD, and SOF regimens can achieve remarkably high SVR rates in real-world clinical practice, especially in genotype 1–infected patients. The main obstacle to curing HCV infection in the maximum possible number of patients is currently the cost of HCV antiviral regimens. It is expected that cost will decline dramatically as more antiviral regimens become FDA-approved, resulting in competition between manufacturers. In fact, costs decreased dramatically within the VA after the completion of our study and after the FDA approval of elbasvir/grazeprevir in January 2016. The VA health care system has budgeted $1.5 billion nationally for antiviral medications for fiscal year 2016, while every health care organization in the United States is faced with similar budgetary constraints due to the cost of antiviral medications. We hope that our results will be used to determine the most cost-effective ways to treat HCV-infected patients and to reassure patients, clinicians, and health care systems that current treatments for HCV, though costly, appear to be effective in the real-world setting.

Acknowledgments
Author contributions: George Ioannou: Study concept and design, acquisition of data, statistical analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript, obtained funding. Pamela Green: Analysis of data. Elliott Lowy: Analysis of data. Kristin Berry: Study design and analysis of data. Feng Su: Study design and critical revision of the manuscript. Michael F. Chang: Study design and critical revision of the manuscript. Judith Tsui: Study design and critical revision of the manuscript. Lauren Beste: Study design and critical revision of the manuscript. George Ioannou is the guarantor of this paper. All authors approved the final version of the manuscript.

Article Outline
  1. Methods
    1. Data Source: The Veterans Affairs Corporate Data Warehouse
    2. Study Population and Antiviral Regimens
    3. Baseline Characteristics
    4. Sustained Virologic Response
    5. Statistical Analysis
  2. Results
    1. Treatment Regimens by Genotype
    2. Patient Characteristics
    3. Early Discontinuation of Treatment
    4. Overall Sustained Virologic Response Rates by Genotype
    5. Utilization and Sustained Virologic Response Rates of 8-Week Ledipasvir/Sofosbuvir Regimens
    6. Utilization and Sustained Virologic Response Rates of 24-Week Ledipasvir/Sofosbuvir and Paritaprevir/Ritonavir/Ombitasvir Regimens
    7. Sustained Virologic Response Rates in Patients With Cirrhosis
    8. Sustained Virologic Response Rates in Treatment-Experienced vs Treatment-Naïve Patients
    9. Independent Predictors of Sustained Virologic Response
    10. Impact of Missing Sustained Virologic Response Data and Imputation for Missing Sustained Virologic Response
  3. Discussion
  4. Supplementary Material
  5. References