Elbasvir-grazoprevir works effectively against HCV despite current drug use

Press Release
Results from Merck’s Phase 3 Study Evaluating ZEPATIER™ (elbasvir and grazoprevir) in Patients with Chronic Hepatitis C Receiving Treatment for Opioid Dependence Published in Annals of Internal Medicine

In The News
New Research Supports the Removal of Drug Use as a Restriction to Hepatitis C Treatment
New, highly curative hepatitis C therapy is both safe and effective as a treatment option for people who inject drugs receiving opioid substitution therapy according to the results of a world-first clinical trial led by professor Gregory Dore at the Kirby Institute at UNSW Australia and published today in the Annals of Internal Medicine.
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Annals of Internal Medicine
Elbasvir–Grazoprevir to Treat Hepatitis C Virus Infection in Persons Receiving Opioid Agonist Therapy: A Randomized Trial

Family Practice:
Elbasvir-grazoprevir works effectively against HCV despite current drug use
By: MARY ANN MOON, Family Practice News Digital Network August 8, 2016

FROM ANNALS OF INTERNAL MEDICINE

Vitals
Key clinical point: A 12-week course of elbasvir plus grazoprevir was effective against HCV in patients receiving opioid agonist therapy for injectable drug addiction.

Major finding: The primary efficacy endpoint, the SVR rate after active treatment, was 91.5% with immediate treatment and 89.5% with deferred treatment.

Data source: An international, randomized, placebo-controlled, double-blind trial involving 301 patients followed for 6 months.

Disclosures: This study was funded primarily by Merck, which markets Zepatier. Dr. Dore reported ties to AbbVie, Merck, Bristol-Myers Squibb, Janssen, Roche, Gilead, GlaxoSmithKline, and Abbott, and his associates reported ties to numerous industry sources.

A 12-week course of elbasvir plus grazoprevir proved effective against hepatitis C virus in 301 patients who were receiving opioid agonist therapy for injectable drug addiction, according to a report published online August 8 in Annals of Internal Medicine.

This patient population showed excellent treatment adherence and achieved sustained virologic response (SVR) rates of approximately 90%, even though most participants continued to use injectable drugs during the study. These findings demonstrate that current drug users can achieve HCV treatment outcomes that are comparable to those in the general HCV population, and “suggest that access to interferon-free direct-acting antiviral therapy should be expanded to patients receiving opioid agonist therapy, including the removal of drug use-based restrictions,” said Gregory J. Dore, MD, of the Kirby Institute, University of New South Wales, Sydney, and his associates.

They assessed elbasvir-grazoprevir (Zepatier) treatment in patients with untreated chronic HCV who were aged 18 and older and had been receiving opioid agonist therapy with methadone, buprenorphine, or buprenorphine-naloxone for at least 3 months at facilities in 13 countries. The study participants were randomly assigned in double-blind fashion to receive either immediate active treatment for 12 weeks (201 patients) or matching placebo for 12 weeks followed by 4 weeks of follow-up followed by deferred open-label active treatment for 12 weeks (100 control subjects).

All patients were followed for 6 months after they completed active treatment. All underwent frequent urine testing for illegal drugs, and more than half of both study groups tested positive for at least one drug during active treatment and follow-up. Illegal drug use was stable throughout the study period and did not affect either treatment adherence or efficacy. Nearly every participant showed excellent adherence (over 95%) to elbasvir-grazoprevir.

The primary efficacy endpoint, the SVR rate immediately after active treatment, was 91.5% in the immediate-treatment group and 89.5% in the deferred-treatment group. Both rates are substantially higher than the historical reference SVR rate of 67%, Dr. Dore and his associates noted (Ann Intern Med. 2016 Aug 8. doi: 10.7326/M16-0816).

Elbasvir-grazoprevir was equally effective against the GT1a, GT1b, and GT4 strains of HCV, but was less effective against the GT6 strain, which occurs primarily in China and Southeast Asia. It also was effective across important subgroups of patients, including those who had cirrhosis and those who carried HCV variants associated with drug resistance.

Regarding treatment safety, the rate of serious adverse events was low in both study groups (3.5% and 4.0%, respectively), and only one event in each group was deemed to be related to elbasvir-grazoprevir.

The incidence of reinfection for the 24-week period after successful treatment was 4.6 per 100 person-years, and it often was attributed to continuing use of contaminated needles or sexual contact with an infected partner. The effect of reinfection is “of considerable clinical and public health interest,” and will be further examined during a 3-year extension of the follow-up of this study, the investigators said.

“Of interest, 3 of the 6 patients categorized as having HCV reinfection subsequently had undetectable HCV-RNA levels without additional HCV treatment, indicating that not all reinfection cases develop viral persistence,” they added.

This study was funded primarily by Merck, which markets Zepatier. Dr. Dore reported ties to AbbVie, Merck, Bristol-Myers Squibb, Janssen, Roche, Gilead, GlaxoSmithKline, and Abbott, and his associates reported ties to numerous industry sources.

Summary - Family Practice News Digital Network August 8, 2016

'Tax haven' Ireland accused of helping US firm treble untaxed profits

'Tax haven' Ireland accused of helping US firm treble untaxed profits

The Americans for Tax Fairness (ATF) group has suggested that an Irish tax loophole allowed Gilead Sciences to increase its untaxed offshore profits three-fold.

In a submission to the Securities and Exchange Commission (SEC) – the US markets regulator – ATF alleges that Gilead began to shift the economic rights for the US patent on the Sovaldi medicine to Ireland in 2013 and that this "most likely" allowed it to lower its US profits and avoid $10bn in tax as a result.

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Why are hepatitis C patients treated differently by NHS England?

Why are hepatitis C patients treated differently by NHS England?
8 AUG 2016 10:01 By Charles Gore

NHS England’s decision to cap access to National Institute for Health and Care Excellence (NICE) approved hepatitis C treatments has been attributed to their cost. These antiviral medicines have led to vast costs for national healthcare systems and huge profits for the pharmaceutical industry. So it is understandable that the mainstream media and general public assume that the cost to the NHS (either per patient or in absolute terms) is prohibitive.

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GS-9857 in Patients With Chronic Hepatitis C Virus Genotype 1–4 Infection

Journal of Viral Hepatitis

GS-9857 in Patients With Chronic Hepatitis C Virus Genotype 1–4 Infection
A Randomized, Double-blind, Dose-ranging Phase 1 Study

M. Rodriguez-Torres; S. Glass; J. Hill; B. Freilich; D. Hassman; A. M. Di Bisceglie; J. G. Taylor; B. J. Kirby; H. Dvory-Sobol; J. C. Yang; D. An; L. M. Stamm; D. M. Brainard; S. Kim; D. Krefetz; W. Smith; T. Marbury; E. Lawitz Disclosures J Viral Hepat. 2016;23(8):614-622.

Abstract and Introduction

Methods

Results 

Discussion

Discussion Only

In this randomized, phase 1b study, the safety, antiviral efficacy and PK of GS-9857 at doses ranging from 50 to 300 mg were assessed in patients with chronic genotype 1–4 HCV infection. GS-9857 was generally well tolerated by patients with chronic HCV infection when administered once daily for 3 days. All AEs were of mild or moderate severity, with diarrhoea and headache occurring most commonly during this study. Although increased incidence of rash, pruritus, nausea and anaemia have been commonly reported with the use of certain protease inhibitor-based regimens,^[7–10] no such events were observed during this study. Grade 3 or Grade 4 laboratory abnormalities occurred in 16.9% of patients receiving GS-9857 and were not associated with GS-9857 dose or AEs. Notably, assessments of ALT, AST and alkaline phosphatase levels did not reveal any Grade 3 or Grade 4 abnormalities, indicating that GS-9857 administration was not associated with significant changes in liver function. Physical examination and ECG evaluation did not reveal clinically significant findings.

Treatment with GS-9857 at doses of 100 mg or 300 mg resulted in >3 log₁₀ IU/mL median maximal reduction in viral load from baseline across all genotypes, including genotype 3, indicating that GS-9857 exhibited potent antiviral activity in HCV-infected patients. This observation is consistent with in vitro data showing that GS-9857 has pan-genotypic activity against genotype 1 to 6 replicons, with the half-maximal effective concentration ranging from 1.5 to 6.6 nm.^[5] With the exception of patients with genotype 3a infection who received GS-9857 doses of <100 mg, a rapid and consistent reduction in HCV RNA was achieved and maintained through day 10. For patients with genotype 3a infection who received GS-9857 50 mg, HCV RNA reductions occurred more slowly.

This study characterized substitutions at positions 36, 41, 43, 54, 55, 80, 122, 155, 156, 168 and 170, which have been reported to be associated with resistance to NS3/4A protease inhibitors.^[11–17] Prior to the start of GS-9857 treatment, 22.4% of patients who were sequenced harboured NS3 RAVs. Treatment with GS-9857 resulted in similar mean maximal viral load reductions in patients with and without NS3 RAVs, indicating that the antiviral efficacy of GS-9857 was maintained in the presence of mutations commonly associated with resistance to treatment. The majority of patients (73.6%) who were sequenced after 3 days of GS-9857 treatment did not have emergent NS3 RAVs, and there were no emergent NS3 RAVs in patients with genotype 2 or 4 infection. A156V or A156T were the most prevalent substitutions to emerge in patients with genotype 1a or 1b infection. In vitro data indicate that GS-9857 has potent activity against the most common genotype 1 RAVs except A156T;^[5] this substitution is associated with high levels of resistance (>100-fold) but low viral fitness (1.5% compared to wild-type genotype 1a replicon).^[12] The overall low frequency of emergent NS3 RAVs suggests that GS-9857 has a relatively high barrier to resistance as compared with other first-generation protease inhibitors, which may be a substantial benefit in the context of retreatment of patients who have failed a prior treatment with a DAA-based regimen.

Administration of GS-9857 at doses ranging from 50 to 300 mg under fasting conditions resulted in dose-proportional increases in exposure. The median half-life across cohorts ranged from approximately 29–42 h, supporting once-daily dosing. Consistent with its long median half-life, significant accumulation of GS-9857 exposure was observed. GS-9857 plasma PK was similar among patients with genotype 1a, 1b, 2, 3 or 4 HCV infection.

Patients with cirrhosis or chronic liver disease were excluded from this preliminary investigational study. As such, the lack of significant safety concerns observed may be the result of selection for a study population less prone to AEs. Further evaluations of GS-9857 in patients with more advanced disease or additional complications will be necessary to confirm the findings of this study.
In summary, administration of multiple doses of GS-9857 was well tolerated and resulted in a robust decline of HCV RNA levels in patients with genotype 1–4 HCV infection. Notably, the potent antiviral activity of GS-9857 was preserved in the presence of commonly observed NS3 mutations associated with resistance to protease inhibitors. GS-9857 demonstrated linear PK when administered at doses ranging from 50 to 300 mg under fasting conditions. The median half-life of GS-9857 ranged from 29 to 42 h, conducive to once-daily dosing. Lastly, GS-9857 has demonstrated additive antiviral activity when evaluated in vitro in combination with sofosbuvir or velpatasvir.^[5] Together, these data support the further development of once-daily GS-9857 in combination with other DAAs for the treatment of patients with chronic HCV infection.

Full Article -  GS-9857 in Patients With Chronic Hepatitis C Virus Genotype 1-4 Infection

This phase 1b study of the investigational drug GS-9857 showed positive results on its efficacy and tolerability in chronic HCV infection, supporting its further evaluation.

August 05, 2016

HCV RNA Persists in Liver After Interferon-Free Treatment Regimens

HCV RNA Persists in Liver After Interferon-Free Treatment Regimens

By Reuters Staff

| August 04, 2016

NEW YORK (Reuters Health) - Hepatitis C virus (HCV) RNA persists in two-thirds of liver explants from patients who were treated with interferon-free regimens, researchers report.

Patients awaiting liver transplant receive antiviral treatment to eradicate the virus in serum and liver in order to prevent HCV graft infection. The duration of treatment needed to accomplish this in patients with advanced cirrhosis using interferon-free regimens is unknown.

Dr. Xavier Forns from the University of Barcelona, Spain, and colleagues assessed the presence of HCV RNA in liver explants from 39 HCV-infected patients treated with an interferon-free regimen (median duration, 17 weeks) on the waiting list for liver transplant and analyzed whether its presence was associated with relapse after liver transplantation.

Although most patients (68%) had undetectable serum HCV RNA by the fourth week of treatment, HCV RNA was present in 26 out of 39 liver explants (67%), the team reports in Gastroenterology, online June 30.

Patients with HCV RNA-positive liver explants received a shorter course of treatment than did those with HCV RNA-negative explants (14 vs. 21 weeks, p=0.014) and had HCV RNA undetectable in serum for a shorter period of time (61 vs. 99 days, p=0.013).

Most patients (33/39, 85%) had sustained virological response after liver transplant, but six patients had recurrent HCV infection after transplant.

HCV RNA was detected in 67% of liver explants both from patients with and without recurrent HCV infection after liver transplant, but the intrahepatic HCV RNA concentration was significantly higher in those who relapsed than in those who achieved posttransplant sustained virological response.

Explant HCV RNA concentrations did not differ between individuals treated with sofosbuvir plus ribavirin and those treated with more than one direct antiviral agent (DAA).

The two patients who relapsed despite having an HCV RNA-negative explant carried HCV resistant variants both at baseline and at relapse.

"Our study demonstrates that despite the use of effective DAAs, residual HCV RNA remains present in liver explants of a significant proportion of HCV-infected patients treated on the waitlist, despite undetectable HCV RNA in serum," the researchers conclude. "Nevertheless, its presence does not seem to be associated with virological relapse after transplantation, except in cases with high liver HCV RNA concentrations."

"The presence of non-functional HCV RNA or a down regulation of the intrahepatic interferon pathway unable to clear residual HCV RNA might explain our findings," they speculate.

No commercial funding was reported for the study, but several co-authors work for Gilead Sciences or have other ties to the company.

Dr. Forns did not respond to a request for comments.

SOURCE: http://bit.ly/2aPgxFM

Gastroenterology 2016.

Major treatment expansion could essentially eliminate hepatitis C in R.I. by 2030

Major treatment expansion could essentially eliminate hepatitis C in R.I. by 2030

PROVIDENCE, R.I. [Brown University] -- A new Brown University study projects that increasing the number of Rhode Islanders treated every year for hepatitis C virus infection (HCV) to about 2,000 by 2020 would reduce cases by 90 percent and prevent more than 70 percent of expected liver-related deaths in the state by 2030.

More moderate increases in treatment such as doubling the number treated each year could reduce death rates by less than 20 percent, the analysis showed.

"Hepatitis C virus-related morbidity and mortality can be reduced significantly in Rhode Island if an aggressive treatment strategy is implemented over the next decade," wrote public health Assistant Professor Brandon Marshall and colleagues in the journal Epidemiology and Infection.

"The medications available today are so effective that -- with increased treatment uptake -- we have the opportunity to all but eliminate the disease by 2030," he added.

Marshall's analysis comes as Rhode Island takes a deep look at the how the disease has impacted the state. July 28 was World Hepatitis Day. The Aug. 6 WaterFire marks that occasion. Meanwhile, next week the Rhode Island Department of Health plans to unveil an epidemiological report, in partnership with the Rhode Island Public Health Institute, describing key aspects of the state of the epidemic.

Hepatitis C can take decades to cause serious disease, but ultimately the liver damage it can cause can be fatal as it progresses to cirrhosis, liver failure or liver cancer. In recent years many baby boomers (infected as long ago as the 1950s, '60s and '70s) have been reaching those critical later stages of progression. One in 30 baby boomers in the U.S. has hepatitis C. At the same time, new treatments have made the disease curable in only a few weeks, very safely, but in the U.S. they are priced at tens of thousands of dollars.

"Hepatitis C kills more people in the United States than any other infectious disease," said study co-author Dr. Lynn E. Taylor, assistant professor of medicine, physician at The Miriam Hospital and founder of Rhode Island Defeats Hepatitis C. "In fact, hepatitis C causes more deaths than all other 60 infectious diseases reportable to the CDC, combined. This is the critical infectious disease epidemic of our time. Our goal is elimination. We need to scale up our testing and treatment with urgency to avert preventable illness and early death."

Modeling mortality


Projections show that the 'eliminiation' strategy could dramatically reduce liver-related deaths in Rhode Island over the next decade and a half.
Credit - Brandon Marshall, et. al.

The new study sought to project the impact of expanding treatment by varying degrees using a sophisticated computer model loaded with data from Rhode Island's epidemic or, when that data wasn't available, from that of the U.S. more broadly.

Marshall's team, including lead author and Brown public health graduate student Dr. Ayorinde Soipe, included figures and estimates for the number of Rhode Islanders infected since 1950, the progression rate of hepatitis C's various strains and the rate of new infections. They also considered many other pertinent factors including how often people die of the disease vs. other causes over time, and the likelihood that they could clear the infection without treatment.

They then used the model to project the course of the next 14 years of the epidemic in Rhode Island based on four different treatment scenarios:

The Base Case: Treatment for 215 residents a year, restricted to patients with stage three fibrosis or worse.

Scale-up 1: Double treatment to 430 residents annually and treating patients with stage two fibrosis or worse.

Scale-up 2: Double treatment to 430 residents annually and treating patients irrespective of HCV disease stage.

The "Elimination" Scenario: Whatever the model says is needed to reduce infections by 90 percent by 2030, which turned out to be treating 2,000 patients a year by 2020.

The greatest reductions in liver-related deaths by 2030 occurred in the elimination scenario: a drop of 72.4 percent compared to the base case.

Scale-up 1 would reduce liver-related deaths by 19.3 percent, and Scale-up 2 would reduce them by 7.4 percent.

Similar patterns of reductions would also bring down the number of cases of cirrhosis, which could lead to more deaths after 2030.

Marshall said that the reason why maintaining a restriction on treating patients with more advanced liver disease would result in fewer deaths (as in Scale-up 1 vs. 2) is because with few people being treated, it would prevent more deaths if treatment resources were focused on those more acutely ill.

The study did not track the costs of expanding treatment, which would likely be in the tens of millions of dollars. The researchers noted, however, that while the upfront investment would be large, it would likely pay off eventually in preventing thousands of cases of cirrhosis, liver failure and liver cancer, which are expensive to treat and would drastically reduce the need for very costly liver transplants.

The study has other limitations, such as the need to make assumptions based on national rather than state data. It also might underestimate the prevalence of hepatitis C because it does not account for rising infection rates among young people amid the state's opioid and heroin epidemic.

Still, Marshall said, the study provides guidance for state policymakers, insurers and care providers about what it will take to bend the curve of the state's epidemic to result in far fewer deaths.

###

In addition to Soipe, Marshall and Taylor, the paper's other authors are Brown public health Assistant Professor Omar Galárraga and Drs. Homie Razavi and Devin Razavi-Shearer of the Center for Disease Analysis in Lafayette, Colorado.

The Rhode Island Foundation's support of R.I. Defeats HepC funded the research. Dr. Soipe was supported by a trainee award from the Lifespan/Tufts/Brown Center for AIDS Research (CFAR), and Dr. Marshall is supported by a Henry Merrit Wriston Fellowship from Brown University.

http://www.eurekalert.org/pub_releases/2016-08/bu-mhc080416.php

Fibrosis Progression in Patients with Chronic Hepatitis C Virus

J Infect Dis. (2016) doi: 10.1093/infdis/jiw332
First published online: August 2, 2016

Fibrosis Progression in Patients with Chronic Hepatitis C Virus

Infection Marija Zeremski1,*, Rositsa B. Dimova2,3,*, Jaroslaw Pillardy4, Ype P. de Jong1, Ira M. Jacobson5 and Andrew H. Talal1

Abstract
Background. 
Fibrosis progression varies markedly in hepatitis C virus (HCV)-infected individuals. We investigated factors that influence fibrosis progression in chronic HCV infection.

Methods. 
HCV-infected patients with at least two liver biopsies were included in this study. Associations between fibrosis progression and epidemiologic, virologic and disease-associated factors were analyzed using logistic regression and multistate Markov modeling.

Results. 
We analyzed 936 biopsies obtained from 378 individuals. Mean age at first biopsy was 48.3±9.3 years, 59.3% of patients were male, 59.9% Caucasian, and 86.7% HCV genotype 1-infected. Fibrosis progression and cirrhosis occurred in 57.4% and 5.8%, respectively. Fibrosis progression between the first and last biopsies was associated with lower fibrosis on the first biopsy (p<0.001) and with the occurrence of at least one ALT flare (>200U/L, p=0.007).

We found the highest fibrosis progression rate between stages 0 and 1 and the lowest between stages 2 and 3. Increased necroinflammation and higher ALT were associated with faster progression. HCV genotype 3-infected patients were more likely to progress to cirrhosis (p<0.001).

Conclusions. 
Fibrosis progression in HCV is not linear but varies according to stage with the highest progression in patients with the lowest fibrosis. Patients who experience ALT flares are also more likely to progress.

10.1093/infdis/jiw336

HCV Patients Face Obstacles to Treatment

HCV Patients Face Obstacles to Treatment

by Shannon Firth
Washington Correspondent, MedPage Today

Barriers include high-cost prices, restrictive state regulations

WASHINGTON -- Hepatitis C virus (HCV) patients, and particularly those on Medicare and Medicaid, continue to battle for access to curative treatments and coverage of those therapies, according to participants at a briefing on Capitol Hill on Tuesday.

The briefing was sponsored by The AIDS Institute, a nonprofit that advocates for patients with HIV and HCV. The session was billed as "An Update on Hepatitis C In the United States," and speakers included a CDC official, a representative of the the Centers for Medicare and Medicaid Services (CMS), and others

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