Showing posts with label zepatier(elbasvir and grazoprevir). Show all posts
Showing posts with label zepatier(elbasvir and grazoprevir). Show all posts

Friday, April 21, 2017

Real-World Observational Study in the U.S. Veterans Affairs System Evaluating Use of Merck’s ZEPATIER® (Elbasvir and Grazoprevir) Shows High Sustained Virologic Response Rates in Patients with Chronic Hepatitis C

Real-World Observational Study in the U.S. Veterans Affairs System Evaluating Use of Merck’s ZEPATIER® (Elbasvir and Grazoprevir) Shows High Sustained Virologic Response Rates in Patients with Chronic Hepatitis C

Study Evaluated VA Population with High Incidence of Co-Morbidities

April 21, 2017 10:00 AM Eastern Daylight Time
KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced the presentation of findings from a retrospective database analysis of patients with chronic hepatitis C virus (HCV) infection who were administered ZEPATIER® in the U.S. Department of Veterans Affairs (VA) healthcare system. For the evaluable population (n=2,436), 95.6 percent of veterans treated with ZEPATIER achieved the primary outcome of sustained virologic response (SVR), defined as undetectable HCV RNA at least twelve weeks after the end of treatment. For patients with no HCV RNA measurements at or after 12 weeks (19% of the study cohort), the analysis used HCV RNA measurements available at least four and less than 12 weeks after the end of treatment. The response rates in the real-world setting of the VA supplement the overall findings from the controlled clinical studies of ZEPATIER. These findings will be presented today in an oral session (abstract #PS-095) at The International Liver Congress™ 2017 being held in Amsterdam, the Netherlands.

In the United States, ZEPATIER is indicated for the treatment of chronic HCV GT1 or GT4 infection in adults. ZEPATIER is indicated for use with ribavirin (RBV) in certain patient populations. The U.S. Prescribing Information for ZEPATIER includes a Boxed Warning about the risk of hepatitis B virus (HBV) reactivation in patients co-infected with HCV and HBV. In controlled clinical studies of ZEPATIER, SVR was the primary endpoint defined as HCV RNA less than lower limit of quantification (LLOQ) at 12 weeks after the cessation of treatment (SVR12).

“U.S. veterans are three times more likely to have chronic hepatitis C compared to the general U.S. population and a high proportion suffer co-morbid conditions that can make treatment challenging,” said Jennifer Kramer, investigator, Michael E. DeBakey VA Medical Center, Houston, Texas, and assistant professor of medicine, department of medicine, Baylor College of Medicine. “This study shows that chronic hepatitis C antiviral treatment can result in a high rate of sustained virologic response in U.S. veterans.”

This retrospective database analysis included patients with chronic HCV treated with ZEPATIER (elbasvir and grazoprevir) in the VA healthcare system between February 1, 2016 and August 1, 2016. Study outcomes include real-world utilization and SVR rates. Please see additional information about the design, methodology and limitations of this observational study below.

After applying study exclusion criteria, 2,436 patients were included in the evaluable population cohort. The mean age of subjects was 63.5 years. The prevalence of co-morbidities as determined by ICD-9 and CPT codes as recorded in the VA database was as follows: cirrhosis (33.2%), diabetes (53.2%), depression (57.2%) and HIV co-infection (3%). Additionally, more than half of the patients had a history of drug (53.9%) or alcohol (60.5%) abuse. The population included 1,988 previously untreated patients and 448 treatment-experienced patients (322 of whom previously received an interferon-based regimen with or without an NS3/4A HCV protease inhibitor, and 126 of whom previously received an interferon-free direct-acting antiviral regimen).

A total of 95.6 percent (2,328/2,436) of patients in the evaluable population achieved SVR following treatment with ZEPATIER. The SVR rates by genotype (GT) were as follows: all GT1, 95.4 percent (2218/2324); GT1a, 93.4 percent (788/844); GT1b, 96.6 percent (1379/1428); and GT4, 96.9 percent (62/64). The SVR rates by baseline viral load (BVL) were as follows: BVL greater than 800,000 IU/ml, 94.7 percent (1497/1580); and BVL less than or equal to 800,000 IU/ml, 97.3 percent (726/746).

The SVR rates by baseline patient characteristics were as follows: male, 95.5 percent (2,245/2,350); female, 96.5 percent (83/86); African American, 95.9 percent (1,342/1,400); Hispanic, 95.1 percent (77/81); White, 95.0 percent (783/824); previously untreated, 96.1 percent (1,910/1,988); treatment-experienced, 93.3 percent (418/448); cirrhosis, 95.5 percent (772/808); without cirrhosis, 95.6 percent (1556/1628); stage 3 chronic kidney disease (CKD) (eGFR 30 to 59 mL/min/1.73m2), 96.7 percent (380/393); stage 4-5 CKD (eGFR less than 30 mL/min/1.73m2), 96.3 percent (392/407); HIV positive, 98.6 percent (73/74); HIV negative, 95.5 percent (2255/2362); history of alcohol abuse, 95.9 percent (1412/1473); no history of alcohol abuse, 95.1 percent (916/963); history of drug abuse, 95.3 percent (1251/1313); no history of drug abuse, 95.9 percent (1077/1123).

Adverse event data were not collected as part of this real-world data analysis.

“Analysis of data from real-world medical settings can provide useful insights to supplement knowledge gained from randomized clinical trials,” said Susan Shiff, senior vice president, center for observational and real-world evidence, Merck. “These data from a real-world VA setting add to the body of evidence on ZEPATIER (elbasvir and grazoprevir) and help deepen scientific understanding of the treatment of this complex disease affecting diverse, sometimes difficult to treat, patient populations.”

Study Methodology

Patients with chronic HCV treated with ZEPATIER from February 1 to August 1, 2016 were identified from the VA Corporate Data Warehouse, a national repository of VA electronic medical records. Inclusion criteria specified initiation of ZEPATIER therapy, at least 18 years of age, positive HCV RNA, and at least one inpatient or outpatient visit within a one-year period prior to treatment initiation (n=2,985). Patients were excluded if they had RBV added greater than one month after treatment initiation (n=23). Patients without SVR data or on-treatment HCV RNA data (n=494), or those treated with ZEPATIER for greater than seventeen weeks (n=32), were excluded as well. The total number of patients in the evaluable population was 2,436.

SVR was assessed based on undetectable HCV RNA at least twelve weeks after the end of treatment. For patients with no HCV RNA measurements at or after 12 weeks, the analysis used HCV RNA measurements available at least four and less than 12 weeks after the end of treatment. SVR was evaluated based on HCV RNA measurement at least 12 weeks post treatment in 81 percent of the study population.

About Real-World Data Analyses and Associated Limitations

Real-world studies analyze data generated outside of randomized clinical trials, such as through analyses of electronic medical records or claims databases, to provide insight into how medicines perform or are used from a clinical and economic viewpoint in real-world clinical settings. Information from real-world analyses alone does not provide sufficient evidence to validate efficacy or safety of a therapeutic regimen and does not provide a substitute for evidence obtained from randomized controlled clinical trials.

This study is subject to certain limitations. The VA population may not be generalizable to the entire U.S. population, due in part to the potential for a differing demographic make-up and/or risk factors. Bias may exist as diagnoses and co-morbidities were identified through ICD-9 and CPT codes. Treatment completion was identified through prescription records which may not reflect adherence. Database analyses are also prone to errors in coding and missing data, including unavailable SVR data at or after the 12-week post-treatment time point. Additionally, some laboratory data including data on the presence of baseline NS5A resistance associated substitutions was not available at the time of this analysis.

About the VA Corporate Data Warehouse (CDW)

The Department of Veterans Affairs Veterans Healthcare Administration (VHA) is supported by one of the largest integrated healthcare information systems in the United States. The VHA's Corporate Data Warehouse (CDW) was developed in 2006 to accommodate the massive amounts of data being generated from more than 20 years of use and to streamline the process of knowledge discovery to application.

Thursday, April 20, 2017

International Liver Congress/Healio - Three HCV drugs may not be better than two

Expert: Three HCV drugs may not be better than two
AMSTERDAM — The benefits of both double and triple direct-acting antiviral therapy combinations depend on myriad patient and disease factors, according to findings presented at the International Liver Congress.

Pawlotsky ran down a laundry list of agents in the pipeline, including NS5A inhibitors odalasvir (Achillion), pibrentasvir (AbbVie), and ruzasvir (Merck), and NS5B inhibitors AL-335 (Achillion), pibrentasvir (AbbVie) and uprifosbuvir (Merck). Although trials are currently underway, he suggested that ruzasvir has improved on previous compounds. “This drug has a virtually no resistance in vitro,” he said, noting that the resistance barrier was lower than Daklinza (daclatasvir, Bristol-Myers Squibb) or ledipasvir (Gilead). “You can see we’re making progress.”
Continue reading....

Recommended Reading
See more from International Liver Congress

Tuesday, April 4, 2017

Elbasvir, grazoprevir in patients with HCV infection and compensated cirrhosis

Safety and Efficacy of Elbasvir/Grazoprevir in Patients With Hepatitis C Virus Infection and Compensated Cirrhosis: An Integrated Analysis

Full Text Article
Persons with hepatitis C virus (HCV) infection are at risk of progressive liver disease, cirrhosis, and decompensation. We analyzed the effects of the direct-acting antiviral agents elbasvir and grazoprevir in patients with HCV infection and compensated cirrhosis, combining data from 6 clinical trials.

Patients with compensated, Child-Pugh A cirrhosis were allowed entry into the EBR/GZR phase 2/3 clinical trial program, and we have therefore conducted an integrated analysis of 402 patients with HCV GT1, 4, or 6 infection and compensated cirrhosis who received EBR/GZR alone or with RBV in these studies.
Continue to full text article published in the May issue of  @ Gastroenterology

Media Coverage Of This Study
From the Journals
Elbasvir, grazoprevir beat HCV despite compensated cirrhosis
Publish date: April 3, 2017
By: Amy Karon Internal Medicine News

Twelve weeks of combination therapy with elbasvir and grazoprevir (EBR/GZR) achieved sustained virologic response in 98% of treatment-naive patients with compensated cirrhosis and chronic hepatitis C (HCV) genotype 1, 4, or 6 infections, and in 89% of treatment-experienced patients, according to a pooled analysis of six industry-sponsored trials.

Concomitant ribavirin offered “no incremental benefit” for treatment-naive patients, while 16 or 18 weeks of EBR and GZR with ribavirin achieved SVR12 in 100% of treatment-experienced patients, wrote Ira M. Jacobson, MD, of Mount Sinai Beth Israel and Icahn School of Medicine at Mount Sinai, New York, and his associates.

Tuesday, March 21, 2017

ZEPATIER® now covered in Quebec for the treatment of chronic hepatitis C 

ZEPATIER® now covered in Quebec for the treatment of chronic hepatitis C 

KIRKLAND, QC, March 21, 2017 /CNW Telbec/ - Merck Canada Inc. today announced that ZEPATIER® (elbasvir/grazoprevir) will be listed among the drugs covered by Quebec's health insurance board, the Régie de l'assurance maladie du Québec (RAMQ), as of March 22. Quebec joins other jurisdictions that have approved the product for reimbursement under their public healthcare plans for chronic hepatitis C patients presenting with recognized criteria. Zepatier is indicated for the treatment of chronic infection by genotypes 1, 3 or 4 of the hepatitis C virus in adults.

The product monograph, including detailed product information and indication, is available online by clicking here.

"This announcement reflects the hepatitis C agreement between Merck and the pan-Canadian Pharmaceutical Alliance (pCPA). We are proud to contribute a solution in the fight against this disease, all the while helping reduce the cost pressure on the healthcare system," says Chirfi Guindo, President and Managing Director of Merck Canada Inc.

Hepatitis C patients without significant hepatic fibrosis who present with certain comorbidities or specific conditions will be eligible for the treatment, including those who have chronic kidney disease, who are co-infected with the human immunodeficiency virus (HIV) or the hepatitis B virus (HBV), who have undergone an organ transplant or who present with extrahepatic manifestations of the disease.

"Zepatier, which was approved in Canada in 2016 for cirrhotic and non-cirrhotic patients with a genotype 1a, 1b or 4 infection who were not previously treated or who experienced relapse after previous treatment meets the unmet needs of some groups, including renally impaired and dialysis patients," adds Dr. Marc Poliquin, a gastroenterologist with the Clinique médicale du Quartier Latin. "It also makes it possible to continue simple anti-reflux treatments, especially for patients who cannot change their acid reflux therapy without interfering with the effectiveness of hepatitis C treatment."

If not treated in time, hepatitis C can lead to serious complications, such as cirrhosis, liver cancer or the need for a liver transplant.2 In 2013, costs related to HCV complications were estimated at $161.4 million in Canada (estimates range from $85.4 million to $251.5 million).

Wednesday, March 15, 2017

HCV Next March Issue - Patient Reported Outcomes Critical in the Fight Against HCV

http://www.healio.com/hepatology/news/print/hcv-next
"HCV Next" offers information on a range of topics, which include diagnosis, new combination therapies, side effects, drug/drug interaction, guidelines, practice management issues, to name a few.

The following articles appeared in the March print edition of HCV NEXT, provided online at Healio.

Table of Contents

When patients are cured, they live longer and feel better. They will have less complications of advanced liver disease and their work productivity improves, which could potentially reduce the economic impact of HCV infection.





Zobair M. Younossi, MD, MPH


March issue of HCV Next

Wednesday, March 8, 2017

Full Text Article - Newer medications can cure HCV infections

March 22, 2017
Media Coverage of this Article
Hepatitis C Cures Lag While New Drugs Wait in the Wings
Newer medications can cure HCV infections
A new analysis reveals a dramatic transformation in the care of patients infected with hepatitis C virus (HCV) as more effective and tolerable medications have become available.

In an analysis of all HCV antiviral treatment regimens (N=107,079) initiated from 1999 through 2015 in the US Veterans Affairs national healthcare system, cure rates increased steadily from 19.2% in 1999 to 36.0% in 2010 before a remarkable increase to 90.5% in 2015. The number of patients achieving sustained virologic response was 1313 in 2010, the last year of the interferon era and increased 5.6-fold to 7377 in 2014 and 21-fold to 28,084 in 2015.

"The introduction of effective direct antiviral agents together with the allocation of appropriate funds and resources allowed the VA healthcare system to treat and cure hepatitis C in unprecedented numbers. In fact, out of approximately 57,500 patients cured of hepatitis C in the VA since 1999, approximately half were cured in a single year in 2015," said. Dr. George Ioannou, senior author of the Alimentary Pharmacology and Therapeutics analysis. "The question is whether we are delivering these medications to the patients who need them and what obstacles there are to treating and curing the majority of hepatitis C infected patients."
Source

March 15, 2017
Medscape Medical News
Dramatic Increase in HCV Cure Rate Among Veterans
Jennifer Garcia
| March 15, 2017
Use of direct-acting antiviral drugs (DAAs) has led to a 21-fold increase in the cure rate for hepatitis C virus (HCV) infections among patients treated in the Veterans Affairs (VA) healthcare system between 1999 and 2015, according to a new study.

"Considering that HCV infection is the most common cause of cirrhosis and liver cancer in the VA and the United States, that the benefits of SVR are long-lasting and that HCV clearance reduces the risk of liver cancer by 76% and all-cause mortality by 50%, the potential public health benefits of large-scale HCV treatment are great," write Dr Ioannou and colleagues.
Continue reading...

Alimentary Pharmacology and Therapeutics
Browse Early View Articles                                        
Online Version of Record published before inclusion in an issue

Transformation of hepatitis C antiviral treatment in a national healthcare system following the introduction of direct antiviral agents
A. M. Moon,P. K. Green,K. Berry,G. N. Ioannou
First published: 8 March 2017
DOI: 10.1111/apt.14021

Summary
Background
Highly effective direct antiviral agents (DAAs) for hepatitis C virus (HCV) were introduced recently. Their utilisation has been limited by high cost and low access to care.

Aim
To describe the effect of DAAs on HCV treatment and cure rates in the United States Veterans Affairs (VA) national healthcare system.

Methods
We identified all HCV antiviral treatment regimens initiated from 1 January 1999 to 31 December 2015 (n = 105 369) in the VA national healthcare system, and determined if they resulted in sustained virological response (SVR).

Results


HCV antiviral treatment rates were low (1981–6679 treatments/year) in the interferon era (1999–2010). The introduction of simeprevir and sofosbuvir in 2013 and ledipasvir/sofosbuvir and paritaprevir/ombitasvir/ritonavir/dasabuvir in 2014 were followed by increases in annual treatment rates to 9180 in 2014 and 31 028 in 2015. The number of patients achieving SVR was 1313 in 2010, the last year of the interferon era, and increased 5.6-fold to 7377 in 2014 and 21-fold to 28 084 in 2015. The proportion of treated patients who achieved SVR increased from 19.2% in 1999 and 36.0% in 2010 to 90.5% in 2015. Within 2015, monthly treatment rates ranged from 727 in July to 6868 in September correlating with the availability of funds for DAAs.

Conclusions
DAAs resulted in a 21-fold increase in the number of patients achieving HCV cure. Treatment rates in 2015 were limited primarily by the availability of funds. Further increases in funding and cost reductions of DAAs in 2016 suggest that the VA could cure the majority of HCV-infected Veterans in VA care within the next few years.

Discussion Only
View full text article
Our results demonstrate a dramatic transformation in HCV care as more effective and tolerable interferon-free DAAs have emerged. Over the last 2 years of our study period (2014–15), the VA healthcare system has significantly scaled up its provision of HCV antiviral treatment. SVR rates in our cohort increased steadily from 19.2% in 1999 to 36.0% in 2010 before a remarkable increase to 90.5% in 2015, including 91.7% among genotype 1-infected patients, which is comparable with SVR rates reported in the clinical trials of LDV/SOF (94–99%)[2-4] and PrOD (95–100%).[5, 7-9] As a result, the number of patients achieving SVR increased 21-fold from 1313 in 2010 to an estimated 28 084 in 2015. The number of patients cured in 2015 (n = 28 084) represented almost half of all patients cured in the entire 17-year period (n = 57 445). Our results suggest that with increased funding and reduced cost of DAAs, both of which already occurred in January 2016, the VA will have the ability to successfully treat the majority of the remaining 124 662 HCV-infected Veterans who were in the VA care as of January 2016 within the next few years.[29]

Several factors likely contributed to the remarkable increases in HCV treatment and cure rates that occurred in 2014 and 2015. Most importantly, the introduction of interferon-free DAAs vastly increased the VA population eligible for and willing to undergo antiviral treatment. Second, given the high relative cost of DAAs, increases in the VA funding were critical. Third, the VA embraced innovative care models including the use of teleconsultation for HCV treatment.[30] Through the Specialty Care Access Network-Extension for Community Healthcare Outcomes (SCAN-ECHO) program, which allows physicians, nurses and pharmacists to get teaching and feedback through videoconferencing from HCV experts, median time from diagnosis to treatment has decreased from more than 2 years to 6 months.[31] Finally, the VA used existing electronic databases to identify and coordinate care for HCV-infected Veterans, employed aggressive screening practises for HCV and encouraged local facilities to set ambitious treatment goals. These goals were facilitated by a national integrated hepatitis C program, which oversees and supports dedicated hepatitis C teams at every VA facility.[32]

Although a record number of highly effective antiviral regimens were prescribed in 2015 (n = 31 028), this still represented only a small proportion of all HCV-infected patients in the VA care. The number of patients who received HCV antiviral treatment could, in theory, be limited by the availability of funds for DAAs, the cost of DAAs, access to experienced treatment providers, identification and linkage to care of eligible HCV-infected patients and willingness of patients to undergo treatment. The nine-fold variation in monthly treatment rates in FY 2015 related to availability of DAA funding suggests that funding for HCV treatment was the most important determinant of treatment rates in 2015 (Figure 4).

Whilst the increases in HCV treatment and cure rates in 2014 and 2015 were impressive, there are reasons to believe that these rates will increase even further in 2016. First, in January 2016, the US Congress approved $1.5 billion for HCV DAA costs in the VA in FY 2016, doubling the funding from FY 2015.[33] Second, the VA was able to purchase LDV/SOF and PrOD in 2016 at approximately half the price paid in 2015.[31, 34] Third, the FDA approval of additional antiviral agents including daclatasvir (approved 24 July 2015), elbasvir/grazoprevir (approved 28 January16) and velpatasvir/sofusbuvir (approved 28 June 2016) will lead to increased treatment and cure rates, particularly for genotype 2 and 3-infected patients who have fewer treatment options and lower SVR rates than genotype 1-infected patients. Finally, the VA employed prioritisation criteria until February 2016, encouraging facilities and providers to give priority to the treatment of patients with advanced fibrosis or cirrhosis, those likely to have rapid progression of fibrosis and those with extrahepatic manifestations of HCV.[35] However, as of February 2016, the VA removed all HCV treatment prioritisation criteria and encouraged treatment of all patients, whilst continuing to emphasise aggressive outreach to patients with advanced fibrosis or cirrhosis.[36] This should further increase treatment rates and is in stark contrast to most healthcare systems, state Medicaid programs and insurance carriers in the US, which still restrict access to DAAs based on severity of liver disease. Following the VA's lead, state Medicaid programs in New York, Washington, Delaware, Florida and Massachusetts announced the removed restrictions on the coverage of DAAs. Also the AASLD Guidance documents, which in 2015 stated that it was ‘most appropriate to treat those at greatest risk of disease complications before treating those with less advanced disease’, were changed in 2016 stating that ‘treatment is recommended for all patients with chronic HCV infection.’[37]

Questions have been raised about the feasibility of large-scale HCV treatment efforts given the high costs of new HCV medications.[38] Some have concluded that whilst eliminating chronic HCV infection is possible, the required universal access to DAAs is not currently feasible.[39] Yet, many of the obstacles of large-scale HCV treatment are not shared by the VA. It is a large, federally funded healthcare system with the ability to negotiate lower medication prices, offer DAAs to patients for free or for a nominal co-pay, obtain influxes of funding in response to demand for DAAs and identify all HCV-diagnosed patients using its comprehensive national electronic medical records. Given these advantages and our data until 2015, the possibility of near universal cure of HCV appears realisable within the VA population. Considering that HCV infection is the most common cause of cirrhosis and liver cancer in the VA and the United States,[21] that the benefits of SVR are long-lasting[40] and that HCV clearance reduces the risk of liver cancer by 76% and all-cause mortality by 50%, the potential public health benefits of large-scale HCV treatment are great.[41-46] In addition, a recent cost-effectiveness analysis reported that DAAs must cost $47 000 per treatment course to achieve incremental cost-effectiveness ratio of $50 000 per QALY for patients with no fibrosis,[47] suggesting that it would be cost-effective or even cost saving[48] for the VA to treat all HCV-infected Veterans.[47] Another recent cost-effectiveness analysis reported that, using wholesale acquisition costs, all-oral DAA regimens such as the LDV/SOF were associated with the lowest yearly costs per SVR and was the most cost-effective option in patients with genotype 1 infection.[49]

This study has a few potential limitations. SVR values were missing in 9.6% of all patients, many of whom initiated antiviral treatment in the latter half of 2015 and had not yet accumulated sufficient follow-up time to ascertain SVR (Table S11). Missing SVR values were imputed using era-specific logistic regression models that included multiple baseline predictors of SVR as well as duration of treatment and antiviral regimen, which increases confidence that the estimated SVR rates are accurate. The magnitude of increases in treatment and cure rates that we report in the VA may not be directly generalisable to the non-Veteran US population for many of the previously mentioned reasons including that some payers have introduced prior authorisation rules limiting HCV treatment to those with advanced liver fibrosis.[50, 51] Although we report dramatic increases in treatment rates temporally related to the introduction of DAAs and to the availability of funding for DAAs especially in 2015 (Figure 4), our study was not designed to formally evaluate other factors that may influence treatment rates such as staffing, infrastructure, administration, training, identification of patients and linkage to care. With the funding increases and DAA price reductions that occurred in 2016, such factors may very well become the limiting factors determining treatment rates in the near future.

In conclusion, the VA health care system has dramatically increased the number of HCV treatments initiated and resulting instances of SVR in 2015. The acceleration in treatment provision, particularly in August and September 2015, demonstrates the abilities of the VA's existing HCV treatment infrastructure when sufficient funding for DAAs is available. These results raise the spectre of near complete eradication of HCV within the VA system, which given the 124 662 VA patients with diagnosed HCV, would substantially reduce the burden of HCV within the entire country and prevent tens of thousands of deaths.

Continue to full text article:
http://onlinelibrary.wiley.com/doi/10.1111/apt.14021/full

Wednesday, February 22, 2017

Ontario Becomes First Province To List EPCLUSA™ On Public Drug Plan To Treat All Six Genotypes Of Chronic Hepatitis C Infection

Feb. 22, 2017
Ontario Becomes First Province To List EPCLUSA™ On Public Drug Plan To Treat All Six Genotypes Of Chronic Hepatitis C Infection

-- Ontario Also Broadens Access for Patients
with Less Advanced Disease with Co-Factors --

MISSISSAUGA, ON, Feb. 22, 2017 /CNW/ - Gilead Sciences Canada, Inc. (Gilead Canada) today announced, effective February 28th, 2017, Ontario will provide public access to EPCLUSA™ (sofosbuvir/velpatasvir) tablets, the first once-daily, pan-genotypic single tablet regimen for the treatment of adults with genotype 1-6 chronic hepatitis C virus (HCV) infection. This listing will support patients to access curative therapy, and will advance Canada's efforts to achieving its World Health Organization commitment to eliminate hepatitis C by 2030.

EPCLUSA, one tablet taken daily for 12 weeks, is for use in adult patients without cirrhosis or with compensated cirrhosis, and in combination with ribavirin (RBV) for those with decompensated cirrhosis. It is also the first single tablet regimen approved for the treatment of patients with genotypes 2 and 3, without the need for RBV.

The approval of EPCLUSA was supported by data from four international Phase 3 studies, ASTRAL-1, ASTRAL-2, ASTRAL-3 and ASTRAL-4. Of the 1,035 patients with compensated disease treated with EPCLUSA for 12 weeks in the ASTRAL-1, ASTRAL-2 and ASTRAL-3 studies, 1,015 (98 per cent) achieved SVR12 (sustained virologic response 12 weeks after the end of treatment). In ASTRAL-4, patients with decompensated cirrhosis receiving EPCLUSA with RBV for 12 weeks achieved a high SVR12 rate (94 per cent) compared to those who received EPCLUSA for 12 weeks or 24 weeks without RBV (83 per cent and 86 per cent, respectively). The most common adverse events in the four ASTRAL studies were headache, fatigue and nausea, and were comparable in incidence to the placebo group included in ASTRAL-1.

The Ontario listing follows the completion of a recent agreement between the pan-Canadian Pharmaceutical Alliance (pCPA) with member provincial, territorial and federal drug plans to fund this innovative therapy for patients. In addition, aligned with the pCPA agreement, Ontario will expand access to include patients with less advanced disease (fibrosis scores of F0 or F1) if they have been diagnosed with certain co-existing factors. All HCV patients with fibrosis scores of F2 or higher also remain eligible for reimbursement.

For more information on the expanded access criteria: http://www.health.gov.on.ca/en/pro/programs/drugs/formulary42/summary_edition42_20170228.pdf

"We now have the ability to cure the majority of patients with chronic HCV with a simple, safe and effective 12-week treatment, regardless of genotype or patient history," said Dr. Curtis Cooper, Associate Professor of Medicine, University of Ottawa, and Director, The Ottawa Hospital and Regional Hepatitis Program. "Broader access to EPCLUSA, particularly at the earlier stage of the disease, means that we can move more quickly to help patients achieve a cure and improve their quality of life, while saving valuable funds associated with the significant long-term burden of illness and costs to the healthcare system."

In Ontario, the Public Health Agency of Canada estimates that more than 102,000 people are living with chronic HCV. In Canada, it is estimated that 250,000 Canadians are living with chronic HCV, with thousands of new cases diagnosed each year. There are six genotypes of hepatitis C. Genotype 1 infection is the most prevalent genotype in Canada representing 64.1 per cent of infected individuals. Genotypes 2 and 3 account for approximately 14.1 per cent and 20.2 per cent of infections in Canada, whereas genotypes 4, 5, and 6 are less prevalent in Canada (0.3 per cent).

"Canada, and other countries, have committed to eliminating hepatitis C by 2030, and to accomplish this goal we need to significantly increase treatment rates," said Dr. Morris Sherman, Chairperson, Canadian Liver Foundation and hepatologist at Toronto General Hospital. "Treatment regimens are getting shorter, simpler and more widely effective across genotypes meaning that treatment is now easier for both patients and physicians to manage.

"Currently, an estimated 44 per cent still remain undiagnosed, so increasing treatment rates also means improving screening and diagnosis, which is why the Canadian Liver Foundation recommends that all Canadians born between 1945-1975 receive a one-time test for hepatitis C," added Dr. Sherman. "Treatment should be an option for everyone, but the cost of treatment has been an obstacle. We're glad to see that the pCPA and the provinces are taking steps to make these treatments accessible regardless of where someone lives or their ability to pay."

"Gilead Canada is pleased that the pCPA and the Ontario Ministry of Health and Long-Term Care are recognizing the innovation and clinical value of EPCLUSA for the treatment of all genotypes of hepatitis C in a single tablet regimen," said Kennet Brysting, General Manager, Gilead Canada. "Broader treatment access for patients will potentially have a profound impact on disease elimination efforts in Canada, and supporting such efforts is a key priority for our company. We will continue to work closely with all jurisdictions to bring this simple and cost-effective curative treatment to all eligible patients, regardless of their genotype or stage of fibrosis."

Related
ZEPATIER®
Feb. 22, 2017
Ontario and British Columbia expand treatment access to chronic hepatitis C (CHC) patients
Effective February 28, Ontario will become the first province to reimburse ZEPATIER®  (elbasvir/grazoprevir), a simple one pill, once daily, 12 week no ribavirin regimen for most patients, and will be followed by British Columbia on March 21

  • In addition to patients with liver fibrosis stage F2+, patients with liver fibrosis stage F0 and F1 with poor prognostic factors, who had no public access to a potential cure under existing public plans, are now eligible for treatment
  • Patients with CHC genotypes 1 and 4, with chronic kidney disease (CKD) and intraveinous drug users - representing the highest number of new cases1 - will have access to treatment

  • KIRKLAND, QC, Feb. 22, 2017 /CNW Telbec/ - An estimated 185,000 people in Ontario and
    British Columbia have hepatitis C, a chronic liver disease that, if left untreated, can lead to cirrhosis, liver cancer and liver transplants.2 Merck Canada Inc. today announced that the Government of Ontario and of British Columbia are strengthening their commitment in the global fight against hepatitis C by becoming the first provinces to reimburse ZEPATIER® (elbasvir/grazoprevir). Zepatier is indicated in the treatment of chronic hepatitis C genotypes 1, 3 or 4 infections in adults patients.3 The product monograph with detailed product indication is available online by clicking here.
    "We're pleased to have worked with the pan-Canadian Pharmaceutical Alliance (pCPA) and participating jurisdictions to provide access to Zepatier to patients who need it, including those at higher risk," says Chirfi Guindo, President and Managing Director, Merck Canada Inc. "Hepatitis C is a curable disease, and today's announcement brings us one step closer to eradicating the virus in Canada."

    For the first time special populations, including hepatitis C patients with fibrosis stage F0 and F1 who are co-infected with human immunodeficiency virus (HIV) or hepatitis B virus or who have chronic kidney disease (CKD), will be eligible for treatment as of February 28th under the Ontario Drug Benefit Program (ODB), and as of March 21st under B.C.'s PharmaCare program.

    "The publicly funded availability of Zepatier in Canada for hepatitis C treatment represents a major milestone in the access to care for patients; not only those patients with advanced liver damage or cirrhosis have access to treatment but now those who may progress to more serious liver damage in the future can be cured. The dedication of Merck to addressing clinical studies in targeted and specific populations in need such as those with cirrhosis, advanced kidney disease and those who inject drugs, allow all treaters to use this treatment regimen to cure their patients safely," said Dr. Sergio Borgia, Medical Director and Corporate Division Head of the Infectious Disease Program at William Osler Health System.

    These provincial public funding announcements follow the World Health Organization's (WHO) adoption of  the first global health strategy on viral hepatitis, which includes a goal of 30% reduction in new cases of hepatitis B and C by 2020 and a 10% reduction in mortality, as well as increased access to treatment for hepatitis B and C.4 In June 2016, the Government of Canada announced its commitment in the global fight against viral hepatitis with the adoption of the Global Strategy on Viral Hepatitis. It has for objective to eliminate hepatitis B and C by 2030.5

    Feb. 22, 2017
    More patients to benefit from hepatitis C treatments
    Thousands of British Columbians living with hepatitis C will have better access to treatment as a result of successful negotiations brokered by the pan-Canadian Pharmaceutical Alliance (pCPA).
    “This agreement changes the landscape for hepatitis C patients living in B.C.,” said Health Minister Terry Lake. “Not only are there four new treatment options for what is now a curable virus, but the savings that were negotiated will allow us to cover treatment options for all hepatitis C patients – rather than just those in more advanced stages of the disease.”
    British Columbia and Ontario co-led the negotiations with the drug manufacturers on behalf of the pCPA. The alliance helps provinces and territories leverage their collective buying power and negotiate better prices for new drugs.....

    Daklinza (daclatasvir) – new
    Epclusa (sofosbuvir/velpatasvir) – new
    Harvoni (ledipasvir/sofosbuvir)
    Sovaldi (sofosbuvir)
    Sunvepra (asunaprevir) – new
    Zepatier (elbasvir/grazoprevir) – new

    Continue Reading...

    Wednesday, February 15, 2017

    Elbasvir/Grazoprevir in Patients with Hepatitis C Virus Infection and Compensated Cirrhosis: an Integrated Analysis

    Safety and Efficacy of Elbasvir/Grazoprevir in Patients with Hepatitis C Virus Infection and Compensated Cirrhosis: an Integrated Analysis
    Ira M. Jacobson, Eric Lawitz, Paul Y. Kwo, Christophe Hézode, Cheng-Yuan Peng, Anita Y.M. Howe, Peggy Hwang, Janice Wahl, Michael Robertson, Eliav Barr, Barbara A. Haber

    DOI: http://dx.doi.org/10.1053/j.gastro.2017.01.050
    Publication stage: In Press Accepted Manuscript
    Published online: February 10, 2017

    Full Text

    Abstract
    Background & Aims
    Persons with hepatitis C virus (HCV) infection are at risk of progressive liver disease, cirrhosis, and decompensation. We analyzed the effects of the direct-acting antiviral agents elbasvir and grazoprevir in patients with HCV infection and compensated cirrhosis, combining data from 6 clinical trials.

    Methods
    We performed an integrated analysis of 402 patients with HCV genotype 1, 4, or 6 infection and Child-Pugh A compensated cirrhosis enrolled in 6 clinical trials. All patients received elbasvir/grazoprevir 50 mg/100 mg once daily, with or without ribavirin, for 12–18 weeks. The primary end point was sustained virologic response 12 weeks after completion of therapy (SVR12), defined as a level of HCV RNA below 15 IU/mL.

    Results
    Among treatment-naïve and treatment-experienced patients receiving elbasvir/grazoprevir for 12 weeks, 97.8% (135/138) and 88.9% (48/54) achieved SVR12, respectively. Among patients receiving elbasvir/grazoprevir for 12 weeks, addition of ribavirin did not increase the proportion of treatment-naïve patients who achieved an SVR12 (90.3%, 28/31) or treatment-experienced patients who achieved an SVR12 (91.4%, 74/81). All (49/49) treatment-experienced patients receiving elbasvir/grazoprevir with ribavirin for 16 or 18 weeks achieved SVR12, and 93.9% (46/49) of patients receiving elbasvir/grazoprevir without ribavirin for 16 or 18 weeks achieved SVR12. Virologic failure was higher among patients with HCV genotype 1a infections compared to patients with genotype 1b or 4 infections—particularly in patients who had not responded to previous interferon therapy. Baseline tests for resistance-associated variants (RAVs) led to an individualized approach for selecting treatment duration and established a need for ribavirin for patients with HCV genotype 1a infection and RAVs, regardless of treatment history. Among patients with HCV genotype 1a infection with and without baseline RAVs in HCV nonstructural protein 5A who received elbasvir/grazoprevir for 12 weeks, 73% (8/11) and 98% (96/98) achieved SVR12, respectively. Both patients with HCV genotype 1a infection with baseline RAVs who received 16 or 18 weeks of elbasvir/grazoprevir and ribavirin achieved SVR12. Grade 3 or 4 increases in levels of alanine aminotransferase and aspartate aminotransferase, which did not cause symptoms, were reported in 2.3% of patients (6/264) receiving elbasvir/grazoprevir. Serious adverse events were reported in 3.0% of patients (8/264) and no patient had a decompensation-related event.

    Conclusion
    In an analysis of data from 6 clinical trials, we found rates of SVR12 to range from 89% to 100% in patients with HCV genotype 1, 4, or 6 infections and compensated cirrhosis treated with elbasvir/grazoprevir, with or without ribavirin. Addition of ribavirin to a 12-week regimen of elbasvir/grazoprevir had little effect on proportion of treatment-naïve or treatment-experienced patients who achieved an SVR12. However, virologic failure did not occur in any treatment-experienced patients when the duration of elbasvir/grazoprevir and ribavirin therapy was extended to 16 or 18 weeks. Baseline analysis of RAVs (or in the absence of this test, a history of nonresponse to interferon) can be used to determine treatment duration and need for ribavirin in patients with HCV genotype 1a infection.

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    Link To Full Text Article 
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    Thursday, January 26, 2017

    Hepatitis C Virus Genotype 4: Genotype 1's Little Brother

    2017 Jan;24(1):4-12. doi: 10.1111/jvh.12620. Epub 2016 Dec 1.

    Hepatitis C Virus Genotype 4: Genotype 1's Little Brother
    J. Llaneras; M. Riveiro-Barciela; M. Buti; R. Esteban


    Introduction
    Chronic hepatitis C virus (HCV) infection affects approximately 130-150 million individuals worldwide.[1] Twenty per cent of chronic HCV infections are caused by HCV genotype 4 (GT4).[2] Infection by this genotype is more common (and highly prevalent), in the Middle East and Africa, where GT4 is responsible for more than 80% of HCV infections. In some Mediterranean European countries, especially Italy, France, Greece and Spain, the prevalence of GT4 has increased, accounting for 10%-20% of HCV infections. This genotype is usually seen in intravenous drugs users, HCV/HIV co-infected patients and immigrants from Africa or the Middle East.[3, 4] The prevalence of this infection in the United States is estimated at around 1%.[5]

    In the last 5 years, HCV treatment has undergone a major change due to emergence of the new direct-acting antiviral (DAA) agents. Various therapeutic strategies have been designed to treat several HCV genotypes with these drugs.

    The Food and Drug Administration (FDA) and the European Medicines Agency (EMA) recently approved several drugs for the treatment of chronic HCV GT4 infection. The classical therapies for GT4, such as pegylated alpha interferon 2a or 2b (PegIFN) and ribavirin (RBV), are giving way to the new DAA agents. The following combinations have been approved for GT4 therapy: sofosbuvir (SOF), an NS5B polymerase inhibitor[6] plus ribavirin; sofosbuvir plus simeprevir (SMV), an NS3/4A protease inhibitor[7]; sofosbuvir plus daclatasvir (DCV), an NS5A protease inhibitor[8]; ombitasvir (OBV), an NS5A protein inhibitor, plus paritaprevir, another NS3/4A protease inhibitor, boosted with ritonavir (PTV/r)[9]; the fixed-dose combination of sofosbuvir with ledipasvir (LDV), an NS5A protease inhibitor[10]; the fixed-dose combination of elbasvir (EBR), an NS5A inhibitor, and grazoprevir (GZR), an NS3/4A protease inhibitor[11]; and sofosbuvir with velpatasvir (VEL), an NS5A protein inhibitor.[12]

    As compared with HCV genotype 1 (GT1), few trials have been performed in GT4 patients, and the samples studied are smaller. All the various DAA combinations have demonstrated effectiveness and safety in the treatment of patients with GT4 infection. However, the AASLD and EASL guidelines do not recommended them all, and rating of the evidence differs because of the type of studies performed, the safety profiles reported, drug–drug interactions, the availability across different countries and the cost of treatment.[13, 14] As in other HCV genotypes, the new DAA agents have led to improvements in the efficacy and safety of treatment in GT4 and have displaced PegIFN combined therapies to a secondary position (Tables 1 and 2).

    Table 1. EASL recommended therapies for chronic HCV gentoype 4[13]
    RecommendationRegimen and daily dosingDuration (weeks)
    1. DCV, daclatasvir; LDV, ledipasvir; OBV, ombitasvir; PTR/r, paritaprevir/ritonavir; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir.
    2. a Patients with compensated cirrhosis with contraindications to the use of ribavirin on treatment should receive the fixed-dose combination of sofosbuvir and ledipasvir for 24 weeks without ribavirin.
    IFN-free regimens in treatment-naive patients with or without cirrhosis
    A1LDV/SOF (90 mg/400 mg)12
    A1SOF/VEL (400 mg/100 mg)12
    A1OBV/PTV/r (25 mg/150 mg/100 mg) + weight-based RBV12
    A1EBR/GZR (50 mg/100 mg)12
    A1SOF + SMV (400 mg/150 mg)12
    B2SOF + DCV (400 mg/60 mg)12
    IFN-free regimens in treatment-experienced patients with or without cirrhosis
    B1LDV/SOF (90 mg/400 mg) + weight-based RBV12a
    A1SOF/VEL (400 mg/100 mg)12
    A1OBV/PTV/r (25 mg/150 mg/100 mg) + weight-based RBV24
    B1SOF + SMV (400 mg/150 mg) + weight-based RBV12a
    B2SOF + DCV (400 mg/60 mg) + weight-based12a

    Table 2. American Association for the Study of Liver Diseases (AASLD) recommended therapies for chronic hepatitis C virus (HCV) genotype 4

    RecommendationRegimen and daily dosingDuration (weeks)
    1. a Patients with prior on-treatment virological failure should be treated with 16 weeks and adding weight-based ribavirin.
    Treatment-naive or treatment-experienced with or without cirrhosis recommended regimens[14]
    A1OBV/PTV/r (25/150/100 mg) + weight-based RBV12
    A1SOF/VEL (400/100 mg)12
    B2EBR/GZR (50/100 mg)12a
    B2LDV/SOF (90/400 mg)12
    This article reviews the currently available data and the new treatments under development for patients with chronic HCV GT4 infection.

    2 Historical Situation
    2.1 Interferon-based therapies
    Four IFN-based therapies have been approved by the FDA and the European Medicines Agency (EMA). Currently, none of them are recommended by the American Association for the Study of Liver Diseases (AASLD) or the European Association for the Study of the Liver (EASL) guidelines because of the superiority of IFN-free therapies in terms of efficacy and safety.

    2.1.1 Pegylated interferon plus ribavirin
    The first treatment for GT4 patients was PegINF plus ribavirin (RBV), which provided a sustained virological response (SVR) rate of around 45% in treatment-naive patients receiving pegylated alpha interferon (2a or 2b) plus RBV for 24-48 weeks.[15-17] In a large real-world cohort study, PROPHESYS, 317 patients with chronic HCV GT4 infection received this regimen.[18] The overall SVR24 rate (sustained virological response at week 24) was 41%, with a lower value (27%) in patients with cirrhosis. The limitations of this therapy are the lengthy duration, adverse events associated with PegINF, and low applicability in patients with advanced liver disease.

    2.1.2 Sofosbuvir plus pegylated interferon plus ribavirin
    Sofosbuvir is a potent nucleotide analogue inhibitor of the HCV NS5B polymerase with activity against all HCV genotypes.[6] SOF plus PegINF and RBV for 12 weeks was evaluated in the NEUTRINO trial,[19] a phase-III study that included 28 patients infected by HCV GT4. SVR12 (sustained virological response at week 12) was achieved in 27 of the 28 patients (96%). The limitation of this regimen is that it is PegIFN-based, with all that this implies.

    2.1.3 Simeprevir plus pegylated interferon plus ribavirin
    Simeprevir, an NS3/4 inhibitor, is active against genotypes 1, 2 and 4.[7] The RESTORE study evaluated the efficacy and safety of SMV plus PegIFN plus RBV for 12 weeks followed by PegIFN and RBV for an additional period of 12 or 36 weeks in 107 patients HCV infected with GT4, including treatment-naïve and treatment-experienced patients.[20] Overall, 65.4% (70/107) of patients achieved SVR12, with a lower rate in treatment-experienced patients.

    2.1.4 Daclatasvir plus pegylated interferon plus ribavirin
    Daclatasvir is an NS5A inhibitor with activity against all HCV genotypes.[8] In the phase-III COMMAND-4 study, 124 GT4 patients were randomized to receive DCV plus PegIFN plus RBV for 24-48 weeks or PegIFN plus RBV for 48 weeks.[21] SVR12 rates were 82% (67/82) with DCV plus PegIFN plus RBV vs 43% (18/42) with PegIFN plus RBV.
    Although SVR12 rates are higher in DAA plus PegIFN regimens than in PegIFN plus RBV, DAA plus PegIFN regimens do not achieve higher SVR12 rates than the currently available IFN-free combinations, which have the additional advantages of a shorter treatment duration and fewer adverse events.

    3 Interferon-Free Therapies
    Direct-acting antiviral agents have brought about a revolution in the efficacy and safety of HCV treatment and have enabled treatment of more complex cases: patients with advanced liver disease or decompensated disease, those with IFN contraindications or intolerance and those unwilling to receive IFN treatment.

    Among IFN-free therapies, four combinations are recommended in the new, updated AASLD guidelines[14] for treating naïve and experienced patients (with or without cirrhosis): two NS5B inhibitor plus NS5A inhibitor combinations, sofosbuvir/ledipasvir and sofosbuvir/velpatasvir; and two NS5A inhibitor plus NS3/4 inhibitor combinations, ombitasvir/paritaprevir/ritonavir (with RBV) and elbasvir/grazoprevir. In most cases, all these combinations are used in 12-week regimens (Table 3).

    Table 3. Interferon-free combination regimens with new DAA agents with activity in GT4

    NS3/4NS5BNS5A
    1. a Fixed-dose combination.
     SofosbuvirLedipasvira
     SofosbuvirVelpatasvira
     SofosbuvirDaclatasvir
    SimeprevirSofosbuvir 
    Paritaprevir/r Ombitasvira
    Grazoprevir Elbasvira

    3.1 NS5B inhibitor plus NS5A inhibitor
    3.1.1 Sofosbuvir/ledipasvir
    The NIAID SYNERGY study, a phase-IIA trial, evaluated the combination of SOF/LDV in a cohort of 21 HCV GT4-infected patients.[22] The regimen was SOF 400 mg combined with LDV 90 mg in one pill, once daily for 12 weeks. The cohort included 13 (62%) treatment-naïve patients and eight (38%) treatment-experienced patients; three patients had moderate–severe liver fibrosis (F3 in 2 and F4 in 1). Twenty (95%) patients achieved SVR12 (100% in the protocol analysis). One patient did not complete the 12-week treatment regimen because of nonadherence. There were no treatment discontinuations due to adverse events. The most common side effects were diarrhoea, fatigue, nausea and upper respiratory tract infection. This controlled study showed that this one-pill once-daily treatment was highly effective and safe in GT4-infected patients. Further studies are needed to expand the recommendations for difficult-to-treat patients with GT4 infection.

    Abergel et al.[23] evaluated SOF/LDV for 12 weeks in 44 patients infected by HCV GT4, including 10 (23%) with cirrhosis and 22 (50%) who were treatment-experienced. The overall SVR12 rate was 93%. As to NS5A resistance-associated substitutions (RASs), 22 of 27 (89%) patients with NS5A RASs and all those without RASs achieved SVR12. L30R was the most prevalent NS5A resistant-associated substitution (RAS) in the cohort. NS5B RASs were not detected at baseline. Three patients relapsed within the first 4 weeks after completion of treatment. Two were treatment-experienced, and none had cirrhosis. The most common side effects were similar to those seen in other cohorts (asthenia, headache and fatigue).

    3.1.2 Sofosbuvir/velpatasvir
    Velpatasvir is a pangenotypic HCV NS5A inhibitor with antiviral activity against genotypes 1-6. The EMA and FDA have authorized use of the SOF 400 mg plus VEL 100 mg fixed combination in one pill daily.[12]

    Sofosbuvir/velpatasvir was evaluated in ASTRAL-1, a phase-III study that enrolled 624 patients with HCV infection, including some cirrhotic and treatment-experienced patients.[24] Patients previously treated with DAA agents were excluded. Overall, 116 (19%) patients had genotype 4 infection, 121 (19%) had cirrhosis, and 423 (68%) were treatment-naïve. All patients received a 12-week regimen of SOF/VEL. SVR12 rates were 100% (116/116) in GT4-infected patients, regardless of their fibrosis status or whether they had previously received treatment. At baseline, 50 GT4-infected patients had NS5A RASs, but all achieved SVR12. No significant differences were observed in adverse event rates between the SOF/VEL regimen and placebo. The most frequent adverse effects were headache, fatigue and nasopharyngitis.

    Although the GT4-infected sample size was small, this 12-week combination regimen was easy to comply with, highly effective, and safe, even in those with advanced liver fibrosis and treatment-experienced patients.

    3.2 NS5A inhibitor plus NS3/4 inhibitor
    3.2.1 Ombitasvir/paritaprevir/ritonavir
    Ombitasvir is a NS5A inhibitor and paritaprevir a NS3/4A protease inhibitor that is coadministered with low-dose ritonavir to increase paritaprevir serum levels.[9] This combination was analysed in the multicentre phase-IIb, PEARL-I study[25] including 135 noncirrhotic GT4 patients, 86 (63.7%) of whom were treatment-naïve. Treatment-experienced patients had failed PegINF plus RBV. Treatment-naïve patients were randomly assigned to a 12-week regimen of OBV plus PTV/r with or without weight-based RBV. All treatment-experienced patients received a 12-week regimen of OBV plus PTV/r with weight-based RBV. In treatment-naïve patients, SVR12 rates were 100% (42/42) in the RBV-containing regimen and 91% (40/44) in the RBV-free regimen, with no significant differences. All treatment-experienced patients achieved SVR12 (49/49). Two patients in the treatment-naïve group with an RBV-free regimen prematurely discontinued treatment: one was lost to follow-up and the other experienced viral breakthrough at week 8 of treatment. Two other patients in the same group relapsed within 12 weeks post-treatment. All were subtype GT4d, and all had RASs at the time of failure that were not present at baseline. The predominant NS3 RAS was D168V, and the NS5A RASs were L28S or L28V. The regimen was found to be safe. The most common adverse effect was headache, but there were no adverse event-related discontinuations or dose interruptions.
    The efficacy and safety of this regimen in cirrhotic patients was evaluated in the multicentre, phase-III AGATE-I study,[26] including HCV GT4-infected treatment-naïve or treatment-experienced patients with compensated cirrhosis. Patients were randomized into two arms; one received a 12-week regimen of OBV plus PTV/R with weight-based RBV once daily and the other a 16-week regimen with the same combination. Preliminary results showed SVR12 rates of 97% (57/59) in patients with the 12-week regimen vs 98% (60/61) with the 16-week regimen. One patient receiving the 12-week regimen who did not achieve SVR12 had discontinued treatment on day 1. The other was a man with HCV subtype GT4a and a previous null response to PegINF plus RBV. At baseline, he had the P58L NS5A RAS and no NS3 RASs. At failure, he showed newly emergent NS5A RASs: L28M and Y93H. Thirty-six patients in the AGATE-I cohort had RASs at baseline, and all but one achieved SVR12. In the 16-week regimen arm, SVR12 results could not be reported for one patient because of missing data. This combination was well tolerated, with no discontinuations due to adverse events. The most important events recorded were asthenia, fatigue, headache and anaemia, which were more common in the lengthier, 16-week arm.

    AGATE-II is a phase-III trial carried out in Egypt, evaluating OBV plus PTV/r with RBV for GT4-infected patients, including those with compensated cirrhosis.[27] In total, 160 patients were enrolled, 100 noncirrhotic and 60 compensated cirrhotic patients. Half were treatment-experienced (61% prior null responders, 24% prior relapsers and 15% partial responders). Noncirrhotic patients received co-formulated OBV plus PTV/R once daily plus weight-based RBV for 12 weeks. Patients with compensated cirrhosis were randomized into two arms with the same regimen for 12 weeks and 24 weeks, respectively. SVR12 rates were high 94% (94/100) in the noncirrhotic arm: one patient failed while on treatment, one discontinued by withdrawing consent, data were missing in another, and three patients relapsed. SVR12 in the 12-week cirrhotic arm was 97% (30/31), with a single patient failing on treatment, and SVR12 in the 24-week arm was 96% (27/29), with missing data in one patient during follow-up and one on-treatment failure. The most common adverse events were fatigue (12%) and headache (15%). Extension of therapy to 24 weeks did not provide any additional benefits in cirrhotic patients, and there were more adverse events and a higher haemoglobin decrease in this arm.

    3.2.2 Elbasvir plus grazoprevir
    Elbasvir is an NS5A inhibitor, active against genotypes 1, 2a, 3, 4, 5 and 6. Grazoprevir is an NS3/4 protease inhibitor that is active against HCV genotypes 1, 2, 4, 5 and 6.[11]
    The C-EDGE treatment-naïve study was an international, randomized, blinded, placebo-controlled trial investigating the combination of EBR 50 mg plus GZR 100 mg in one daily pill for 12 weeks in treatment-naive cirrhotic and noncirrhotic patients with chronic HCV genotype 1, genotype 4 and genotype 6 infection.[28] The overall SVR12 rate for all genotypes was 95%. SVR12 in GT4 treatment-naive patients was 100% (18/18). RASs were analysed in GT4 patients at baseline. NS3 RASs were present in seven of 18 (39%) patients, NS5A RASs in nine of 18 (50%) patients, and both RASs (NS5A and NS3) were found in two patients. In this study, the presence of RASs did not have an impact on SVR12 in GT4 patients. The most common adverse events in the cohort were headache (17%), fatigue (16%) and nausea (9%).

    The C-EDGE treatment-experienced study evaluated the efficacy of a 12-week or 16-week regimen in HCV-infected patients who had failed PegIFN treatment. Patients received a one-pill regimen of EBR plus GZR with or without weight-based RBV.[29] SVR12 rates in GT4 patients receiving the 12-week regimen without or with RBV were 78% (7/9) and 93% (14/15), respectively. SVR12 rates in those receiving the 16-week regimen without or with RBV were 60% (3/5) and 100% (8/8), respectively. Baseline RASs and subgenotypes did not seem to have an impact on SVR12 rates.
    Asselah et al.[30] reported data from phase-II and phase-III studies including a total of 103 GT4-infected patients treated with EBR/GZR. Sixty-six treatment-naïve patients were enrolled to receive EBR/GZR for 12 weeks and another 10 patients received the same regimen plus weight-based RBV for 12 weeks. Ninety-six (54/56) patients achieved SVR12 in the RBV-free regimen, one patient was lost to follow-up, and other relapsed. In the RBV regimen, SVR12 rates were 100% (10/10). Treatment-experienced patients were divided into four arms, 12 weeks or 16 weeks of treatment with or without weight-based RBV. SVR12 rates were higher in the 16-week regimens and RBV-associated regimens than in the 12-week regimens or RBV-free regimens. Two patients in the 12-week regimen relapsed, one in the RBV-associated regimen and the other in the RBV-free regimen. The other two patients failed on treatment in the 16-week regimen without RBV. All treatment-naive patients who had NS5A RASs at baseline achieved SVR12. In total, 81% (13/16) of treatment-experienced patients who achieved SVR12 had NS5A RASs at baseline, and 100% of treatment-experienced patients with NS3 RASs at baseline achieved SVR12.

    The 12-week regimen without RBV is an attractive combination for treatment-naïve patients and PegIFN relapsers, including patients with compensated cirrhosis. In treatment-failed patients, 16-week therapy duration is associated with a higher SVR12 (Table 4).

    Table 4. (a) SVR12 in GT4 hepatitis C virus (HCV)-infected patients without liver cirrhosis treated with IFN-free regimens. (b) SVR12 in GT4 HCV-infected patients with liver cirrhosis treated with IFN-free regimens. (c) SVR12 in GT4 HCV-infected patients with and without liver cirrhosis treated with IFN-free regimens
    Treatment regimenDuration (weeks)NoPrior HCV treatmentSVR12 rate % (no SVR/total)Virological failures (no of cases)
    1. EBR, elbasvir; GZR, grazoprevir; LDV, ledipasvir; OBV, ombitasvir; PTR/R, paritaprevir/ritonavir; RBV, ribavirin; SOF, sofosbuvir; TE, treatment-experienced patients; TN, treatment-naive patients; VEL, velpatasvir.
    2. a Regimen without ribavirin.
    3. b Regimen with ribavirin.
    (a) NS5B/NS5A
    SOF/VEL (ASTRAL-1)[24]1289Treatment-experienced Treatment-naive100% (89/89)
    SOF/LDV (NIAID SYNERGY)[22]1214Treatment-experienced Treatment-naive93% (13/14)
    SOF/LDV Abergel et al.[23]1234Treatment-experienced Treatment-naive91% (31/34)Relapsers: 3
    NS5A/NS3/4
    OBV/PTV/r (PEARL-1)[25]12135Treatment-experienced Treatment-naive91% (40/44) TNaVirological breakthrough: 1 Relapsers: 2
    100% (42/42) TNb
    100% (49/49) TEb
    OBV/PTV/r + RBV (AGATE-II)[27]12100Treatment-experienced Treatment-naive94% (94/100)Breakthrough: 1 Relapsers: 3
    (b) NS5B/NS5A
    SOF/VEL (ASTRAL-1)[24]1227Treatment-experienced Treatment-naive100% (27/27)
    SOF/LDV (NIAID SYNERGY)[22]127Treatment-experienced Treatment-naive100% (7/7)
    SOF/LDV Abergel et al.[23]1210Treatment-experienced Treatment-naive100% (10/10)
    NS5A/NS3/4
    OBV/PTV/r + RBV (AGATE-I)[26]12
    16
    120Treatment-naive
    Treatment-experienced
    97% (57/59) 12 weeks
    98% (60/61) 16 weeks
    Virological breakthrough: 1
    OBV/PTV/r + RBV (AGATE-II)[27]12
    24
    60Treatment-naive
    Treatment-experienced
    97% (30/31) 12 weeks
    96% (27/29) 24 weeks
    Virological breakthrough: 2
    (c) NS5A/NS3/4
    GZR/EBR (C-EDGE TN)[28]1218Treatment-naive100% (18/18)
    GZR/EBR (C-EDGE TE)[29]12
    16
    37Treatment-experienced78% (7/9) 12 weeksa
    93% (14/15) 12 weeksb
    60% (3/5) 16 weeksa
    100% (8/8) 16 weeksb
    GZR/EBR Asselah et al.[30]12
    16
    103Treatment-experienced Treatment-naiveTN
    96% (54/56) 12 weeksa
    100% (10/10) 12 weeksb
    TE
    78% (7/9) 12 weeksa
    93% (14/15) 12 weeksb
    66% (3/5) 16 weeksa
    100% (8/8) 16 weeksb
    Relapsers: 3 Virological breakthrough: 2

    3.3 Other interferon-free regimens accepted for treating HCV GT4 infection
    3.3.1 Sofosbuvir plus ribavirin
    Sofosbuvir plus RBV was the first IFN-free therapy used for GT4 infection, but it is no longer recommended. In a phase-II study, 60 patients of Egyptian ancestry with chronic HCV GT4 infection received a combination of SOF plus RBV.[31] Half of the patients had been previously treated. Patients were randomly allotted 1:1 to receive SOF 400 mg and weight-based RBV in both groups, but with treatment durations of either 12 or 24 weeks. SVR12 was achieved in 68% of patients in the 12-week group and 93% in the 24-week group. The most common adverse events were headache, insomnia and fatigue. A larger number of adverse events were reported in the 24-week group due to the longer treatment duration. This study had a limited sample, and it included only a few difficult-to-treat patients.

    Another trial carried out in Egypt analysed the efficacy and safety of the same combination in 103 patients,[32] 52% treatment-experienced and 17% with cirrhosis at baseline. Patients were randomly assigned to one of two arms: SOF 400 mg and a weight-based daily dose of RBV for 12 or 24 days. SVR12 was 90% in the 24-week group and 77% in the 12-week group. Patients with cirrhosis had lower SVR12 rates than those without cirrhosis in both arms.
    Despite the favourable SVR12 rates at 24 weeks, this combination is suboptimal compared with combinations including two DAAs, which allow shorter duration and show fewer associated side effects, particularly in patients with cirrhosis.

    3.3.2 Sofosbuvir plus simeprevir
    PLUTO is a multicentre Spanish study including 40 patients with HCV GT4 infection.[33] This single-arm study evaluated the efficacy and safety of a 12-week regimen of SOF 400 mg plus SMV 150 mg daily. All patients achieved SVR12 regardless of their baseline characteristics (18% cirrhosis and 68% treatment-experienced). Adverse events occurred in 50%; all were grade 1 and grade 2. The most common adverse event was headache (20%).

    The preliminary efficacy results of the phase-IIa OSIRIS study are in line with those seen in the PLUTO study.[34] OSIRIS is being conducted in Egypt and includes 63 treatment-naïve or experienced patients with and without cirrhosis. All have HCV GT4 infection and are under treatment with SMV 150 mg plus SOF 400 mg daily. High SVR4 rates (95%-100%) have been seen with 12 weeks of treatment regardless of the prior PegIFN plus RBV response or cirrhosis stage. The initial safety data show no discontinuations due to adverse events, and no grade 3 or 4 treatment-related adverse events. The study remains open pending SVR12.

    The SOF plus SMV regimen has also been evaluated in the real world. In the French HEPATHER cohort, 34 HCV GT4 patients (82% with compensated cirrhosis and 73% treatment-experienced) were treated with SOF 400 mg plus SMV for 12 or 24 weeks with or without RBV.[35] SVR12 was attained in all patients receiving RBV in their regimen. In a study conducted in the Netherlands, HCV GT4-infected patients were treated with SOF plus SMV (with or without RBV) for 12 weeks. Treatment-naive and treatment-experienced patients were included, and SVR12 was achieved in 49 of 53 patients (92%).[36]

    Regarding these results, SOF plus SMV would be a combination option for HCV GT4 infected patients. RBV addition could be considered in treatment-experienced patients.

    3.3.3 Sofosbuvir plus daclatasvir
    The ATU study investigated a French cohort including 215 patients with HCV GT4 infection and characteristics associated with a low response to treatment, such as moderate liver fibrosis, extrahepatic manifestations, recurrence following liver transplantation and placement on the liver or kidney transplant lists.[37] Among the total, 110 (52%) patients were treated with a 24-week regimen including SOF 400 mg and DCV 30 mg daily, and 63 (30%) patients received the same regimen for 12 weeks. RBV was added in eight patients in the 12-week regimen group and in 31 patients receiving the 24-week regimen. The overall SRV12 rate in HCV GT4 patients was around 91%. SVR12 in patients with cirrhosis (including decompensated cirrhosis) was 90%. The 12-week regimen group showed the highest number of treatment failures. This is a safe regimen with few discontinuations (1%), and the most common adverse event was asthenia in 10% of patients.

    4 Treatment of Decompensated Cirrhosis
    There are few available studies using the new DAA agents in GT4-infected patients with decompensated cirrhosis. The phase-II SOLAR-I study enrolled GT1- and GT4-infected patients with cirrhosis and moderately or severely impaired liver function, and liver transplant recipients with or without cirrhosis and mild, moderate or severe liver impairment, or fibrosing cholestatic hepatitis.[38] Patients were randomized into two arms to receive 12 or 24 weeks of LDV/SOF plus RBV, respectively. In total, 337 patients were enrolled, and 1% (4/337) had HCV GT4. Overall SVR12 rates in patients with moderate hepatic impairment were 87% in the 12-week regimen and 88% in the 24-week regimen. In liver transplant recipients, SVR12 was lower in those in Child–Turcotte–Pugh class C, with 60% and 75% in the 12- and 24-week regimens, respectively, compared noncirrhotic transplant recipients, with SVR12 rates of 96% and 98%, respectively. Treatment had to be discontinued prematurely in 4% patients because of adverse events. Ten patients died, mainly from complications related to hepatic decompensation. LDV/SOF plus weight-based RBV was associated with high SVR12 rates and good tolerance in decompensated and severe liver impairment, but there were only four GT4 patients in the cohort.

    SOLAR-II was a multicentre study that extended data on the LDV/SOF plus RBV regimen in GT4 decompensated cirrhotic patients.[39] In total, 333 patients with advanced liver impairment were enrolled, 37 of whom (11%) were HCV GT4. LDV/SOF plus weight-based RBV were administered in 12- or 24-week regimens. SVR12 rates in GT4 were 78% (14/18) in the group receiving a 12-week regimen and 94% (16/17) in those treated for 24 weeks. The discontinuation rates were similar to those of SOLAR-I. Seventeen patients died due to complications of hepatic decompensation.
    The phase-III study, ASTRAL-4, enrolled treatment-naive and treatment-experienced patients with decompensated cirrhosis infected with HCV genotypes 1 (78%), 2 (4%), 3 (15%), 4 (3%) and 6 (<1%).[40] Patients were randomized at a 1:1:1 ratio to receive SOF/VEL once daily for 12 weeks, SOF plus RBV once daily for 12 weeks or SOF/VEL once daily for 24 weeks. Overall SVR12 rates were 83% in patients receiving 12 weeks SOF/VEL (100%, 4/4 in GT4 patients), 94% in those receiving SOF/VEL plus RBV (100%, 2/2 in GT4 patients) and 86% in those with 24 weeks of SOF/VEL (100%, 2/2 in GT4 patients). All GT4-infected patients achieved SVR12. There were no significant differences in SVR rates between the three groups. NS5A RASs were detected in 72 of 255 patients (28%). Of these 72 patients, 64 (89%) achieved SVR12 compared with 169 of 183 patients (92%) without RASs. Serious adverse events were observed in approximately 16%-18% of patients in each group.

    Real-life data are scarce in GT4-infected patients with decompensated cirrhosis. Welzel et al.[41] reported on 49 decompensated HCV patients receiving SOF plus DCV with or without RBV. The overall SVR12 was 92% (45/49). Three patients had GT4 infection, and all achieved SVR12. According to the Child–Turcotte–Pugh scoring system for cirrhosis, 15 were classified as B and eight as C. SVR12 rates in these patients were 80% and 88%, respectively. Please note the low representation of genotype 4 in this cohort.
    The benefits of this treatment are unclear, particularly in patients with an advanced Child–Turcotte–Pugh score, because viral clearance seems to have little impact on liver impairment or liver complications.

    5 HCV/HIV Co-Infected Patients
    The efficacy and safety of treatment for HCV GT4 infection in the HIV co-infected population has been evaluated in a few studies.

    ION-4 is a multicentre study involving patients co-infected with HIV-1 and HCV genotypes 1 or 4.[42] All patients received an antiretroviral regimen of tenofovir and emtricitabine with efavirenz, rilpivirine or raltegravir. In addition, all received LDV 90 mg plus SOF 400 mg in a single pill once daily for 12 weeks. In total, 335 patients were enrolled, 20% had cirrhosis, and 55% had received prior HCV treatment. SVR12 was achieved in 96% of the total cohort and in all patients (8/8) with GT4 infection. SVR12 rates were similar in the various subgroups regardless of treatment experience or cirrhosis stage. There were no cases of HIV-1 virological rebound, and none of the patients discontinued treatment because of adverse events.

    The ALLY-2 study analysed 203 HCV/HIV co-infected patients (three patients had GT4) receiving 12 or 8 weeks of SOF 400 mg plus DCV 60 mg, daily.[43] SVR12 rates were 97% after 12 weeks of treatment and 76% after 8 weeks. All GT4-infected patients achieved SVR12.
    A subanalysis by antiretroviral regimen class reported that SVR12 was 97% and was similar across the antiretroviral regimens included.[44] SOF plus DCV is an attractive combination for HCV/HIV co-infected patients, but further data in GT4-infected patients are needed.

    The phase-III C-EDGE CO-INFECTION study is a multicentre trial including HIV patients co-infected with HCV genotypes 1, 4 and 6.[45] In total, 218 patients were enrolled and all received GZR/EBR for 12 weeks. The SVR12 rate in patients with GT4 infection was 96% (27/28), with only one relapse, occurring in a noncirrhotic patient. This RBV-free combination achieved a high SVR12 in HCV/HIV co-infected patients without RBV adverse events.

    There is little information on GT4 HCV/HIV co-infected patients treated with ombitasvir and paritaprevir regimens. This would likely be an effective, safe combination, as indicated in genotype 1 by the TURQUOISE-I study,[46] but additional data are needed to recommend this combination in this specific population.

    6 DAA Failures
    6.1 Genotype 4. Resistance-associated substitutions
    Only 2% to 5% of HCV GT4 patients fail DAA treatment. Pawlosky et al. reviewed the profiles of patients who experienced treatment failure in each of the major studies using any type of combination therapy. Most of the information came from HCV GT1-infected patients and very little from HCV GT4.

    The emergence of HCV RASs is determined by the genetic barrier to the drug, the fitness of the resistant viral population and blood levels of the drug. The dynamics of RASs after discontinuation of DAAs differs depending on the antiviral agent. NS3/4 protease inhibitor RASs disappear within some time after completion of treatment. However, NS5A RASs persist for years and could impact on the selection of retreatment strategies.[47]

    RASs to NS5A inhibitors at baseline did not demonstrate a significant impact on SVR12 in combination regimens of SOF/LDV, SOF/VEL or SOF plus DCV, except in treatment-experienced GT1a patients, with or without cirrhosis, in whom lower SVR12 rates were observed. Very limited data are available in GT4 infection. In patients with NS5A RASs failing DAA treatment, the current recommendation is to extend treatment to 24 weeks and add RBV. This is based on the findings from small studies showing a higher SVR12.[48] Although there are no available data in GT4 infection, NS5A inhibitor resistance did not have an impact on SVR12 in GT1 patients receiving an OBV/PTV/R regimen with RBV. Similar results were found for the EBR/GZR combination, with the exception of GT1a patients and treatment-experienced GT1b patients, in whom SVR12 rates were lower. Hence, associated RBV and 16-week or 18-week duration are required in these patients. Again, no resistance data are available in GT4 for this combination. NS3 RASs at baseline do not appear have impact on SVR12.

    Presence of the Q80K NS3 resistance substitution does not affect SVR12 in GT4 infection, unlike what occurs in GT1a patients, especially treatment-experienced ones.[49]
    Some re-treatment strategies after failing DAAs have been explored in a small number of patients. In a recent study, 15 GT1- and GT4-infected patients who failed a DCV-based regimen (DCV plus PegIFN plus RBV, with or without asunaprevir) received SOF plus SMV without RBV for 12 weeks. Thirteen (87%) achieved SVR12, including all those with GT4 infection.[50] Further data on re-treatment of GT4 patients are needed before a strong recommendation can be established. In the meantime, one re-treatment approach could be a combination of SOF with a DAA of a different class than that previously used plus RBV, and extending therapy to 24 weeks.

    7 Summary
    In summary, the treatment options for HCV GT4 are now continually growing. The lower SVR rates reported in the past have been eliminated since the development of the new DAA agents. The NS5B-inhibitor, sofosbuvir, has been and remains the cornerstone of the current IFN-free therapies, achieving high SVR12 rates with a good safety profile. Combinations of NS5B inhibitors with NS5A or NS3/4 may be optimal strategies for the treatment of GT4-infected patients with compensated cirrhosis and those previously treated with PegIFN/RBV regimens. Nonetheless, other combinations without NS5B inhibitors, such as NS5A plus NS3/4-inhibitors, have shown SVR rates and safety profiles similar to those of the sofosbuvir combination. Despite the paucity of studies in HCV GT4 infection, some cohorts have provided information of promising SVR12 rates and safety profiles in special populations, such as HCV/HIV co-infected patients and patients with decompensated cirrhosis. These limited data encourage more aggressive use of DAA agents in these populations.
    Unfortunately, data on re-treatment strategies for GT4-infected patients who fail IFN-free therapy are nonexistent. We need a greater representation of GT4 patients in real-life studies to provide GT4 infection with a proper identity and remove it from the shadow of GT1.

    Disclosures
    Maria Buti and Rafael Esteban have received grant for Gilead, MSD, Abbvie and BMS. Mar Riveiro-Barciela has received grant for Gilead. Jordi Llaneras has no personal interests to declare.

    References
    Source - http://onlinelibrary.wiley.com/doi/10.1111/jvh.12620/full