Showing posts with label Epclusa®. Show all posts
Showing posts with label Epclusa®. Show all posts

Thursday, September 27, 2018

Gilead Subsidiary to Launch Authorized Generics of Epclusa® (Sofosbuvir/Velpatasvir) and Harvoni® (Ledipasvir/Sofosbuvir) for the Treatment of Chronic Hepatitis C

Of Interest
October 29, 2018
Gilead $1,100 a day drug. Now it will launch a generic at quarter the price
Sep 27, 2018
An ‘unusual decision’: Gilead to launch hep C generics ten years early

Sept 26 2018
The U.S. drug pricing system is a mess. It's an absolute disaster. Just about every entity involved, from drug companies to consumers to insurers to the government, agrees that offering discounts off the list price is a convoluted way to sell a life-saving product.

Maria Carolina Marcello, Gram Slattery
A Brazilian court has stripped the patent protection of a Gilead Sciences Inc big-selling hepatitis C treatment in Brazil, paving the way for cheaper generics, a presidential candidate who pushed for the move said on Monday....

Gilead Sciences to Sell Authorized Generics of Hepatitis C Drugs
Gilead Sciences will sell authorized generics of its blockbuster hepatitis C drugs Epclusa and Harvoni, Bloomberg reported. The brand-name versions sparked widespread debate about US pharmaceutical costs when they were introduced at a price of more than $1000 per pill. The less expensive versions will cost $24,000 for a course of treatment, which compares with a list price for Harvoni of $94,500. The company’s hepatitis C drugs remain among the best-selling pharmaceutical products in history, but they've also made Gilead the subject of congressional hearings and accusations of greed.

Gilead Press Release
United States
Gilead Subsidiary to Launch Authorized Generics of Epclusa® (Sofosbuvir/Velpatasvir) and Harvoni® (Ledipasvir/Sofosbuvir) for the Treatment of Chronic Hepatitis C
-- List Price of Authorized Generics to Reflect Discounts in the System Today --

FOSTER CITY, Calif.--(BUSINESS WIRE)--Sep. 24, 2018-- Gilead Sciences, Inc. (NASDAQ: GILD) announced today plans to launch authorized generic versions of Epclusa® (sofosbuvir 400mg/velpatasvir 100mg) and Harvoni® (ledipasvir 90mg/sofosbuvir 400mg), Gilead's leading treatments for chronic hepatitis C virus (HCV), in the United States, through a newly created subsidiary, Asegua Therapeutics LLC. The authorized generics will launch at a list price of $24,000 for the most common course of therapy and will be available in January 2019.

Since the launch of Gilead's first HCV medication in 2013, the average price paid for each bottle of medicine in the United States has decreased by more than 60 percent off of the public list prices, across health insurers and government payers. Due to the complexity and structure of the U.S. healthcare system, however, these discounts provided by Gilead may not always translate into lower costs for patients. Further, existing contracts, together with laws associated with government pricing policies, make it challenging to quickly lower a product's list price once it is on the market.

The authorized generics are priced to more closely reflect the discounts that health insurers and government payers receive today. Insurers will have the choice of offering either the authorized generics or the branded medications for both Epclusa and Harvoni. In the Medicare Part D setting, the authorized generics could save patients up to $2,500 in out-of-pocket costs per course of therapy. The authorized generics will also offer substantial savings to state managed Medicaid plans that do not currently benefit from negotiated rebates and that represent a significant number of people in need, potentially opening up access to our medications to beneficiaries who were previously denied coverage.

"Launching these authorized generics is the best solution available to us today to quickly introduce a lower-priced alternative to our HCV medications without significant disruption to the healthcare system and our business," said John F. Milligan, PhD, President and Chief Executive Officer, Gilead Sciences. "This launch also will hopefully help increase transparency by more closely aligning our medications' list prices with their cost. Our ultimate goal is to lower the list price of Epclusa - a medication we believe is of great importance given its clinical profile across genotypes - and Harvoni. We are committed to working with all of our partners in the healthcare system to help enable list price reductions of our HCV medications and find better solutions to reduce patients' out-of-pocket costs."

Beyond the company's efforts to reduce patient costs, Gilead is continuing to pursue innovative collaborations and long-term financing models, such as a potential subscription model, that could not only expand access, but aim to eliminate HCV in the United States and around the world.

About Gilead Sciences, Inc.
Gilead Sciences, Inc. is a research-based biopharmaceutical company that discovers, develops and commercializes innovative medicines in areas of unmet medical need. The company strives to transform and simplify care for people with life-threatening illnesses around the world. Gilead has operations in more than 35 countries worldwide, with headquarters in Foster City, California.

Forward-Looking Statement
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors that could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead's Quarterly Report on Form 10-Q for the quarter ended June 30, 2018, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

Wednesday, September 12, 2018

Epclusa® (Sofosbuvir/Velpatasvir) with or without ribavirin in patients with decompensated cirrhosis

Journal of Gastroenterology - September 10, 2018 

Efficacy and safety of sofosbuvir–velpatasvir with or without ribavirin in HCV-infected Japanese patients with decompensated cirrhosis: an open-label phase 3 trial
Tetsuo Takehara Naoya Sakamoto Shuhei Nishiguchi Fusao IkedaTomohide TatsumiYoshiyuki UenoHiroshi Yatsuhashi Yasuhiro Takikawa Tatsuo Kanda Minoru Sakamoto Akihiro Tamori Eiji MitaKazuaki Chayama Gulan Zhang Shampa De-Oertel Hadas Dvory-SobolTakuma Matsuda Luisa M. Stamm Diana M. Brainard Yasuhito Tanaka Masayuki Kurosaki

Sofosbuvir –velpatasvir for 12 weeks provides a highly effective and well-tolerated therapy for Japanese patients with HCV and decompensated cirrhosis. Ribavirin did not improve efficacy but increased toxicity.

Open Access 
First Online: 10 September 2018
Full text article available online: 

Abstract
Background
In Japan, hepatitis C virus (HCV)-infected patients with decompensated cirrhosis currently have no treatment options. In this Phase 3 study, we evaluated sofosbuvir–velpatasvir with or without ribavirin for 12 weeks in patients with any HCV genotype and decompensated cirrhosis [Child–Pugh–Turcotte (CPT) class B or C] in Japan.

Methods
Patients were randomized 1:1 to receive sofosbuvir–velpatasvir with or without ribavirin for 12 weeks. Randomization was stratified by CPT class and genotype. Sustained virologic response 12 weeks following completion of treatment (SVR12) was the primary efficacy endpoint.

Results
Of the 102 patients enrolled, 57% were treatment naive, 78% and 20% had genotype 1 and 2 HCV infection, respectively, and 77% and 20% had CPT class B and C cirrhosis, respectively, at baseline. Overall, 61% of patients were female and the mean age was 66 years (range 41–83). SVR12 rates were 92% (47/51) in each group. Among patients who achieved SVR12, 26% had improved CPT class from baseline to posttreatment week 12. Most adverse events (AEs) were consistent with clinical sequelae of advanced liver disease or known toxicities of ribavirin. Four patients (8%) who received sofosbuvir–velpatasvir and seven (14%) who received sofosbuvir–velpatasvir plus ribavirin experienced a serious AE. The 3 deaths (bacterial sepsis, gastric varices hemorrhage, hepatocellular carcinoma) were attributed to liver disease progression.

Conclusion
Sofosbuvir–velpatasvir for 12 weeks provides a highly effective and well-tolerated therapy for Japanese patients with HCV and decompensated cirrhosis. Ribavirin did not improve efficacy but increased toxicity.

Thursday, June 21, 2018

Sofosbuvir/velpatasvir and Resistance-associated Substitutions in HCV genotype 3

SOF/VEL and Resistance-associated Substitutions in HCV GT3
Alimentary Pharmacology & Therapeutics, June 21, 2018
J. von Felden; J. Vermehren; P. Ingiliz; S. Mauss; T. Lutz; K. G. Simon; H. W. Busch; A. Baumgarten; K. Schewe; D. Hueppe; C. Boesecke; J. K. Rockstroh; M. Daeumer; N. Luebke; J. Timm; J. Schulze zur Wiesch; C. Sarrazin; S. Christensen

Does the presence of resistance-associated substitutions impact the efficacy of therapy with sofosbuvir/velpatasvir with or without ribavirin in patients with HCV genotype 3?
Medscape - Full Text

Abstract and Introduction
Abstract
Background Twelve weeks of the pangenotypic direct–acting antiviral (DAA) combination sofosbuvir/velpatasvir (SOF/VEL) was highly efficient in patients with hepatitis C virus (HCV) genotype 3 (GT3) infection in the ASTRAL–3 approval study. However, presence of resistance–associated substitutions (RASs) in the HCV nonstructural protein 5A (NS5A) was associated with lower treatment response.

Aim To assess the efficacy and safety of SOF/VEL ± ribavirin (RBV) and the impact of NS5A RASs and RBV use on treatment outcome in HCV GT3 infection in a real–world setting.

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Wednesday, May 30, 2018

China Drug Administration Approves Epclusa® (Sofosbuvir/Velpatasvir)

China Drug Administration Approves Epclusa® (Sofosbuvir/Velpatasvir), Gilead's Pan-Genotypic Treatment for Chronic Hepatitis C Virus Infection

- Epclusa is the First Approved Pan-Genotypic Once Daily Single Table Regimen for Chronic Hepatitis C Virus Infection in China -

FOSTER CITY, Calif.--(BUSINESS WIRE)--May 30, 2018-- Gilead Sciences, Inc. (NASDAQ: GILD) announced today that the China Drug Administration (CDA) has approved Epclusa® (sofosbuvir 400 mg/velpatasvir 100 mg) for the treatment of adults with genotype 1-6 chronic hepatitis C virus (HCV) infection. The CDA also approved Epclusa in combination with ribavirin (RBV) for adults with HCV and decompensated cirrhosis. Epclusa is the first pan-genotypic HCV single tablet regimen (STR) approved in China.

The approval of Epclusa in China is supported by five international Phase 3 studies, ASTRAL-1, ASTRAL-2, ASTRAL-3, ASTRAL-4 and ASTRAL-5. High overall rates of SVR12 (defined as undetectable HCV RNA 12 weeks after completing therapy), ranging from 92-100 percent, were achieved across difficult-to-cure patient populations including treatment-experienced patients and those with compensated or decompensated cirrhosis.

"The safety and efficacy profile of Epclusa are supported by large clinical and real-world global datasets," said Professor Lai Wei, Peking University People's Hospital and Institute of Hepatology, Peking University. "With high cure rates across all HCV genotypes, Epclusa could increase HCV treatment in China by potentially eliminating the need for genotype testing, which can be a barrier to treatment in many settings."

HCV is the fourth-most commonly reported infectious disease in China, with approximately 10 million people infected. HCV genotypes 1, 2, 3 and 6 account for more than 96 percent of all cases.

In the ASTRAL-1, ASTRAL-2 and ASTRAL-3 studies, 1,035 treatment-naïve and treatment-experienced patients with genotype 1-6 HCV infection, without cirrhosis or with compensated cirrhosis, received 12 weeks of Epclusa. Ninety-eight percent (1,015/1,035) of patients achieved SVR12. In the ASTRAL-5 study, 106 treatment-naïve and treatment-experienced patients with genotype 1-6 HCV infection, without cirrhosis or with compensated cirrhosis, who were coinfected with HIV and on a stable antiretroviral therapy, received 12 weeks of Epclusa. Ninety-five percent (101/106) of patients achieved SVR12.

The ASTRAL-4 study assessed the safety and efficacy of 12 weeks of Epclusa with or without RBV or 24 weeks of Epclusa in 267 HCV-infected patients with genotypes 1-4 and 6 decompensated cirrhosis (Child-Pugh B). Patients with decompensated cirrhosis receiving Epclusa with RBV for 12 weeks achieved 94 percent (82/87) SVR12.

The most common adverse reactions (=10 percent) experienced by patients treated with Epclusa in ASTRAL-1, ASTRAL-2, ASTRAL-3 and ASTRAL-5 were headache and fatigue. The placebo-treated patients in the ASTRAL-1 experienced headache and fatigue at a similar frequency. The most common adverse reactions (=10 percent) experienced by HCV-infected patients with decompensated cirrhosis treated with Epclusa and RBV in ASTRAL-4 were fatigue, anemia, nausea, headache, diarrhea and insomnia. Four patients treated with Epclusa with RBV, discontinued treatment due to adverse events.

"As the first once-daily, interferon-free single tablet regimen for HCV patients regardless of genotype, Epclusa offers physicians in China an important new option for effectively treating their patients while potentially helping to reduce the significant burden of HCV at a population level," said John F. Milligan, PhD, Gilead's President and Chief Executive Officer. "Gilead has now launched two direct-acting antiviral treatments in China, and we are committed to supporting efforts to screen and link patients to treatment, to help address the country's HCV epidemic."

Epclusa received marketing approval from the U.S. Food and Drug Administration (FDA) and the European Commission in 2016 as the first pan-genotypic STR for HCV infection. It is also approved for use in 54 countries.

Sovaldi (sofosbuvir) as a single agent received marketing approval from the China Food and Drug Administration in 2017 for the treatment of adults infected with HCV genotype 1, 2, 3, 4, 5 or 6 and for adolescents (aged 12 to 18 years) with HCV genotype 2 or 3, as a component of a combination antiviral treatment regimen.

Wednesday, February 28, 2018

Ontario Expands Patient Access to Chronic Hepatitis C Therapies On Public Drug Plan

Ontario Expands Patient Access to Chronic Hepatitis C Therapies On Public Drug Plan


  • Gilead applauds Ontario's Ministry of Health for expanding access to curative hepatitis C therapies to all diagnosed patients, regardless of severity of illness
  • Ontario's expanded access includes EPCLUSA®, a 12 week treatment for patients with chronic hepatitis C across all six genotypes
  • Gilead's new product, VOSEVI™ is now available under the Ontario Drug Benefit Program
  • The removal of the fibrosis level criterion for access furthers Canada's commitment to the World Health Organization's Global Hepatitis C elimination efforts
MISSISSAUGA, ON, Feb. 28, 2018 /CNW/ - Gilead Sciences Canada, Inc. (Gilead Canada) today recognizes the Ontario Ministry of Health and Long-Term Care for its leadership in the expansion of access to therapies that treat chronic hepatitis C virus infection under the Ontario Drug Benefit (ODB) Program. Today, all eligible ODB recipients will have greater access to treatment, regardless of the severity of disease (fibrosis level), to achieve a cure and improve their quality of life. Patients with chronic hepatitis C will no longer have to wait for their disease to progress before starting treatment.

"Expanded access is an important milestone to achieve Canada's commitment to eliminating hepatitis C by 2030," said Kennet Brysting, General Manager of Gilead Canada. "Increasing hepatitis C treatment rates among patients and high-risk populations will help to reduce the burden of illness, the risk of transmission and the significant associated costs to the healthcare system."

Today's announcement will allow more patients to access a broad selection of therapies, including all those developed by Gilead Canada – EPCLUSA (velpatasvir/sofosbuvir), VOSEVI (voxilaprevir/velpatasvir/sofosbuvir), HARVONI® (ledipasvir/sofosbuvir) and SOVALDI® (sofosbuvir). EPCLUSA is a publicly accessible treatment that can be used for patients with hepatitis C infection across all six genotypes, and VOSEVI is approved for use in patients who have failed on a previous direct-acting antiviral (DAA) treatment regimen.

"Canada has 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 requires improving screening and diagnosis, which is why the Canadian Liver Foundation recommends that everyone in Canada born between 1945 and 1975 receive a one-time test for hepatitis C," added Dr. Sherman. "Treatment should be an option for everyone, regardless of disease severity, where they live in the province or their ability to pay. We're glad to see that the Ontario government is taking steps to make treatments accessible for more Ontarians with chronic hepatitis C."

https://www.newswire.ca/news-releases/ontario-expands-patient-access-to-chronic-hepatitis-c-therapies-on-public-drug-plan-675380743.html

For more information on the expanded access for hepatitis C therapies and VOSEVI listing: http://www.health.gov.on.ca/en/pro/programs/drugs/formulary43/summary_edition43_20180221.pdf

Monday, December 18, 2017

China: MSF challenges Gilead’s patent application for hepatitis C treatment

In case you missed it

China: MSF challenges Gilead’s patent application for hepatitis C treatment

Médecins Sans Frontières (MSF) has filed a legal patent challenge in China against US pharmaceutical corporation Gilead’s patent application for the combination of two crucial oral hepatitis C medicines, sofosbuvir and velpatasvir. This combination is the first direct-acting antiviral (DAA) treatment to be registered for use against all genotypes of the disease. Rejection of patents for this combination would pave the way towards the availability of affordable generic versions of this treatment that millions of people need in China and around the world....

Tuesday, October 17, 2017

The changing HCV treatment cascade

Pharmacology Consult
The changing HCV treatment cascade
Infectious Disease News, October 2017
Jocelyn Mason, PharmD; Kimberly D. Boeser, PharmD, MPH, BCPS, AQ-ID
The rapid development of DAA combinations provides simplified regimens, shorter durations, improved efficacy and greater tolerability, unlike the previous interferon and ribavirin cornerstone regimens. Although the IDSA/AASLD guidelines provide the map to managing HCV, they do not identify the ideal interferon-free regimen to begin with, nor have they given a clear path to treating genotype 3 and those with decompensated cirrhosis. This ever-changing field will require collaboration among health care providers, including those specializing in infectious diseases, hepatology and gastroenterology, as well as pharmacists, to optimize treatment strategies. As the landscape of HCV continues to update with new literature and new medications, this subspecialty continues to be dynamic.
Continue to article - https://www.healio.com/infectious-disease/hepatitis-c/news/print/infectious-disease-news/%7B87b74536-f358-43d3-a804-f37a98402b0b%7D/the-changing-hcv-treatment-cascade

Tuesday, October 10, 2017

SMC accepts medicines for hepatitis C and multiple myeloma for use by NHS Scotland

October 2017 decisions news release

SMC accepts medicines for hepatitis C and multiple myeloma for use by NHS Scotland
The Scottish Medicines Consortium (SMC), which advises on newly licensed medicines for use by NHS Scotland, has today published advice accepting two new medicines.

Daratumumab (Darzalex) was accepted for the treatment of multiple myeloma, a rare cancer of the white blood cells that may result in complications including severe bone pain, kidney damage and a depleted immune system with a consequent risk of serious infection. Following consideration through SMC’s Patient and Clinician Engagement (PACE) process for medicines used to treat end of life and very rare conditions, daratumumab was accepted for the treatment of patients who have received at least three prior treatment regimens. Through PACE, patient groups and clinicians highlighted that patients become resistant to treatments over time and that there are limited treatment options available at this stage. While there is currently no cure for multiple myeloma, daratumuab may provide an opportunity to improve control of the condition and disease associated symptoms.

Sofosbuvir/velpatasvir (Epclusa) was accepted for the treatment of specific sub-types of hepatitis C, a blood-borne virus that predominantly infects the cells of the liver, resulting in inflammation and significant damage. This affects the liver's ability to perform its essential functions, which include fighting infection and removing toxins from the body. Sofosbuvir/velpatasvir provides an opportunity to eradicate the Hepatitis C virus. Through a submission to SMC, patient groups highlighted that this medicine could enable patients to be treated with minimum disruption to their working and family lives.

SMC chairman Dr Alan MacDonald said:

“I am pleased the committee has been able to accept daratumumab and sofosbuvir/velpatasvir for use by NHS Scotland.

“Daratumumab offers a further treatment option for those patients with multiple myeloma who have already had a number of previous treatments. Through our PACE meeting, we know this decision will be welcomed by both patients and their families.

“Eradicating hepatitis C is considered a major health issue by both Scottish Government and the World Health Organisation, so being able to accept sofosbuvir/velpatasvir for certain types of hepatitis C may help meet this key public health aim.”

PharmaTime
Darzalex, Epclusa will be funded on NHS Scotland

Saturday, September 23, 2017

Gilead Receives Approval in Canada for Expanded Indication of EPCLUSA® for Chronic Hepatitis C in Patients Co-Infected with HIV

Gilead Receives Approval in Canada for Expanded Indication of EPCLUSA® (Sofosbuvir/Velpatasvir) for the Treatment of Chronic Hepatitis C in Patients Co-Infected with HIV

– New Data for First Approved Pan-genotypic Once-Daily Single Tablet Regimen for
Chronic Hepatitis C Virus Infection –
MISSISSAUGA, ON, Sept. 21, 2017 /CNW/ - Gilead Sciences Canada, Inc. (Gilead Canada) today announced that Health Canada has granted a Notice of Compliance (NOC) for updated labeling of EPCLUSA® (sofosbuvir 400mg/velpatasvir 100mg), the first all-oral, pan-genotypic, once-daily single tablet regimen (STR) for the treatment of adults with chronic hepatitis C virus (HCV) infection, to include use in patients co-infected with HIV-1. Health Canada granted EPCLUSA an NOC in July 2016, for the treatment of adults with genotype 1-6 chronic HCV infection without cirrhosis or with compensated cirrhosis, or with decompensated cirrhosis in combination with ribavirin.

"HCV co-infection remains a major cause of morbidity in HIV-infected individuals. With this expanded indication, EPCLUSA provides co-infected patients with a much-needed one-pill-a-day regimen that works across all HCV genotypes and at all stages of disease. Being compatible with most widely-used antiretroviral regimens adds to its convenience," said Dr. Brian Conway, President and Medical Director, Vancouver Infectious Diseases Centre. "With EPCLUSA, physicians have an important new treatment option for their HCV/HIV co-infected patients."
The supplemental new drug submission was supported by data from the open-label, Phase 3 ASTRAL-5 study, which evaluated 12 weeks of treatment with EPCLUSA in 106 subjects with genotype 1-4 HCV infection who were co-infected with HIV and on stable antiretroviral therapy. In the study, 95 per cent (101/106) of patients achieved the primary endpoint of SVR12, defined as an undetectable viral load 12 weeks after completing therapy. The study also included patients with compensated cirrhosis.

The safety profile of EPCLUSA in HCV/HIV co-infected patients was similar to that observed in HCV mono-infected patients. The most common adverse events (in at least 10 per cent of subjects) were fatigue (22 per cent) and headache (10 per cent).

"Canada has committed to eliminating hepatitis C by 2030. To accomplish this goal, it is imperative that steps be taken to increase treatment rates in Canada, including treatment for people who are co-infected with hepatitis C and HIV," said Dr. Morris Sherman, Chairperson, Canadian Liver Foundation and Hepatologist at Toronto General Hospital. "Hepatitis C progresses faster in individuals who are co-infected with HIV, often increasing and speeding up the onset of liver damage. Today, with pan-genotypic curative hepatitis C therapies approved for treatment in hepatitis C and HIV co-infected patients, it is an important time for patients to discuss treatment options with their health care providers."

"EPCLUSA has already helped further simplify HCV treatment among mono-infected patients, and we are pleased that HCV/HIV co-infected patients can benefit from this pan-genotypic single tablet regimen," said Kennet Brysting, General Manager, Gilead Canada. "This approval advances the commitment we've made to the HCV and HIV communities to deliver innovative new treatments that address their unmet medical needs."
http://www.newswire.ca/news-releases/gilead-receives-approval-in-canada-for-expanded-indication-of-epclusa-sofosbuvirvelpatasvir-for-the-treatment-of-chronic-hepatitis-c-in-patients-co-infected-with-hiv-646369933.html

Saturday, August 26, 2017

The new paradigm in the treatment of chronic hepatitis C disease: Faster, Higher and Stronger

Citius Altius Fortius: The new paradigm in the treatment of chronic hepatitis C disease

Aug 26, 2017

Download Full Text Article
Provided By Henry E. Chang‏ via Twitter

Abraham GM, et al. – This study focuses on the treatment of chronic hepatitis C disease. Findings reveal that most of the direct–acting antiviral agents (DAAs) for chronic hepatitis C infection had a high barrier to resistance and are extremely well–tolerated by patients. DAAs, in addition, demonstrate 90% or higher efficacy rates.
  • The treatment paradigm for chronic hepatitis C infection has dramatically changed with the advent of the direct–acting antiviral agents (DAAs), especially the duration, tolerability and response to therapy.
  • The DAAs are classified in to several classes and are variously indicated in the treatment of one or more genotypes of infection.
  • All these agents are orally administered, and they, in majority, are eliminated renally (with exceptions), and don'’t require adjustment in mild to moderate renal insufficiency.
Abstract
With the advent of the direct-acting antiviral agents (DAAs) for chronic hepatitis C infection, the treatment paradigm has dramatically changed, especially the duration, tolerability and response to therapy. The DAAs fall into several classes and are variously indicated in the treatment of one or more genotypes of infection. All these agents are orally administered, and they are largely renally eliminated (with exceptions), don’t require adjustment in mild to moderate renal insufficiency. Most of these agents demonstrate a high barrier to resistance and are extremely well-tolerated by patients. Overall efficacy rates are 90% or higher.
Download Article

Of Interest
Systematic review: cost-effectiveness of DAAs for treatment of HCV genotypes 2-6

New At Hepatitis C Online:
Vosevi and Mavyret
Information on Gilead's newly FDA approved Vosevi and AbbVie's Mavyret  is now available.

Full Text Articles
I highly suggest you follow Henry E. Chang on Twitter if you are interested in reading full text articles about the treatment and management of hepatitis C.

Tuesday, August 1, 2017

FDA Approves Expanded Labeling for Epclusa® for Hepatitis C in Patients Co-Infected with HIV

U.S. FDA Approves Expanded Labeling for Epclusa® (Sofosbuvir/Velpatasvir) for the Treatment of Chronic Hepatitis C in Patients Co-Infected with HIV

- New Data for First Approved Pan-genotypic Once-Daily Single Tablet Regimen for Chronic Hepatitis C Virus Infection -

FOSTER CITY, Calif.--(BUSINESS WIRE)--Aug. 1, 2017-- Gilead Sciences, Inc. (NASDAQ: GILD) today announced that the U.S. Food and Drug Administration (FDA) has approved updated labeling for Epclusa® (sofosbuvir 400mg/velpatasvir 100mg), the first all-oral, pan-genotypic, once-daily single tablet regimen (STR) for the treatment of adults with chronic hepatitis C virus (HCV) infection, to include use in patients co-infected with HIV. Epclusa received regulatory approval for the treatment of adults with genotype 1-6 chronic HCV infection without cirrhosis or with compensated cirrhosis, or with decompensated cirrhosis in combination with ribavirin, in the United States on June 28, 2016.

Epclusa has a boxed warning in its product label regarding the risk of hepatitis B virus (HBV) reactivation in HCV/HBV co-infected patients. See below for important safety information.
"HCV co-infection remains a major cause of morbidity in HIV-infected individuals. With this expanded use, Epclusa provides co-infected patients with a much needed one-pill-a-day regimen that works across all HCV genotypes and is compatible with widely-used antiretroviral regimens," said David Wyles, M.D., Chief, Division of Infectious Disease, Denver Health Medical Center; Associate Professor of Medicine, University of Colorado School of Medicine. "With Epclusa, physicians have an important new treatment option for their HCV/HIV co-infected patients."

The supplemental new drug application (sNDA) was supported by data from the open-label, Phase 3 ASTRAL-5 study, which evaluated 12 weeks of treatment with Epclusa in 106 subjects with genotype 1-4 HCV infection who were co-infected with HIV and on stable antiretroviral therapy. In the study, 95 percent (101/106) of patients achieved the primary endpoint of SVR12, defined as an undetectable viral load 12 weeks after completing therapy.

The safety profile of Epclusa in HCV/HIV co-infected patients was similar to that observed in HCV mono-infected patients. The most common adverse events (in at least 10 percent of subjects) were fatigue (22 percent) and headache (10 percent).

"Epclusa has already helped further simplify HCV treatment among mono-infected patients, and we are pleased that HCV/HIV co-infected patients can benefit from this pan-genotypic single tablet regimen," said John F. Milligan, PhD, Gilead's President and Chief Executive Officer. "This approval advances the commitment we've made to the HCV and HIV communities to deliver innovative new treatments that address their unmet medical needs."

U.S. Patient Support Program
To support these patients and their families, Gilead's U.S. Support Path® program provides information regarding access and reimbursement coverage options to patients in the United States who need assistance with coverage for their medications, including Epclusa. Support Path conducts benefits investigations and provides patients with information regarding their insurance options.
Further, the Epclusa Co-pay Coupon Program offers co-pay assistance for eligible patients with private insurance who need assistance paying for out-of-pocket medication costs.
To learn more about Support Path for Epclusa, please visit www.MySupportPath.com or call 1-855-7-MYPATH (1-855-769-7284) between 9:00 a.m. and 8:00 p.m. (Eastern), Monday through Friday.

Global Availability
The prevalence of HCV genotypes varies regionally throughout the world. In resource-limited settings genotype testing can often be costly or unreliable, posing yet another barrier to treatment. As a pan-genotypic therapeutic option, Epclusa may help eliminate the need for genotype testing and has the potential to accelerate access to treatment for patients worldwide.
Gilead is committed to helping enable access to Epclusa around the world. Gilead works with a network of regional business partners, generic licensing partners and other stakeholders to expand treatment globally. Epclusa is already licensed to Gilead's 11 Indian manufacturing partners who produce and distribute generic versions of this medicine for 101 developing countries.

Important U.S. Safety Information for Epclusa

BOXED WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN HCV/HBV CO-INFECTED PATIENTS
Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with Epclusa. HBV reactivation has been reported in HCV/HBV co-infected patients who were undergoing or had completed treatment with HCV direct acting antivirals (DAAs) and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported in patients who are HBsAg positive, in patients with serologic evidence of resolved HBV, and also in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV DAAs may be increased in patients taking these other agents. Monitor HCV/HBV co-infected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.
Contraindications
  • If Epclusa is used in combination with ribavirin (RBV), all contraindications, warnings and precautions, in particular pregnancy avoidance, and adverse reactions to RBV also apply. Refer to RBV prescribing information.
Warnings and Precautions
  • Serious Symptomatic Bradycardia When Coadministered with Amiodarone: Amiodarone is not recommended for use with Epclusa due to the risk of symptomatic bradycardia, particularly in patients also taking beta blockers or with underlying cardiac comorbidities and/or with advanced liver disease. A fatal cardiac arrest was reported in a patient taking amiodarone who was coadministered a sofosbuvir containing regimen. In patients without alternative, viable treatment options, cardiac monitoring is recommended. Patients should seek immediate medical evaluation if they develop signs or symptoms of bradycardia.
  • Risk of Reduced Therapeutic Effect Due to Concomitant Use of Epclusa with P-gp Inducers and/or Moderate to Potent Inducers of CYP2B6, CYP2C8 or CYP3A4: Rifampin, St. John's wort, and carbamazepine are not recommended for use with Epclusa as they may significantly decrease sofosbuvir and/or velpatasvir plasma concentrations.
Adverse Reactions
  • The most common adverse reactions (=10%, all grades) with Epclusa were headache and fatigue; and when used with RBV in decompensated cirrhotics were fatigue, anemia, nausea, headache, insomnia, and diarrhea.
Drug Interactions
  • Coadministration of Epclusa is not recommended with topotecan due to increased concentrations of topotecan.
  • Coadministration of Epclusa is not recommended with proton-pump inhibitors, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine, efavirenz, and tipranavir/ritonavir due to decreased concentrations of sofosbuvir and/or velpatasvir.
Consult the full Prescribing Information for Epclusa for more information on potentially significant drug interactions, including clinical comments.

About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company's mission is to advance the care of patients suffering from life-threatening diseases. Gilead has operations in more than 30 countries worldwide, with headquarters in Foster City, California.

Forward-Looking Statement
This press release includes forward-looking statements, within the meaning of the Private Securities Litigation Reform Act of 1995, that are subject to risks, uncertainties and other factors, including the risk that physicians may not see the benefits of prescribing Epclusa for the treatment of adults with chronic HCV infection, for expanded use in patients co-infected with HIV. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead's Quarterly Report on Form 10-Q for the quarter ended March 31, 2017, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

U.S. Full Prescribing Information for Epclusa, including BOXED WARNING, is available at www.gilead.com.

Epclusa is a registered trademark of Gilead Sciences, Inc., or its related companies.
For more information on Gilead Sciences, please visit the company's website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

Monday, April 3, 2017

EPCLUSA™ - Alberta Also Broadens Access for Patients with Less Advanced Disease Who Have Other Health Conditions

-- Alberta Also Broadens Access for Patients with Less Advanced Disease Who Have Other Health Conditions --

MISSISSAUGA, ON , April 3, 2017 /CNW/ - Gilead Sciences Canada, Inc. ( Gilead Canada ) today announced, effective immediately, Alberta 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 without cirrhosis or with compensated cirrhosis 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 who received 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 and fatigue, and were comparable in incidence to the placebo group included in ASTRAL-1.

The listing in Alberta 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, Alberta 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:
https://www.ab.bluecross.ca/dbl/pdfs/dbl_full_list.pdf


"We now have the ability to cure almost all patients with chronic HCV with a simple and safe 12-week treatment, regardless of viral genotype or patient history," said Dr. Stephen Shafran , Professor of Medicine, Division of Infectious Disease, University of Alberta. "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, improve their quality of life, and prevent cases of advanced liver disease that is a significant financial burden for the healthcare system."

In Alberta , the Public Health Agency of Canada estimates that more than 24,000 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 Alberta Health 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."

Monday, March 20, 2017

2017 / Hepatitis C: Down but Not Out - Oral Direct-Acting Agent Therapy for HCV

Media Coverage Of This Article
Wednesday, March 22, 2017
Hepatitis C Cures Lag While New Drugs Wait in the Wings
Will new hepatitis C treatments eliminate the virus for good?

NEJM Journal Watch
All FDA-Approved, Oral Direct-Acting Antivirals for Hepatitis C Safe and Effective for Genotype 1
By Kelly Young
Edited by Jaye Elizabeth Hefner, MD   
The FDA-approved interferon-free regimens for treating hepatitis C appear to be safe and effective, suggests an Annals of Internal Medicine review.

Researchers examined 42 randomized trials of oral hepatitis C treatments that included at least two direct-acting antivirals. Among the findings:
  • For genotype 1 infection, the most common HCV type, sustained virologic response rates were above 95% for six regimens.
  • For patients with HCV genotype 3 and without cirrhosis, sofosbuvir plus velpatasvir or daclatasvir for 12 weeks seemed to be most effective.
  • For genotype 3 with cirrhosis, velpatasvir-sofosbuvir had higher response rates. That drug combination was also highly effective (99% response rate) for genotypes 2, 4, 5, and 6.
  • Patient groups traditionally considered difficult to treat — including those with HIV, severe kidney disease, or liver transplant — had high response rates and limited adverse events.
Editorialists conclude that "hepatitis C is down but not out," noting that screening for HCV is not yet routine, and the drugs are still priced high.
NEJM Journal Watch

Editorials |21 March 2017
Annals of Internal Medicine
Hepatitis C: Down but Not Out
Jay H. Hoofnagle, MD; Averell H. Sherker, MD                   
Within the past 4 years, no fewer than 10 potent, orally available antiviral drugs have received U.S. Food and Drug Administration (FDA) approval as therapy for chronic hepatitis C virus (HCV) infection. These small molecules are directed at 1 of 3 HCV targets: NS3/4A protease (“-previrs” [simeprevir, paritaprevir, and grazoprevir]), NS5B RNA polymerase (“-buvirs” [sofosbuvir and dasabuvir]), or NS5A polypeptide (“-asvirs” [daclatasvir, elbasvir, ledipasvir, ombitasvir, and velpatasvir]). Most important, combinations of 2 or 3 of these agents have proven highly effective in inducing a sustained virologic response (SVR), with persistent loss of HCV RNA from serum. Long-term follow-up of patients who have achieved SVR shows resolution of the accompanying liver disease and permanent loss of HCV RNA from both serum and the liver, suggesting a “cure” of the chronic viral infection. These new all-oral regimens typically have SVR rates of 95% or more with only 8 to 12 weeks of treatment and minimal adverse effects; in contrast, previous interferon-based regimens yielded rates of 50% to 60%, but only in highly selected patients and after 48 weeks of poorly tolerated treatment with serious adverse effects and significant contraindications. The new antiviral regimens have transformed management of chronic HCV infection.
http://annals.org/aim/article/2613307/hepatitis-c-down-out

Annals of Internal Medicine
Oral Direct-Acting Agent Therapy for Hepatitis C Virus Infection: A Systematic Review
Oluwaseun Falade-Nwulia, MBBS, MPH (*); Catalina Suarez-Cuervo, MD (*); David R. Nelson, MD; Michael W. Fried, MD; Jodi B. Segal, MD, MPH; Mark S. Sulkowski, MD
View Full Text Article Online

Abstract
Background:

Rapid improvements in hepatitis C virus (HCV) therapy have led to the approval of multiple oral direct-acting antiviral (DAA) regimens by the U.S. Food and Drug Administration (FDA) for treatment of chronic HCV infection.Purpose:
To summarize published literature on the efficacy and safety of oral DAAs for treatment of persons with chronic HCV infection.

Data Sources: MEDLINE and EMBASE from inception through 1 November 2016.Study Selection:

42 English-language studies from controlled and single-group registered clinical trials of adults with HCV infection that evaluated at least 8 weeks of an FDA-approved interferon-free HCV regimen that included at least 2 DAAs.

Data Extraction: Two investigators abstracted data on study design, patient characteristics, and virologic and safety outcomes sequentially and assessed quality independently.

Data Synthesis: Six DAA regimens showed high sustained virologic response (SVR) rates (>95%) in patients with HCV genotype 1 infection without cirrhosis, including those with HIV co-infection. Effective treatments for HCV genotype 3 infection are limited (2 DAA regimens). Patients with hepatic decompensation, particularly those with Child–Turcotte–Pugh class C disease, had lower SVR rates (78% to 87%) than other populations. The addition of ribavirin was associated with increased SVR rates for certain DAA regimens and patient groups. Overall rates of serious adverse events and treatment discontinuation were low (<10% in the general population); regimens that included ribavirin had more mild or moderate adverse events than those without.

Limitations: Twenty-three studies had moderate risk of bias (10 were open-label single-group trials, 11 had limited information on concealment of the allocation scheme, and 5 had selective outcome reporting). All but 1 of the studies were industry-funded. Heterogeneity of interventions precluded pooling.

Conclusion:
Multiple oral DAA regimens show high rates of safety, tolerability, and efficacy for treatment of HCV genotype 1 infection, particularly among persons without cirrhosis.

Primary Funding Source:Patient-Centered Outcomes Research Institute. (PROSPERO: CRD42014009711)

In the United States, 3.2 to 5 million people are chronically infected with hepatitis C virus (HCV) and are at risk for cirrhosis, liver cancer, and death if untreated (1, 2). Infection with HCV is the primary indication for liver transplantation and causes more deaths than all other notifiable infectious diseases in the United States combined (3, 4). Cure of this infection, defined as the absence of detectable HCV RNA in the blood at least 12 weeks after treatment completion (sustained virologic response [SVR]), is strongly associated with reduced liver-related morbidity and mortality (5, 6). The development of drugs that directly inhibit key steps in viral replication has led to availability of several oral HCV treatment regimens (7). We systematically reviewed the efficacy and safety of oral interferon-free HCV treatment regimens that have been approved by the U.S. Food and Drug Administration (FDA) and include at least 2 direct-acting antivirals (DAAs). We also assessed the effect of ribavirin on rates of SVR and adverse events. We reviewed phase 2 and 3 clinical trial data for patients infected with HCV genotypes 1 to 6 and patients previously considered difficult to cure with decompensated cirrhosis, HIV infection, renal failure, or liver transplantation.

Methods
Data Sources and Searches
We developed a protocol for this systematic review and registered it in PROSPERO (CRD42014009711). We searched MEDLINE and EMBASE for literature published in English from inception through 1 November 2016. The search strategy included terms for HCV infection and the medications of interest (Figure 1). We also searched ClinicalTrials.gov and hand-searched the reference lists of included articles and related systematic reviews.

Study Selection

We included English-language, single-group, randomized, controlled trials (RCTs) of adults with chronic HCV infection that evaluated at least 8 weeks of an FDA-approved interferon-free HCV regimen that included at least 2 DAAs. We included trials that used DAA combinations—including inhibitors of HCV NS3 protease (grazoprevir, paritaprevir, and simeprevir), NS5A (daclatasvir, elbasvir, ledipasvir, ombitasvir, and velpatasvir), and NS5B polymerase (sofosbuvir and dasabuvir), as well as the oral antiviral ribavirin—and for which the primary outcome was SVR. We excluded studies published only as abstracts; dose-finding studies; those in which the primary outcome was pharmacokinetics; or those in which the regimens included interferon, DAAs that were not FDA-approved, or only 1 DAA (for example, sofosbuvir plus ribavirin). Trials were included regardless of participants' cirrhosis, HIV, or liver transplantation status, but trials of limited populations (for example, DAA-experienced patients or those of a single race) were excluded.

Data Extraction and Quality Assessment

Two reviewers independently screened titles and abstracts and then the full text of potentially eligible articles to identify studies meeting inclusion criteria. Using standardized forms, 1 reviewer extracted information from the selected studies about study characteristics, design, outcomes, and the funding source. A second reviewer confirmed the accuracy of the extractions. Differences were resolved through consensus. Two reviewers independently assessed risk of bias for each selected study by using 5 items from the Cochrane risk-of-bias tools for RCTs and a Cochrane tool for assessment of risk of bias in nonrandomized trials and observational studies (8, 9).

Data Synthesis and Analysis

Detailed evidence tables were generated, and studies were summarized by outcomes. The results were organized by genotype and then by the specific population studied. The heterogeneity of the interventions precluded quantitative pooling of results.

Role of the Funding Source

The Patient-Centered Outcomes Research Institute (PCORI) funded the study and reviewed the report but did not participate in the formulation of the review's questions, data searches, study appraisals, evidence interpretation, or the preparation or approval of the manuscript for publication.

Results
Study and Quality Characteristics

Of 1796 citations evaluated, we included 42 studies published in 40 articles (Figure 1). All but 1 of the studies were funded by industry (10). Ten were open-label, single-group studies (10–19); 5 had a placebo group with deferred treatment (20–24); 11 evaluated different durations of therapies and the addition of ribavirin (for example, 8 vs. 12 weeks or 12 vs. 24 weeks of therapy with or without ribavirin) (25–35); 5 evaluated the same duration of therapy with and without ribavirin (36–39); 6 evaluated different durations with ribavirin (40–45); and 3 evaluated different durations of therapy without ribavirin (46–48). Only 2 studies had an active comparator group receiving an HCV treatment regimen other than that being evaluated in the trial (49). Three studies had 48 weeks of posttreatment follow-up, whereas the remainder had 12 or 24 weeks of follow-up.

Of the 42 studies, 19 had low risk of bias and 23 had moderate risk. Sources of possible bias included single-group design (n = 10), lack of information on sequence generation or concealment of the allocation scheme (n = 11), and selective reporting of outcomes (n = 5). Because SVR is a highly objective outcome measure, lack of blinding was not considered an important threat to validity. Rates of loss to follow-up were low (<10% for all studies).

HCV Genotype 1 Infection

Thirty-two studies enrolled persons with HCV genotype 1 infection (Table; Figure 2, continued Figure 2; and Table 1 of the Supplement). Download Supplemental Content

Regimens That Include NS3/4A Protease Inhibitors

Grazoprevir–Elbasvir.

Grazoprevir is an NS3 protease inhibitor that is available in a fixed-dose combination with elbasvir, an NS5A inhibitor. This regimen was studied in 4 multicenter randomized trials published in 6 articles (11, 20, 21, 25–27). Risk of bias was moderate in 3 of these studies due to lack of a comparator group (n = 1) and selective reporting (n = 2). Daily grazoprevir–elbasvir for 12 weeks was associated with SVR rates of 92% and 99% to 100% in treatment-naive and treatment-experienced patients with genotype 1a and 1b infection, respectively (20, 26, 27). Among patients with genotype 1a but not genotype 1b infection, lower SVR rates were associated with pretreatment presence of naturally occurring resistance-associated substitutions (RASs) at positions 28, 30, 31, and 93 of the NS5A region (20, 27). Prolongation of therapy to 16 weeks and addition of ribavirin led to SVR among 49 treatment-experienced patients, including all 6 patients with baseline NS5A RASs (27). Ribavirin was associated with greater incidence of anemia (3% to 16% vs. 0%), fatigue, and nausea (25–27). With the exception of patients with genotype 1a infection with baseline RASs, the SVR rate was similar in those treated with or without ribavirin. Cirrhosis was not associated with lower SVR rates (14, 16).

Paritaprevir–Ritonavir–Ombitasvir and Dasabuvir.

Paritaprevir is an NS3 protease inhibitor that is coformulated with ritonavir (to provide pharmacologic boosting) and ombitasvir (an NS5A inhibitor). For patients with genotype 1 infection, dasabuvir (a nonnucleoside NS5B polymerase inhibitor) was added. We identified 1 study with low risk of bias that used the two-DAA regimen without dasabuvir (45) and 9 studies (5 with low risk of bias and 4 with moderate risk of bias) that used the three-DAA regimen for 12 or 24 weeks (12, 13, 22, 23, 37, 38, 40, 41). Moderate risk of bias was due to lack of a comparator group (n = 2) and unclear sequence generation and allocation scheme concealment (n = 2). The three-DAA regimen without ribavirin yielded lower SVR rates in persons with genotype 1a infection (90%) than those with genotype 1b infection (99%); however, with the addition of ribavirin, the SVR rate among noncirrhotic patients with genotype 1a infection increased to 97% (38). Compared with placebo, ribavirin was associated with more anemia, fatigue, insomnia, and rash (22, 38). Among cirrhotic patients with genotype 1a infection, the three-DAA regimen plus ribavirin for 24 weeks led to higher SVR rates than 12 weeks of treatment (94.2% vs. 88.6%) (41). High rates of SVR were seen among cirrhotic and noncirrhotic patients with genotype 1b infection treated for 12 weeks with the three-DAA regimen alone or with ribavirin (97% to 100%) (22, 23, 37, 38, 41, 45).

Simeprevir and Sofosbuvir.

Simeprevir is an NS3 protease inhibitor that is used once daily in combination with sofosbuvir, a nucleoside analogue NS5B polymerase inhibitor. We identified 3 studies using this regimen (14, 28, 46). Risk of bias was moderate in 2 studies due to unclear sequence generation (n = 1) and lack of a comparator group (n = 1). When used for 12 weeks, the regimen was associated with high rates of SVR (97%) in persons with HCV genotype 1a or 1b infection without cirrhosis (46). In this population, pretreatment presence of naturally occurring simeprevir RASs at position 80 of the NS3 region (Q80K) was not associated with lower SVR rates (46). However, lower SVR rates were observed among patients with cirrhosis (79% to 88%) and, in this population, the presence of the Q80K RAS was associated with lower SVR rates in patients with genotype 1a infection (74% with Q80K and 92% without) (14).

Regimens That Do Not Include NS3/4A Protease Inhibitors

Daclatasvir and Sofosbuvir.

Daclatasvir is an NS5A inhibitor used with sofosbuvir. Clinical trial data on this combination are limited but suggest high SVR rates with 12- and 24-week treatment (96% to 100%), based on data from 2 studies with moderate risk of bias (29, 48). Among patients with advanced liver disease, SVR rates were lower (82%) (15).

Ledipasvir–Sofosbuvir.

Ledipasvir, an NS5A inhibitor, is coformulated with sofosbuvir as a once-daily tablet. Eight studies (4 with low risk of bias and 4 with moderate risk of bias) evaluated different treatment durations (8, 12, and 24 weeks) and the addition of ribavirin (17, 30–34, 43, 44). Moderate risk of bias was due to lack of a comparator (n = 1) and unclear sequence generation or allocation scheme concealment (n = 3). In treatment-naive patients, SVR rates were greater than 95% with 12 weeks of treatment, and longer treatment did not yield higher rates (30, 31, 33). Although 8 weeks of therapy was assessed in 1 RCT and was found to lead to high SVR rates in noncirrhotic persons with pretreatment HCV RNA levels less than 6 × 106 IU/mL (33), the most data on efficacy are for 12 weeks. In treatment-naive patients, ribavirin was not associated with higher SVR rates regardless of cirrhosis status, whereas in treatment-experienced patients, either longer therapy (24 weeks) with ledipasvir–sofosbuvir or the addition of ribavirin to the regimen for 12 weeks was associated with higher SVR rates in patients with cirrhosis (97% vs. 96%) (34). The addition of ribavirin led to more adverse events, notably anemia, fatigue, and insomnia (31–33).

Velpatasvir–Sofosbuvir.

Velpatasvir, a pangenotypic NS5A inhibitor, is coformulated with sofosbuvir as a once-daily tablet. This regimen for 12 weeks was associated with high SVR rates (97% to 99%) in patients with HCV genotype 1a or 1b infection, including those with cirrhosis and prior treatment experience (24). In this placebo-controlled, double-blind trial with low risk of bias, the incidence of adverse events was similar in patients receiving velpatasvir–sofosbuvir and those receiving placebo.

HCV Genotype 2 Infection

Six studies enrolled patients with HCV genotype 2 infection (Table and Figure 3); 3 studies (2 with low risk of bias and 1 with moderate risk of bias) evaluated the fixed-dose combination of velpatasvir–sofosbuvir (24, 35, 49), and 3 with moderate risk of bias evaluated daclatasvir plus sofosbuvir (15, 29, 48).

Daclatasvir and Sofosbuvir

In the ALLY-2 study, all 13 HIV-infected patients with genotype 2 infection who were treated for 12 weeks achieved SVR (48). In another study, 24 of 26 (92%) treatment-naive, noncirrhotic, HIV-seronegative patients treated for 24 weeks with or without ribavirin achieved SVR; 2 patients were lost to follow-up (29).

Velpatasvir–Sofosbuvir

The ASTRAL-1 and ASTRAL-2 studies reported SVR in 237 of 238 patients (99%) with genotype 2 infection who received velpatasvir–sofosbuvir for 12 weeks; 1 patient was lost to follow-up (24, 49). Rates of SVR were not affected by cirrhosis or prior treatment experience. In an RCT, velpatasvir–sofosbuvir was superior to sofosbuvir plus ribavirin (SVR of 99% vs. 94%) and was associated with fewer adverse events (49).

HCV Genotype 3 Infection

Eight studies enrolled patients with HCV genotype 3 infection (Table and Figure 3).

Daclatasvir and Sofosbuvir

In a phase 2 study, 16 of 18 noncirrhotic patients treated with or without ribavirin for 24 weeks achieved SVR (29). In the single-group ALLY-3 trial, which had moderate risk of bias, 94% to 97% of noncirrhotic treatment-naive and treatment-experienced patients achieved SVR with 12 weeks of treatment (16). In the same study, cirrhosis was associated with a marked reduction in SVR (58% to 69%) (16). The addition of ribavirin to the regimen for 12 or 16 weeks in patients with advanced liver disease led to SVR in 86% of cirrhotic patients (n = 36) in the ALLY-3+ study, which had moderate risk of bias due to unclear sequence generation and allocation scheme (42).

Ledipasvir–Sofosbuvir

In a single-center study with low risk of bias, all 26 treatment-naive patients treated with ledipasvir–sofosbuvir plus ribavirin for 12 weeks achieved SVR (39). The SVR rate was lower without ribavirin (64%) and in treatment-experienced patients (82%) (39).

Velpatasvir–Sofosbuvir

In a phase 3 RCT with 552 patients and low risk of bias, velpatasvir–sofosbuvir for 12 weeks (95%) was superior to sofosbuvir plus ribavirin for 24 weeks (80%) and was associated with fewer adverse events, particularly less anemia (49). Lower SVR rates were observed in patients with pretreatment presence of velpatasvir NS5A RASs, particularly at position 93 (88%), compared with those without RASs (97%).

HCV Genotype 4 Infection

Twelve studies enrolled persons with HCV genotype 4 infection (Table and Figure 3).

Grazoprevir–Elbasvir

In the C-EDGE study, efficacy of grazoprevir–elbasvir was demonstrated among 18 of 18 treatment-naive patients with genotype 4 infection (SVR of 100%) who received the regimen for 12 weeks; baseline presence of NS5A RASs did not affect SVR (20). Among treatment-experienced patients in a randomized trial of 12 or 16 weeks of the regimen with or without ribavirin, SVR rates were below 95% in all groups except patients who received 16 weeks of the regimen with ribavirin (27).

Paritaprevir–Ritonavir–Ombitasvir

In 1 trial with low risk of bias, paritaprevir–ritonavir–ombitasvir plus ribavirin resulted in high efficacy (SVR of 100%) in both treatment-naive (n = 42) and treatment-experienced (n = 44) patients with genotype 4 infection (36). The absence of ribavirin was associated with a lower SVR rate (91%).

Simeprevir and Sofosbuvir

In an RCT with moderate risk of bias due to unclear sequence generation and allocation scheme concealment, simeprevir plus sofosbuvir was associated with SVR in all 43 patients (100%) treated for 12 weeks, including those with cirrhosis (n = 23); however, SVR rates were lower in 20 patients treated for 8 weeks (75%) (47).

Ledipasvir–Sofosbuvir

In a single-group trial of 21 patients, 95% who received 12 weeks of ledipasvir–sofosbuvir achieved SVR; the study included few patients with cirrhosis (n = 7) or prior treatment experience (n = 8) (10). In a similar trial conducted in France, 41 of 44 patients (93%) who were treated for 12 weeks achieved SVR (19). No serious adverse events were reported in these studies (10, 19).

Velpatasvir–Sofosbuvir

In the ASTRAL-1 RCT, which had low risk of bias, velpatasvir–sofosbuvir led to SVR in all 116 treatment-naive and treatment-experienced patients (100%) who were treated, including those with cirrhosis (24).

HCV Genotype 5 and 6 Infection

Six studies enrolled persons with HCV genotype 5 and/or 6 infection (18, 20, 24, 27, 35, 39) (Figure 3).

Ledipasvir–Sofosbuvir

This combination led to high SVR rates in persons with genotype 5 (n = 41; SVR of 95%) and genotype 6 (n = 25; SVR of 96%) infection (18, 39). Although the numbers of patients in these subgroups were small, SVR rates were high in treatment-experienced patients (≥95%) and those with cirrhosis (89%) (18).

Velpatasvir–Sofosbuvir

In 1 RCT with low risk of bias, patients with genotype 5 (n = 35) and genotype 6 (n = 41) infection achieved high rates of SVR (97% and 100%, respectively) with 12 weeks of treatment; only 1 patient did not achieve SVR (death unrelated to treatment) (24).

Subpopulations

Patients With HIV Co-infection

Direct-acting antiviral regimens used for 12 or 24 weeks showed high SVR rates (91% to 98%) and low adverse event rates (<10%). These rates were similar to those observed in persons without HIV (11, 17, 26, 40, 48). Shorter therapy (8 weeks) was evaluated in 1 RCT of daclatasvir plus sofosbuvir and led to lower rates of SVR (76%) than 12 weeks of therapy (97%) (48).

Patients With Decompensated Cirrhosis

Relatively few patients with decompensated liver disease (for example, those with jaundice, ascites, encephalopathy, or variceal hemorrhage) have been enrolled in DAA trials. Because of impaired metabolism, NS3 protease inhibitors are not recommended (simeprevir) or are contraindicated (paritaprevir or grazoprevir) in patients with Child–Turcotte–Pugh class B and C disease. These patients have been treated in trials of sofosbuvir plus NS5A inhibitors, including daclatasvir, ledipasvir, and velpatasvir (15, 35, 43, 44). In 1 RCT, velpatasvir–sofosbuvir with ribavirin for 12 weeks was more effective than velpatasvir–sofosbuvir alone for 12 or 24 weeks; however, ribavirin was associated with more treatment discontinuation due to adverse events (35). Across all studies, rates of serious adverse events were higher in patients with decompensated cirrhosis (10% to 52%) than in the general HCV patient populations (<10%).

Patients After Liver Transplantation

Four trials evaluated DAAs in patients who had undergone liver transplantation. Overall, SVR rates observed in these trials were similar to those reported in patients without a transplant (12, 15, 43, 44). However, among liver transplant patients with decompensated liver disease due to recurrent HCV infection, SVR rates were lower (50% to 80%) and adverse event rates were higher (16% to 75%) than those observed in liver transplant patients with compensated cirrhosis or those with minimal liver disease (6% to 21%) (12, 43, 44).

Patients With Chronic Kidney Disease

In 2 studies of patients with advanced renal dysfunction, including those receiving hemodialysis, high SVR rates were reported in those with HCV genotype 1 infection (13, 21). In 1 study with low risk of bias, grazoprevir–elbasvir for 12 weeks resulted in SVR in 94% of patients (n = 111) (21). In a smaller study with moderate risk of bias due to lack of a comparator group, a regimen of paritaprevir–ritonavir–ombitasvir and dasabuvir was effective (SVR of 90%), but ribavirin, which was used for patients with genotype 1a infection, was poorly tolerated and was discontinued due to adverse events in 8 of 14 patients (48).

Discussion
Multiple interferon-free, oral DAA regimens are available for treatment of chronic HCV infection. We found high SVR rates for all FDA-approved DAA regimens, with some evidence of variable response influenced by specific patient and virus characteristics. Rates of serious adverse events (<10%), loss to follow-up (<10%), and treatment discontinuation (<5%) were low even in patients with comorbid conditions, such as HIV infection and cirrhosis.

The evidence was robust for persons with genotype 1 infection, which is the most common genotype worldwide, infecting approximately 84 million persons (50). We reviewed 6 distinct DAA regimens for genotype 1 infection, with SVR rates greater than 95% for most drug combinations and patient populations. Our findings represent an important update of other systematic reviews of DAA regimens with and without interferon for treatment of HCV genotype 1 infection, which reported SVR rates in the range of 95% (50, 51) and 92% (52). The high treatment response rates in persons with genotype 1 infection are particularly important in light of the historically poor SVR rates observed with interferon in this population.

In contrast, fewer DAA regimens are available and effective for the treatment of HCV genotype 3 infection, which is the second most prevalent HCV genotype globally, infecting approximately 54 million persons. Our findings indicate that the most effective DAA regimens for patients who have genotype 3 infection without cirrhosis are sofosbuvir plus the NS5A inhibitors velpatasvir or daclatasvir for 12 weeks, whereas higher SVR rates were observed with velpatasvir–sofosbuvir in patients with cirrhosis. This agrees with recent systematic reviews, identified through MEDLINE searches from 2014 to 2016, that identified velpatasvir–sofosbuvir as the most effective treatment for genotype 3 infection (51, 52). Our findings also suggest that lower SVR rates were achieved in patients with compensated and decompensated cirrhosis, prior treatment experience, or NS5A RASs; the addition of ribavirin and longer treatment duration were associated with higher SVR rates in these patient groups (42, 53).

Although relatively few studies enrolled patients with genotype 2, 4, 5, or 6 infection, high rates of SVR (>92%) were observed for all regimens administered for at least 12 weeks. Rates of SVR were particularly high (99%) for patients with genotype 2, 4, 5, or 6 infection treated with velpatasvir–sofosbuvir (24). For treatment of genotype 4 infection, all but 1 of the DAA regimens (paritaprevir–ritonavir–ombitasvir) led to high SVR rates (93% to 100%) without ribavirin and were associated with minimal adverse effects in treatment-naive patients.

Oral DAA regimens also showed high SVR rates and minimal adverse events in patient populations that were poorly responsive or could not be treated with interferon, including those with HIV co-infection, decompensated cirrhosis, severe chronic kidney disease, and a liver transplant. Patients co-infected with HIV and HCV and those receiving immunosuppressive agents after liver transplantation had SVR rates similar to those of persons without immune dysfunction, suggesting that oral DAAs mitigate the effect of an impaired HCV immune response (54–56). Direct-acting antiviral options for persons with severe chronic kidney disease remain limited, and although high SVR rates (85% to 100%) were observed in 2 RCTs for persons with HCV genotype 1 infection, no trials were identified in persons with genotype 2 or 3 infection, for whom interferon is still recommended (57). Treatment options also remain limited in patients with decompensated liver disease. Current NS3 protease inhibitors are hepatically metabolized and are contraindicated in this population; as such, trials have been restricted to sofosbuvir plus NS5A inhibitors. The evidence indicates that these regimens provide high rates of SVR (>85%), but serious adverse events are common (10% to 52%). In addition, questions remain with regard to the long-term clinical benefit of cure of HCV infection in persons with severe liver dysfunction.

Across multiple trials, our findings indicate that ribavirin continues to have a role in maximizing SVR rates in certain patients, including those with genotype 1a or 3 infection, cirrhosis, or prior treatment experience. Clinical trials for patients with decompensated cirrhosis and a liver transplant have also largely included ribavirin. Although ribavirin was associated with an increase in anemia, fatigue, and insomnia, the rates of serious adverse events and treatment discontinuation were similar in patients treated with and without it.

Limitations of this study include the fact that safety data from clinical trials may not fully represent patient experience in clinical practice. Persons with chronic hepatitis B virus infection were excluded from trials, and the risk for hepatitis B virus reactivation was not examined. We also included noncontrolled trials; however, spontaneous cure of HCV infection is rare. Most of the studies were industry-funded; such studies are more likely to be published if results are favorable (58), but we are not aware of large, unpublished studies in this field and the risk of bias with the objective outcome of SVR is low. The heterogeneity of the interventions studied also prevented quantitative pooling of results, and the relatively short follow-up limits our ability to comment on late relapse of HCV infection. Several studies were also population-specific, thus limiting generalizability of findings to all patients. Given the multitude of effective oral DAA regimens with similar rates of SVR and adverse events, RCTs will be needed to determine the best HCV treatments for different patient populations. One such trial, the PRIORITIZE study (ClinicalTrials.gov: NCT02786537), is under way in persons with genotype 1 infection (59).

Finally, our systematic review is limited by the rapidly evolving HCV treatment landscape and the inability to include all DAA regimens in ongoing or recently completed clinical trials that we identified on ClinicalTrials.gov (Table 7 of the Supplement). These ongoing clinical trials include 2 novel nucleotide analogue NS5B polymerase inhibitors, MK-3682 and AL-335, which are being evaluated in combination with approved NS3 protease inhibitors and novel NS5A inhibitors (ruzasvir and odalasvir), as well as 2 novel pangenotypic NS3 protease inhibitors, voxilaprevir and glecaprevir, which are being evaluated in combination with approved (sofosbuvir–velpatasvir–voxilaprevir) and novel (glecaprevir–pibrentasvir) DAAs (60).

In conclusion, oral DAA regimens that are highly efficacious, well-tolerated, and relatively short in duration are now available for all HCV genotypes and for patient populations historically considered difficult to cure. The ease of dosing, safety profile, and effectiveness of these agents provide an opportunity to expand the number of patients who can be treated for HCV infection and the pool of treating providers. Rapid developments in oral DAA therapies can be beneficial only if they are linked to efforts to improve rates of HCV detection, linkage to care, and access to DAA therapy.

References
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