HCV New Drugs: 6/1/16

Tuesday, June 28, 2016

FDA Approved Gilead's Epclusa® (Sofosbuvir/Velpatasvir) to treat Genotype 1-6

As a quick reference click the links following Gilead's press release for study results (full text) from ASTRAL 1-4 clinical trials.

Prescribing Information: EPCLUSA
Press Release

Gilead’s New Hepatitis C Drug Approved by FDA, Priced at $74,760
Gilead has set a list price of $74,760 for a 12-week course of treatment, Chief Executive Officer John Milligan said by telephone. That’s lower than the list prices of its best-selling treatments Sovaldi, at $84,000, and Harvoni, $94,500. The Foster City, California-based company has been criticized in the past for the costs of its drugs.
Continue reading...

FDA Press Release

FDA Approves Epclusa for Treatment of Chronic Hepatitis C Virus Infection

First regimen to treat all six major HCV genotypes

Silver Spring, Maryland–(ENEWSPF)–June 28, 2016. The U.S. Food and Drug Administration approved Epclusa to treat adult patients with chronic hepatitis C virus (HCV) both with and without cirrhosis (advanced liver disease). For patients with moderate to severe cirrhosis (decompensated cirrhosis), Epclusa is approved for use in combination with the drug ribavirin. Epclusa is a fixed-dose combination tablet containing sofosbuvir, a drug approved in 2013, and velpatasvir, a new drug, and is the first to treat all six major forms of HCV.

“This approval offers a management and treatment option for a wider scope of patients with chronic hepatitis C,” said Edward Cox, M.D., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

Hepatitis C is a viral disease that causes inflammation of the liver that can lead to diminished liver function or liver failure. There are at least six distinct HCV genotypes, or strains, which are genetically distinct groups of the virus. Knowing the genotype helps inform treatment recommendations and the duration of treatment. Approximately 75 percent of Americans with HCV have genotype 1; 20-25 percent have genotypes 2 or 3; and a small numbers of patients are infected with genotypes 4, 5 or 6. According to the Centers for Disease Control and Prevention, HCV infection becomes chronic in approximately 75 to 85 percent of cases. Patients who suffer from chronic HCV infection over many years may have complications, such as bleeding, jaundice (yellowish eyes or skin), fluid accumulation in the abdomen, infections, liver cancer and death.

The safety and efficacy of Epclusa for 12 weeks was evaluated in three Phase III clinical trials of 1,558 subjects without cirrhosis or with compensated cirrhosis (mild cirrhosis). Results demonstrated that 95–99 percent of patients who received Epclusa had no virus detected in the blood 12 weeks after finishing treatment, suggesting the patients’ infections had been cured. The safety and efficacy of Epclusa was also evaluated in a clinical trial of 267 subjects with decompensated cirrhosis (moderate to severe cirrhosis), of whom 87 subjects received Epclusa in combination with ribavirin for 12 weeks, and 94 percent of these patients had no virus detected in the blood 12 weeks after finishing treatment.

The most common side effects of Epclusa include headache and fatigue. Epclusa and ribavirin combination regimens are contraindicated for patients for whom ribavirin is contraindicated.

Epclusa carries a warning for patients and health care providers that serious slowing of the heart rate (symptomatic bradycardia) and cases requiring pacemaker intervention have been reported when amiodarone is used with sofosbuvir in combination with another HCV direct-acting antiviral. Co-administration of amiodarone with Epclusa is not recommended. Epclusa also carries a warning not to use with certain drugs that may reduce the amount of Epclusa in the blood which could lead to reduced efficacy of Epclusa.

Epclusa was reviewed under the FDA’s priority review program, which provides for an expedited review of drugs that treat serious conditions and, if approved, would provide significant improvement in safety or effectiveness.

Epclusa is manufactured and marketed by Gilead Sciences, Inc., of Foster City, California.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency is also responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Source: http://www.fda.gov

June 28, 2016 - 10:25 a.m.

Gilead's Press Release

U.S. Food and Drug Administration Approves Gilead's Epclusa® (Sofosbuvir/Velpatasvir) for the Treatment of All Genotypes of Chronic Hepatitis C

Date(s): 28-Jun-2016 10:25 AM

- Epclusa is the First and Only All-Oral, Pan-genotypic Single Tablet Regimen for Chronic Hepatitis C Virus Infection and Gilead's Third Sofosbuvir-Based Regimen -

FOSTER CITY, Calif.--(BUSINESS WIRE)--Jun. 28, 2016-- Gilead Sciences, Inc. (NASDAQ: GILD) today announced that the U.S. Food and Drug Administration (FDA) has approved Epclusa^® (sofosbuvir 400 mg/velpatasvir 100 mg), the first all-oral, pan-genotypic, single tablet regimen for the treatment of adults with genotype 1-6 chronic hepatitis C virus (HCV) infection. Epclusa is also the first single tablet regimen approved for the treatment of patients with HCV genotype 2 and 3, without the need for ribavirin. Epclusa for 12 weeks was approved in patients without cirrhosis or with compensated cirrhosis (Child-Pugh A), and in combination with ribavirin (RBV) for patients with decompensated cirrhosis (Child-Pugh B or C).

"The approval of Epclusa represents an important step forward in the global effort to control and potentially eliminate HCV as it provides a safe, simple and effective cure for the majority of HCV-infected patients, regardless of genotype," said Ira Jacobson, MD, Chairman of the Department of Medicine at Mount Sinai Beth Israel, New York City and a principal investigator in the Epclusa clinical trials. "Building on the established backbone of sofosbuvir, Epclusa demonstrated consistently high cure rates across all genotypes, including among patients with genotype 2 and 3, who traditionally have required ribavirin or other multi-pill regimens."

The FDA granted Epclusa a Priority Review and Breakthrough Therapy designation, which is given to investigational medicines that may offer major advances in treatment over existing options.
Epclusa's approval is supported by data from four international Phase 3 studies, ASTRAL-1, ASTRAL-2, ASTRAL-3 and ASTRAL-4. In the ASTRAL-1, ASTRAL-2 and ASTRAL-3 studies, 1,035 patients with genotype 1-6 chronic HCV infection, without cirrhosis or with compensated cirrhosis received 12 weeks of Epclusa. The ASTRAL-4 study randomized 267 patients with genotype 1-6 HCV infection, with decompensated cirrhosis (Child-Pugh B), to receive 12 weeks of Epclusa with or without RBV or 24 weeks of Epclusa. The primary endpoint for all studies was SVR12.

Of the 1,035 patients treated with Epclusa for 12 weeks in the ASTRAL-1, ASTRAL-2 and ASTRAL-3 studies, 1,015 (98 percent) achieved SVR12. In ASTRAL-4, patients with decompensated cirrhosis receiving Epclusa with RBV for 12 weeks achieved a high SVR12 rate (94 percent) compared to those who received Epclusa for 12 weeks or 24 weeks (83 percent and 86 percent, respectively).

Headache and fatigue were the most common adverse reactions (=10 percent) experienced by HCV-infected patients treated with Epclusa in ASTRAL-1, ASTRAL-2 and ASTRAL-3 and occurred at a similar or higher frequency in placebo-treated patients. In the 87 HCV-infected patients with decompensated cirrhosis treated with Epclusa and ribavirin in the ASTRAL-4 study, fatigue, anemia, nausea, headache, insomnia and diarrhea were the most common adverse reactions (=10 percent). Two and four patients treated with Epclusa and Epclusa with RBV respectively discontinued treatment due to adverse events.

"Today's approval represents a significant advance for patients with HCV genotypes 2 and 3, who previously required more complex and costly regimens," said John Milligan, Ph.D., President and Chief Executive Officer of Gilead. "As the first and only pan-genotypic cure for hepatitis C, Epclusa has the potential to eliminate the need for genotype testing, which can be a barrier to treatment in certain resource-constrained settings. We look forward to making Epclusa available to patients around the world as quickly as possible."

Epclusa should not be administered with ribavirin in patients for whom ribavirin is contraindicated. See below for Important Safety Information for Epclusa.

U.S. Patient Support Program
To assist eligible hepatitis C patients in the United States with access to Epclusa, Gilead has added the medicine to its Support Path^® (www.MySupportPath.com) program. The program consists of an integrated offering of support services for patients and providers, among them:

Call center staffed with associates trained to help patients and their providers with insurance-related needs.
Education and support, including a 24/7 nursing support service line.
The Epclusa Co-pay Coupon Programs, which provide co-pay assistance for eligible patients with private insurance who need assistance paying for out-of-pocket medication costs. Most patients will pay no more than $5 per co-pay.
The Support Path Patient Assistance Program, which will provide Epclusa at no charge for eligible patients with no other insurance options.

Gilead also provides support to independent non-profit organizations that provide assistance for eligible federally-insured and privately-insured patients who need help covering out-of-pocket medication costs.
To learn more about Support Path for Epclusa, please visit www.MySupportPath.com or call 1-855-769-7284 between 9:00 a.m. - 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 eliminates 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, the Medicines Patent Pool and other stakeholders to expand treatment globally. Epclusa is already licensed to Gilead's 11 Indian manufacturing partners who may now begin production and distribution of a generic version of this medicine for 101 developing countries.

IMPORTANT SAFETY INFORMATION

Contraindications
If EPCLUSA is used in combination with ribavirin (RBV), all contraindications, warnings and precautions, and adverse reactions to RBV also apply. Refer to RBV prescribing information.

Warnings and Precautions
Risk of Serious Symptomatic Bradycardia When Sofosbuvir Is Coadministered with Amiodarone and Another HCV Direct Acting Antiviral: 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. 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 risks that physicians and patients may not see advantages of Epclusa over other therapies and may therefore be reluctant to prescribe the product, and the risk that payers may be reluctant to approve or provide reimbursement for the product. 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, 2016, 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 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.

Links

Last month Healio published; ASTRAL studies: New combination yields encouraging patient-reported outcomes from patient-reported data presented at Digestive Disease Week 2016.

HCV Advocate - The Breakdown
November 2015
The Phase 3 clinical trials—ASTRAL-1, ASTRAL-2, and ASTRAL-3. There were 1,035 of whom 116 patients received placebo (sugar pills). There were 267 people in the ASTRAL-4 trial—this trial included the patients with genotypes 1 through 6 with decompensated cirrhosis. There was not a breakdown by genotype. The breakdown is here, from HCV Advocate.

New England Journal Of Medicine
December 2015
ASTRAL 1-4 results published in the December 2015 issue of New England Journal of Medicine (NEJM) *or free online @ NATAP

New England Journal Of Medicine
Full Text - Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection

New England Journal Of Medicine - Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection
Full Text NEJM Article @ NATAP

New England Journal Of Medicine - Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis
Full Text NEJM Article @ NATAP

In addition this article; Hepatitis C treatment studies from NEJM: Closer to One Size for All written by Donald Jensen, MD., provides a nice summary of each study.

EASL 2016 Coverage
April 2016
On-Treatment HCV RNA as a Predictor of SVR12 in Patients With Genotype 1-6 HCV Infection Treated With Sofosbuvir/Velpatasvir for 12 Weeks: An Analysis of the ASTRAL-1, ASTRAL-2, and ASTRAL-3 Studies - (04/26/16)

Resistance Analysis in 1284 Patients With Genotype 1-6 HCV Infection Treated With Sofosbuvir/Velpatasvir in the Phase 3 ASTRAL-1, ASTRAL-2, ASTRAL-3, and ASTRAL-4 Studies - (04/15/16)

Drug-Drug Interaction Profile of Sofosbuvir/Velpatasvir Fixed-Dose Combination - 4/21/16

Sofosbuvir/Velpatasvir in Combination With Ribavirin for 24 Weeks Is Effective Retreatment for Patients Who Failed Prior NS5A-Containing DAA Regimens: Results of the Retreatment Study - (04/15/16)

Complete EASL coverage @ NATAP

Journalists: 9 tips to combat stem cell hype in your news stories

Journalists: 9 tips to combat stem cell hype in your news stories

Joy Victory is deputy managing editor of HealthNewsReview.org. She tweets as @thejoyvictory.

At this moment, only a handful of stem cell therapies have been proven safe and effective through clinical research, according to the International Society for Stem Cell Research (ISSCR).

Yet, that’s not evident from a recent Google News Search for stem cells, which pulls up 800,000+ results of varying quality, as we’ve seen in our examinations of stem cell stories on spinal cord injuries, muscular dystrophy, chronic obstructive pulmonary disease, severe combined immunodeficiency, and multiple sclerosis, among others.

This explosion of news coverage and stem cell hype is partly why, for the first time, ISSCR has added a section on communication to their guidelines for stem cell research and the development of new clinical therapies (see page 28 of the PDF).

Resources to help you avoid these pitfalls include this ISSCR patient information article, this STAT piece on the FDA’s efforts to crack down on clinics, a NEJM report on the “Wild West” of U.S. stem cell clinics, as well as this tipsheet from stem cell scientist Paul Knoepfler.

Monday, June 27, 2016

Regulus Reports Clinical Hold of RG-101

Update
Tuesday, January 31, 2017

Regulus Announces Continuation of RG-101 Clinical Hold - FDA requests longer-term follow-up data from ongoing studies

Regulus Reports Clinical Hold of RG-101

Timelines of On-going Studies are not Expected to be Impacted
Conference Call Today at 5:00 p.m. ET
16:10 ET from Regulus Therapeutics Inc.

LA JOLLA, Calif., June 27, 2016 /PRNewswire/ -- Regulus Therapeutics Inc. (Nasdaq: RGLS), a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs, today announced it received verbal notice from the U.S. Food and Drug Administration (FDA) that its Investigational New Drug (IND) for RG-101 for the treatment of chronic hepatitis C virus (HCV) infection has been placed on clinical hold. Regulus anticipates it will receive a formal clinical hold letter from the FDA within 30 days and plans to work diligently with the agency to seek the release of the clinical hold.

The FDA initiated the clinical hold after Regulus reported a second serious adverse event (SAE) of jaundice. The SAE occurred in a HCV patient with end-stage renal disease on dialysis enrolled in its on-going Phase I US study 117 days after receiving a single dose of RG-101.

Timelines for Regulus' three on-going studies of RG-101 are not expected to be impacted as all patients have been enrolled and completed their dosing of RG-101 and will continue with protocol scheduled visits. Regulus remains on track to deliver follow-up results from these studies at upcoming relevant scientific meetings.

Conference Call Details

Regulus will host a conference call and webcast today at 5:00 p.m. Eastern Time to discuss today's announcement. A live webcast of the call will be available online at www.regulusrx.com. To access the call, please dial (877) 257-8599 (domestic) or (970) 315-0459 (international) and refer to conference ID 41706266. To access the telephone replay of the call, dial (855) 859-2056 (domestic) or (404) 537-3406 (international), passcode 41706266. The webcast and telephone replay will be archived on the company's website following the call.

About Regulus

Regulus Therapeutics Inc. (Nasdaq: RGLS) is a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs. Regulus has leveraged its oligonucleotide drug discovery and development expertise to develop a well-balanced microRNA therapeutics pipeline complemented by a maturing microMarkersSM biomarkers platform and a rich intellectual property estate to retain its leadership in the microRNA field. Regulus is developing RG-101, a GalNAc-conjugated anti-miR targeting microRNA-122 for the treatment of chronic hepatitis C virus infection, and RG-012, an anti-miR targeting microRNA-21 for the treatment of Alport syndrome, a life-threatening kidney disease driven by genetic mutations with no approved therapy. In addition, RG-125, a GalNAc-conjugated anti-miR targeting microRNA-103/107 for the treatment of NASH in patients with type 2 diabetes/pre-diabetes, has entered Phase I clinical development through its strategic alliance with AstraZeneca. Regulus is also advancing several programs toward clinical development in renal, hepatic and central nervous systems diseases, both independently and with our strategic alliance partners, Sanofi and AstraZeneca. Regulus' commitment to innovation has resulted in multiple peer-reviewed publications in notable scientific journals and has resulted in the formation of strategic alliances with AstraZeneca and Sanofi. Regulus maintains its corporate headquarters in La Jolla, CA. For more information, please visit http://www.regulusrx.com.

About microRNAs

The discovery of microRNAs in humans during the last decade is one of the most exciting scientific breakthroughs in recent history. microRNAs are small RNA molecules, typically 20 to 25 nucleotides in length, that do not encode proteins but instead regulate gene expression. More than 800 microRNAs have been identified in the human genome, and over two-thirds of all human genes are believed to be regulated by microRNAs. A single microRNA can regulate entire networks of genes. As such, these molecules are considered master regulators of the human genome. microRNA expression, or function, has been shown to be significantly altered or dysregulated in many disease states, including oncology, fibrosis, metabolic diseases, immune-inflammatory diseases and HCV. Targeting microRNAs with anti-miRs, chemically modified, single-stranded oligonucleotides, offers a unique approach to treating disease by modulating entire biological pathways and may become a new and major class of drugs with broad therapeutic application.

About RG-101 for HCV

RG-101 is Regulus' wholly-owned, GalNAc-conjugated anti-miR targeting miR-122 for the treatment of HCV. In a completed Phase I human proof-of-concept study, Regulus demonstrated that treatment with a single subcutaneous dose of RG-101 as monotherapy resulted in significant and sustained viral load reductions in all treated HCV patients, including patients with difficult to treat genotypes, various liver fibrosis status and those who have experienced viral relapse after a prior IFN-containing regimen.

Forward-Looking Statements

Statements contained in this press release regarding matters that are not historical facts are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including statements associated with the expected ability of Regulus to undertake certain activities and accomplish certain goals (including with respect to development and other activities related to RG-101), the projected timeline of clinical development activities, and expectations regarding future therapeutic and commercial potential of Regulus' business plans, technologies and intellectual property related to microRNA therapeutics and biomarkers being discovered and developed by Regulus. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Words such as "believes," "anticipates," "plans," "expects," "intends," "will," "goal," "potential" and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon Regulus' current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, risks associated with the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such drugs. These and other risks concerning Regulus' financial position and programs are described in additional detail in Regulus filings with the Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made. Regulus undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.

Logo - http://photos.prnewswire.com/prnh/20160519/370141LOGO

Chronic fatigue syndrome is in your gut, not your head

Chronic fatigue syndrome is in your gut, not your head

Physicians have been mystified by chronic fatigue syndrome, a condition where normal exertion leads to debilitating fatigue that isn't alleviated by rest. There are no known triggers, and diagnosis requires lengthy tests administered by an expert.

Now, for the first time, Cornell University researchers report they have identified biological markers of the disease in gut bacteria and inflammatory microbial agents in the blood.

In a study published June 23 in the journal Microbiome, the team describes how they correctly diagnosed myalgic encephalomyeletis/chronic fatigue syndrome (ME/CFS) in 83 percent of patients through stool samples and blood work, offering a noninvasive diagnosis and a step toward understanding the cause of the disease.

"Our work demonstrates that the gut bacterial microbiome in chronic fatigue syndrome patients isn't normal, perhaps leading to gastrointestinal and inflammatory symptoms in victims of the disease," said Maureen Hanson, the Liberty Hyde Bailey Professor in the Department of Molecular Biology and Genetics at Cornell and the paper's senior author. "Furthermore, our detection of a biological abnormality provides further evidence against the ridiculous concept that the disease is psychological in origin."

"In the future, we could see this technique as a complement to other noninvasive diagnoses, but if we have a better idea of what is going on with these gut microbes and patients, maybe clinicians could consider changing diets, using prebiotics such as dietary fibers or probiotics to help treat the disease," said Ludovic Giloteaux, a postdoctoral researcher and first author of the study.

In the study, Ithaca campus researchers collaborated with Dr. Susan Levine, an ME/CFS specialist in New York City, who recruited 48 people diagnosed with ME/CFS and 39 healthy controls to provide stool and blood samples.

The researchers sequenced regions of microbial DNA from the stool samples to identify different types of bacteria. Overall, the diversity of types of bacteria was greatly reduced and there were fewer bacterial species known to be anti-inflammatory in ME/CFS patients compared with healthy people, an observation also seen in people with Crohn's disease and ulcerative colitis.

At the same time, the researchers discovered specific markers of inflammation in the blood, likely due to a leaky gut from intestinal problems that allow bacteria to enter the blood, Giloteaux said.

Bacteria in the blood will trigger an immune response, which could worsen symptoms.

The researchers have no evidence to distinguish whether the altered gut microbiome is a cause or a whether it is a consequence of disease, Giloteaux added.

In the future, the research team will look for evidence of viruses and fungi in the gut, to see whether one of these or an association of these along with bacteria may be causing or contributing to the illness.

###

The study was funded by the National Institutes of Health.
http://mediarelations.cornell.edu/2016/06/27/3770/

Saturday, June 25, 2016

Now that we have the hepatitis C virus on the run, can a universal cure be attained?

Medscape Gastroenterology

COMMENTARY

Hepatitis C: Let's Get 'Real'
Digestive Disease Week (DDW) 2016
Clinical trials have shown that current treatment approaches for hepatitis C are highly successful. Can this degree of success be attained in real-world populations?

Medscape Gastroenterology, June 24, 2016

William F. Balistreri, MD
June 24, 2016

Hepatitis C virus (HCV) infection remains a significant problem worldwide, with risk for progression to cirrhosis, liver failure, and hepatocellular carcinoma. The good news is that with the development and validation of a spate of new direct-acting antiviral (DAA) drugs and novel treatment strategies, a significant proportion of patients can be cured of HCV infection.

Current highly successful strategic treatment approaches have achieved high sustained virologic response (SVR) rates in clinical trials. However, the question remains: Can this degree of success be replicated in a real-world application of these strategies? And will this level of success apply to all patients? Research presented at this year's Digestive Disease Week (DDW) discussed real-world outcomes and the prospects for ensuring the best outcome for all patients with chronic hepatitis C, including certain patient populations—those with cirrhosis or decompensated liver disease and those who failed to respond to treatment—who may require enhanced strategies such as a longer duration of therapy, the addition of ribavirin, or the use of new ribavirin-free combinations. There are also new possibilities, therapeutic agents that will soon be available to add to the expanding armamentarium of DAAs and combination regimens. For example, the next-generation investigational pangenotypic once-daily combination tablet containing 400 mg of sofosbuvir (SOF) and 100 mg of velpatasvir (VEL) was granted priority review designation from the US Food and Drug Administration (FDA) and is scheduled for approval this quarter. A key area of concern is the possibility of treatment failure due to the existence and emergence of resistant variants of the virus. Investigators discussed the potential impact and use of regimens that offer non-overlapping resistance profiles.

Curative treatment has clear advantages compared with the management of end-stage disease, yet treatment costs and access to treatment for HCV infection are ongoing issues, even though increased competition among pharmaceutical manufacturers may ultimately reduce the price of DAA regimens.

Some of the relevant presentations from DDW 2016 in which investigators shed light on these important issues are highlighted herein.

Continue reading commentary.....

* Free registration required

Index
Hepatitis C: Let's Get 'Real'
Efficacy and Impact of Treatment
New Strategies
Special Populations
Can We Improve Outcomes?
Cost and Access

In The Journals
Access to Treatment Regimens in Chronic HCV Patients
Journal of Viral Hepatitis, June 24, 2016

The Direct-acting Antiviral Era in HCV Cirrhosis
Alimentary Pharmacology & Therapeutics, June 24, 2016

HCV Transmission Associated With a CAM Injection Therapy
Morbidity & Mortality Weekly Report, June 23, 2016

Direct Acting Antiviral Therapy After Liver Transplantation
Current Opinion in Gastroenterology, June 22, 2016

Surveillance for Liver Cancer in Hepatitis C Patients
Liver International, June 21, 2016

Monday, June 20, 2016

Enanta Initiates Proof-of-Concept Study with Pan-genotypic Cyclophilin Inhibitor EDP-494/Geno 1 or Geno 3 Chronic Hepatitis C Virus

Enanta Pharmaceuticals Initiates Proof-of-Concept Study with Pan-genotypic Cyclophilin Inhibitor EDP-494 in Patients with Genotype 1 or Genotype 3 Chronic Hepatitis C Virus

New non-DAA mechanism retains potency against important DAA resistance-associated variants (RAVs), regardless of class

EDP-494 represents a new host-targeted approach that may play an important role in future treatment regimens for chronic hepatitis C virus (HCV) patients that have failed therapy due to resistance arising from direct-acting antiviral (DAA) therapies currently on the market

WATERTOWN, Mass.--(BUSINESS WIRE)--Jun. 20, 2016-- Enanta Pharmaceuticals, Inc., (NASDAQ:ENTA), a research and development-focused biotechnology company dedicated to creating small molecule drugs for viral infections and liver diseases, today announced that it has initiated a proof of concept study (POC) and has begun dosing with EDP-494, a potent, pan-genotypic cyclophilin inhibitor to treat patients with genotype 1 (GT1) or genotype 3 (GT3) chronic hepatitis C virus.

The double-blind, randomized POC portion of this ongoing phase 1 study will assess the safety, pharmacokinetics and anti-viral activity of two planned different doses of EDP-494 in treatment-naïve HCV patients dosed orally, once daily for 14 days. Safety and pharmacokinetics of single and multiple ascending doses of once daily, orally administered EDP-494 have been established in healthy volunteers and these data support the testing of EDP-494 in a proof-of-concept study in HCV patients.

EDP-494, a Cyclophilin Inhibitor for HCV Infection
Due to resistance arising with direct-acting antiviral HCV therapies currently on the market, Enanta has developed an alternative treatment approach to HCV that targets the human host protein cyclophilin, which is essential for replication of HCV. Since cyclophilin inhibitors act as host-targeted antivirals, the viral mutation resistance that arises from direct-acting antiviral (DAA) treatments would not be expected for this mechanism, and thus cyclophilin inhibitors may have the highest barrier to resistance of any class of HCV treatments.

“As the number of patients treated with the current HCV DAA regimens on the market rapidly increases, the treatment failure population will become an important unmet medical need in patients with hepatitis C and may require new mechanisms of therapy such as cyclophilin inhibition,” commented Professor Edward J. Gane, MD, Professor of Medicine at the University of Auckland, New Zealand and Chief Hepatologist, Transplant Physician and Deputy Director of the New Zealand Liver Transplant Unit at Auckland City Hospital and chief investigator of the EDP-494 study. “This host-targeted approach may prove valuable not only in the toughest to treat patients with DAA resistance, but also in the general HCV patient population, given its pangenotypic mechanism of action and high barrier to resistance.”

Data presented at the International Liver Congress™ ¹in Barcelona in April, 2016 demonstrated that EDP-494 in replicon assays is a potent inhibitor of HCV replication and has shown no loss of potency against all major NS5A RAVs, NS5B RAVs (both Nucleotide and non-Nucleotide) as well as NS3 protease inhibitor RAVs.

Following the completion of the phase 1 study, Enanta plans to develop EDP-494 in combination with one or more DAAs for the treatment of any emerging HCV resistance to currently marketed therapies or any other therapies in development that use DAAs. Enanta anticipates that a DAA-cyclophilin inhibitor combination could provide one of the highest barrier to resistance combination treatments for HCV.

About EDP-494
EDP-494 is a cyclophilin inhibitor that targets the human host protein, cyclophilin, which is essential for replication of chronic hepatitis C virus (HCV). Host-targeted antivirals (HTAs) such as cyclophilin inhibitors are not affected by changes in the virus and, therefore, use of this class of inhibitor may provide a unique solution for a subset of hard-to-treat HCV patients. Enanta has demonstrated in replicon assays that EDP-494 is a potent inhibitor of HCV. A phase 1 clinical study in HCV patients is currently underway.

About Enanta
Enanta Pharmaceuticals is a research and development-focused biotechnology company that uses its robust chemistry-driven approach and drug discovery capabilities to create small molecule drugs for viral infections and liver diseases. Enanta’s research and development efforts are currently focused on four disease targets: Hepatitis C Virus (HCV), Hepatitis B Virus (HBV), Non-alcoholic Steatohepatitis (NASH) and Respiratory Syncytial Virus (RSV).
Enanta has discovered novel protease inhibitors and NS5A inhibitors that are members of the direct-acting-antiviral (DAA) inhibitor classes designed for use against the hepatitis C virus (HCV). Enanta’s protease inhibitors, developed through its collaboration with AbbVie, include paritaprevir, which is contained in AbbVie’s marketed DAA regimens for HCV, and ABT-493, Enanta’s second protease inhibitor, which AbbVie is developing in phase 3 studies in combination with ABT-530, AbbVie’s NS5A inhibitor. Enanta has also discovered a cyclophilin inhibitor, EDP-494, a novel host-targeting mechanism for HCV, which is now in phase 1 clinical development, and EDP-305, an FXR agonist, which Enanta plans to advance into clinical development for NASH later in 2016. Please visit www.enanta.com

Friday, June 17, 2016

Kiwis chase overseas drugs to help battle Hepatitis C

Kiwis chase overseas drugs to help battle Hepatitis C
CATE BROUGHTON
Last updated 05:00, June 18 2016

50,000 people have Hep C in New Zealand, but a recent Pharmac announcement about funding for two new drug treatments will not help all of them, CATE BROUGHTON writes.

Naomi Wickens lived with Hepatitis C (HVC) for 45 years, but was cured with a generic drug imported from India this year at a cost of $2500.

Wickens, 67, is one among many Kiwis forced to use generic drugs sourced from overseas to treat their condition.

This month, Pharmac announced it would fund two new hepatitis C treatments, Harvoni and Viekira Pakbut, but doctors say it will only help 50 per cent of those with the illness.

Pharmac's money will help patients with genotype 1 and a small number who are on death's door with severe liver failure, giving them hope for a healthy future.

But for 50 per cent of patients with other genotypes there is no celebrating.

"While it is good news for those with genotype 1 Hepatitis C, there is no funded Direct Acting Anti-Virals (DAAV) for people with the other strains so that's difficult for those patients," says hepatitis specialist Catherine Stedman.

Faced with this news many sufferers will do like Wickens and consider importing generic drugs produced in India, China or Bangladesh which they are legally entitled to do with a prescription from a New Zealand doctor.

However, in recent weeks, doctors who have prescribed drugs for HCV patients have been sent a warning letter and prescription form to complete from Medsafe about "unapproved" medications...

Listen - Overcoming Hepatitis C

Listen - Overcoming Hepatitis C

Guest: Carleen McGuffy, Hepatitis C Survivor

From the Show: Melanie Cole's Health Radio

Summary: Treatment is now available for hepatitis C.

Duration: 10 Minutes

Prevalence of extrahepatic manifestations of Hepatitis C

Prevalence of extrahepatic manifestations of Hepatitis C

This month's issue of Gastroenterology reviews the prevalence, quality of life, and economic burden of extrahepatic manifestations of Hepatitis C.

Hepatitis C virus infection has hepatic and extrahepatic manifestations with various costs and impairments to health-related quality of life.

Dr Zobair Younossi and colleagues from Virginia, USA performed a meta-analysis to determine the prevalence of extrahepatic manifestations in patients with HCV infection, how these impair HRQL, and their costs.

The researchers performed systematic reviews of the literature using MEDLINE, CINAHL, and the Cochrane Systematic Review Database, from 1996 through 2014.

The research team identified studies of the following extrahepatic manifestations of HCV infection: mixed cryoglobulinemia, chronic kidney or end-stage renal disease, type 2 diabetes, B-cell lymphoma, lichen planus, Sjögren’s syndrome, porphyria cutanea tarda, rheumatoid-like arthritis, or depression.

The researchers performed a separate meta-analysis for each condition to determine prevalence rates of extrahepatic manifestations of HCV infection and their effects on health-related quality of life.
The team determined the annual costs associated with extrahepatic manifestations of HCV infection.

In an analysis of data from 102 studies, the research team found the most common extrahepatic manifestations to be diabetes, and depression.

HRQL data showed that HCV infection had negative effects on overall physical and mental health.

The research team found that total direct medical costs of extrahepatic manifestations of HCV infection, in 2014 US dollars, were estimated to be $1506 million.

Dr Younossi's team concludes, "In a systematic review and meta-analysis we determined the prevalence, risks, and costs associated with extrahepatic manifestations of HCV infection."
"These estimates should be added to the liver-related burden of disease to obtain a more accurate assessment of the total burden of chronic HCV infection."

"Prospective, real-world studies are needed to increase our understanding of the total clinical and economic effects of HCV infection and treatment on patients and society."

Gastroenterol 2016: 150(7): 1599–1608
17 June 2016

Source Abstract http://www.gastrohep.com/news/news.asp?id=111904

Thursday, June 16, 2016

June - Recruiting and upcoming hepatitis C clinical trials

Hello folks, as we wait for the FDA's final decision on the approval of Gilead's Sofosbuvir/Velpatasvir expected on June 28, here is a short list of recruiting and upcoming hepatitis C clinical trials for the month of June.

Peppered throughout this post you will find correlating news and interim results from ongoing hepatitis C clinical trials placed before some recruiting information.

However, this is not a complete list; to find out if a study is enrolling patients in your area, please click here, or here for hepatitis trials listed by state, as well as HCV Advocate Monthly Pipeline Update for additional information.

News

GS-9857, in combination with sofosbuvir and velpatasvir

June 14 2016

New Combination Therapy May Be Effective Against Chronic HCV Infection
NEW YORK (Reuters Health) - The new NS3/4A protease inhibitor GS-9857, in combination with sofosbuvir and velpatasvir (SOF/VEL), produces sustained viral response in most patients with hepatitis C virus (HCV) genotype 1 or 3 infections, according to a phase 2 trial from Gilead Sciences.

Recruiting

Safety, Tolerability and Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Subjects With Previous DAA Experience

Please refer to this study by its ClinicalTrials.gov identifier: NCT02745535
Condition: Chronic Hepatitis C
Intervention: Drug: Sofosbuvir/Velpatasvir/GS-9857
Contacts
Contact: Eleanor Wilson, MD 410-706-1710 ewilson@ihv.umaryland.edu
Contact: Jennifer Hoffmann, MSN/MPH 410-706-0294 jhoffmann@som.umaryland.edu

Locations
United States, Maryland
Institute of Human Virology Recruiting
Baltimore, Maryland, United States, 21201

News

Sofosbuvir/Velpatasvir

Jan 2016
Gilead's Sofosbuvir/Velpatasvir for Treatment of All Genotypes of Chronic Hepatitis C Infection received FDA priority review status in January 2016 -- Final FDA Decision Anticipated by June 28, 2016 --

May 2016
EU regulators recommend approving Gilead's Epclusa® (Sofosbuvir/Velpatasvir) for All HCV Genotypes
--Epclusa is Gilead’s Third Sofosbuvir-Based Treatment to Receive a CHMP Positive Opinion for the Treatment of Chronic HCV Infection--

Research

Healio

VIDEO: Sofosbuvir/velpatasvir may offer improved patient reported outcomes

June 6

SAN DIEGO — In this exclusive video from DDW 2016, Zobair Younossi, MD, MPH, chairman of the department of medicine, Inova Fairfax Hospital, and vice president for research of Inova Health System, discusses new data showing the pan-genotypic regimen of a fixed-dose combination of Sovaldi (sofosbuvir, Gilead Sciences) and velpatasvir (Gilead Sciences) was associated with improved patient reported outcomes, or PROs.

Watch the video, here

Additional Information on this blogs website - Sovaldi /Velpatasvir

Not Recruiting Yet

This study is not yet open for participant recruitment

Efficacy and Safety of Sofosbuvir/Velpatasvir Fixed Dose Combination (FDC) and Sofosbuvir/Velpatasvir FDC and Ribavirin in Participants With Chronic Genotype 3 HCV Infection and Cirrhosis

Please refer to this study by its ClinicalTrials.gov identifier: NCT02781558
Contacts - Locations
Contact: Gilead Study Team 342-2097alerts@gilead.com
Condition: Hepatitis C Virus Infection
Interventions: Drug: SOF/VEL; Drug: RBV

Not Recruiting Yet

This study is not yet open for participant recruitment
Sofosbuvir/Velpatasvir Fixed Dose Combination in Participants With Chronic Hepatitis C Virus Infection Who Have Received a Liver Transplant

Please refer to this study by its ClinicalTrials.gov identifier: NCT02781571
Contacts - Locations
Contact: Gilead Study Team 342-2104alerts@gilead.com
Condition: Hepatitis C Virus Infection Intervention: Drug: SOF/VEL Sponsor: Gilead Sciences

verified May 2016 (Source: ClinicalTrials.gov)
May 20, 2016

Recruiting
Efficacy and Safety of Sofosbuvir/Velpatasvir Fixed Dose Combination for 12 Weeks in Participants With Chronic HCV
Please refer to this study by its ClinicalTrials.gov identifier: NCT02671500
Condition: Hepatitis C Virus Infection
Intervention: Drug: SOF/VEL
Locations
Malaysia
University of Malaya Recruiting
Kuala Lumpur, Malaysia, 59100
Hospital Tengku Ampuan Afzan Recruiting
Pahang, Malaysia, 25100
Singapore
National University Hospital Recruiting
Singapore, Singapore, 119074
Singapore General Hospital Recruiting
Singapore, Singapore, 169608

Recruiting

Ledipasvir/Sofosbuvir Fixed-Dose Combination for 12 Weeks in Participants With Chronic Genotype 2 HCV Infection

Please refer to this study by its ClinicalTrials.gov identifier: NCT02738333

Locations - Japan

Contacts
Contact: Gilead Study Team GS-US-337-1903@gilead.com
Condition: Hepatitis C Virus Infection
Interventions: Drug: LDV/SOF; Drug: SOF; Drug: RBV

Research

Daclatasvir and Sofosbuvir

Hepatology May 2016

Daclatasvir, sofosbuvir, and ribavirin for hepatitis C virus genotype 3 and advanced liver disease: A randomized phase III study (ALLY-3+)

Patients with hepatitis C virus (HCV) genotype 3 infection, especially those with advanced liver disease, are a challenging population in urgent need of optimally effective therapies. The combination of daclatasvir (DCV; pangenotypic nonstructural protein 5A inhibitor) and sofosbuvir (SOF; nucleotide nonstructural protein 5B inhibitor) for 12 weeks previously showed high efficacy (96%) in noncirrhotic genotype 3 infection. The phase III ALLY-3+ study (N = 50) evaluated DCV-SOF with ribavirin (RBV) in treatment-naïve (n = 13) or treatment-experienced (n = 37) genotype 3-infected patients with advanced fibrosis (n = 14) or compensated cirrhosis (n = 36).

Patients were randomized 1:1 to receive open-label DCV-SOF (60 + 400 mg daily) with weight-based RBV for 12 or 16 weeks. The primary endpoint was sustained virological response at post-treatment week 12 (SVR12). SVR12 (intention-to-treat) was 90% overall (45 of 50): 88% (21 of 24) in the 12-week (91% observed) and 92% (24 of 26) in the 16-week group. All patients with advanced fibrosis achieved SVR12. SVR12 in patients with cirrhosis was 86% overall (31 of 36): 83% (15 of 18) in the 12-week (88% observed) and 89% (16 of 18) in the 16-week group; for treatment-experienced patients with cirrhosis, these values were 87% (26 of 30), 88% (14 of 16; 93% observed), and 86% (12 of 14), respectively. One patient (12-week group) did not enter post-treatment follow-up (death unrelated to treatment). There were 4 relapses (2 per group) and no virological breakthroughs. The most common adverse events (AEs) were insomnia, fatigue, and headache. There were no discontinuations for AEs and no treatment-related serious AEs.

Conclusion: The all-oral regimen of DCV-SOF-RBV was well tolerated and resulted in high and similar SVR12 after 12 or 16 weeks of treatment among genotype 3-infected patients with advanced liver disease, irrespective of past HCV treatment experience.

Wednesday, June 15, 2016

Making Hepatitis C A Rare Disease In The United States

Making Hepatitis C A Rare Disease In The United States
Victor Roy, Dave Chokshi, Stephen Kissler, and Prabhjot Singh

New breakthrough medicines for Hepatitis C present an important choice about setting goals and taking systemic action to achieve public health advances in the United States. Despite appearing to offer cure rates greater than 90 percent, high-priced Hepatitis C drugs have driven treatment rationing since their approval over two years ago. Gaps in the screening, diagnosis, and treatment of Hepatitis C pose significant public health consequences.

Target: A ‘Rare Disease’ By 2025

Multiple indicators could be used to define such a target for Hepatitis C, such as deaths averted, percent treated and/or cured, incidence, or population prevalence. We demonstrate one possible approach, using a model published last November in Health Affairs by Van Nuys and colleagues. With a baseline scenario of using older interferon-based therapies, the model considered three treatment scenarios for Hepatitis C with the newest medicines: treat patients with advanced disease, treat all diagnosed patients regardless of disease stage, or treat 5 percent of diagnosed patients across all disease stages. They found that the option of treating 5 percent of the infected population annually would best balance potential benefits with affordability.

Hepatitis C and beyond: Never a dull moment

Published on Jun 13, 2016

Hepatitis C and beyond: Never a dull moment

Air date: Wednesday, June 8, 2016, 3:00:00 PM

Category: WALS - Wednesday Afternoon Lectures

Runtime: 01:03:03

Description: NIH Director’s Wednesday Afternoon Lecture Series

The Annual George Khoury Lecture

From the emergence of a mystery virus associated with post-transfusion hepatitis to the discovery of the hepatitis C virus (HCV), we are now witnessing a remarkable new era of highly effective, curative treatments. Despite this, challenges remain to effectively implement these medical advances on a national and global scale. For the molecular virologist, many questions remain unanswered. Why are clinical isolates of HCV so difficult to culture? What is the link between chronic HCV and liver cancer? Where did HCV come from and should we rest on our laurels assuming that hepacivirus-associated disease will soon vanish? These and other topics will be the subject of this Khoury lecture.

For more information go to https://oir.nih.gov/wals

Author: Charles M. Rice, Ph.D., The Rockefeller University

Permanent link: http://videocast.nih.gov/launch.asp?1...

New Combination Therapy May Be Effective Against Chronic HCV Infection

New Combination Therapy May Be Effective Against Chronic HCV Infection
By Will Boggs MD
June 14, 2016

NEW YORK (Reuters Health) - The new NS3/4A protease inhibitor GS-9857, in combination with sofosbuvir and velpatasvir (SOF/VEL), produces sustained viral response in most patients with hepatitis C virus (HCV) genotype 1 or 3 infections, according to a phase 2 trial from Gilead Sciences.

Various combinations of direct-acting antiviral agents (DAAs) provide sustained virologic responses in most patients infected with HCV, but there are ongoing efforts to optimize and shorten regimens.

Dr. Edward J. Gane from Auckland City Hospital in New Zealand and colleagues evaluated the efficacy and safety of short-duration regimens (four, six, or eight weeks) of SOF/VEL plus GS-9857 in a broad range of patients with genotype 1 (n=120) and 3 (n=41) HCV infections, including 63 treatment-naïve patients and 98 previously-treated patients.

Sustained viral response at 12 weeks (SVR12) was achieved by 27% of treatment-naïve patients with genotype 1 infection without cirrhosis after four weeks of treatment and by 93% after six, the team reports in Gastroenterology, online May 27.

SVR12 was 87% among treatment-naïve patients with cirrhosis after six weeks of treatment, while it was 67% among DAA-experienced patients with and without cirrhosis. In patients who had received other previous treatment and did or did not have cirrhosis, SVR12 with eight weeks of therapy ranged from 89% to 100%.

Among patients with genotype 3 infection, SVR12 was achieved by 83% of treatment-naïve patients with cirrhosis after six weeks of treatment and by 100% of previously treated patients with or without cirrhosis after eight weeks of treatment.

Of the 30 patients who did not achieve SVR12, 28 had virologic relapse after completing treatment, one withdrew consent four weeks after the treatment ended (at which time the patient had undetectable HCV RNA), and one never attained HCV RNA below 15 IU/mL on treatment.

Relapse rates were 73% among patients who received only four weeks of treatment, 19% among those who received six weeks of treatment, and 4% among those who received eight weeks of treatment.

SVR12 rates were also high among patients who had resistance-associated substitutions at baseline (84%-86%, depending on the threshold), and no treatment-emergent resistance-associated substitutions were detected in 26 of 28 patients who relapsed.

Common adverse events included headache, nausea, fatigue, and diarrhea, most of which were mild in severity. No patient discontinued treatment due to an adverse event.

"These results suggest that 8 weeks is the threshold of treatment duration with combination DAAs for the easier-to-treat patient population, not 4 or 6 weeks as suggested by recent viral kinetic models," the researchers note. "Future attempts to shorten duration of DAA regimens to less than 8 weeks will probably require the addition of a host-targeting agent such as RG-101, an miR-122 antagonist, which has been shown to do so in the interim results of an ongoing phase 2 study."

"SOF/VEL/GS-9857 is now coformulated as a single tablet which is being evaluated in the larger Phase III program, which includes different patient populations, including DAA-experienced patients," they add. "This group of DAA-experienced patients is growing and currently represents an unmet medical need."

Dr. Assy Nimer from Ziv Medical Center in Haifa, Israel, who has studied various aspects of HCV infection and its treatment, told Reuters Health by email, "The most interesting or surprising results is the low rate of SVR at week 4 in naïve HCV genotype 1 patients without cirrhosis, indicating that the combination of three potent DAA is not effective for 4 weeks but is highly effective for 8 weeks of treatment."

"The best treatment duration of the new DAA combination would be between 8 and 12 weeks," he concluded, adding that "this type of new medications will likely be effective in minimizing resistance-associated variants (RAV), which persist for years."

Gilead Sciences supported the trial, employed several authors, and had various relationships with the rest, including Dr. Gane.

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

http://www.journalofclinicalpathways.com/news/new-combination-therapy-may-be-effective-against-chronic-hcv-infection

SOURCE: http://bit.ly/1UaduVG
Gastroenterology 2016.

Tuesday, June 14, 2016

Hep C sufferers angered by activist website ban - fixhepc website will be geoblocked

A website which raises awareness about a medical cure for hepatitis C could be hidden from Australians.
11:09pm, Jun 14, 2016
Richard Woolveridge

Hepatitis C patients are angry and perplexed that the government’s drug regulator is backing a campaigning website into a corner where it feels it has no choice but to make the site invisible to Australians.

The fixhepc website has been making thousands of sufferers aware of an affordable cure for their lethal illness since it launched last October seeing an initial audience of 5000 visitors mushroom to six million visits over seven months.

But from Wednesday, the fixhepc website will be geoblocked, meaning people using computers with Australian IP addresses will not be able to see it or the information it contains about a disease which affects nearly a quarter of a million Australians. Any of the 150 million sufferers elsewhere in the world will still be able to see the site.

Why?
The Therapeutic Goods Administration has threatened the website’s campaigning founder Dr James Freeman, of Tasmania, with legal action because it argues his site “appears to promote the use and supply of prescription-only medicines”, an offence under Australian law.

Continue reading...

Check Out Our Website For Today's Additional HCV News

Comparative effectiveness of ledipasvir/sofosbuvir ± ribavirin vs. ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin HCV genotype 1 patients

Original Article

Comparative effectiveness of ledipasvir/sofosbuvir ± ribavirin vs. ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin in 6961 genotype 1 patients treated in routine medical practice

Authors •L. I. Backus,
author notes Corresponding author1.Department of Veterans Affairs, Population Health Services, Palo Alto Health Care System, Palo Alto, CA, USA
First published: 13 June 2016
Full publication history •DOI: 10.1111/apt.13696

View Full Text Article

Summary
Background Real-world data are needed to inform hepatitis C virus (HCV) treatment decisions.

Aim

Methods

Observational intent-to-treat cohort of genotype 1 patients initiating 8 or 12 weeks of LDV/SOF ± RBV or 12 weeks of OPrD ± RBV. Sustained virological response (SVR) required RNA below the limit of quantification at least 10 weeks after end of treatment.
Results 6961 patients initiated LDV/SOF (N = 4478), LDV/SOF + RBV (N = 1269), OPrD (N = 297), and OPrD + RBV (N = 917) at 126 facilities. Intention-to-treat SVR rates were 91.4% (3813/4170) for LDV/SOF, 90.0% (1098/1220) for LDV/SOF + RBV, 95.1% (269/283) for OPrD and 85.8% (746/869) for OPrD + RBV. SVR rates in those completing 8 weeks of LDV/SOF were 91.7% (1223/1333) and 12 weeks of LDV/SOF 94.6% (2475/2615), LDV/SOF + RBV 92.2% (1033/1120), OPrD 98.0% (248/253) and OPrD + RBV 95.5% (705/738). Significant predictors of SVR were African American race (OR 0.71, 95%CI 0.59–0.86, P < 0.001), body mass index (BMI) > 30 kg/m2 (OR 0.73, 95% CI 0.60–0.89, P = 0.002), FIB4 > 3.25 (OR 0.60, 95% CI 0.49–0.72, P < 0.001), OPrD + RBV compared to LDV/SOF (OR 0.60, 95% CI 0.48–0.76, P < 0.001) and subtype 1b (OR 1.38, 95% CI 1.11–1.71, P = 0.003). For those completing 12 weeks, FIB-4 > 3.25 and high BMI remained significant predictors.

Conclusions

In this robust real-world cohort, SVR rates were similar to clinical trials. FIB-4 > 3.25 and high BMI were significant negative predictors of SVR. Reduced odds of SVR in African Americans and with OPrD + RBV likely arose from excess early discontinuation as these factors were no longer
significant, when limited to patients completing a 12-week course.

Introduction

The landscape of antiviral therapy for chronic hepatitis C virus (HCV) infection continues to advance as all-oral options expand. Sustained virological response (SVR) rates reported in clinical trials with all-oral regimens are consistently above 90% for most HCV-infected patient populations and have become the expected norm. Because of the rapidity with which HCV therapies are progressing and the absence of comparative clinical trials, providers are left to extrapolate information to make clinical decisions about medication selection. Emerging real-world data of individual therapies have demonstrated results comparable to registration trials, however, comparative effectiveness evaluations are needed to determine whether clinical differences exist between regimens.[1-6] Comparative effectiveness analyses will become increasingly important as patients, providers, healthcare systems and managed care organisations consider additional nuances of convenience, drug interactions, treatment duration and ultimately cost effectiveness.

Ledipasvir/sofosbuvir (LDV/SOF) and ombitasvir/paritaprevir/ritonavir plus dasabuvir (OPrD) have been extensively evaluated individually in clinical trials of HCV-infected adults. The SVR rates in LDV/SOF trials of genotype 1 patients with and without cirrhosis ranged from 94% to 99% and in OPrD trials SVR rates ranged from 89% to 99%.[7-14] While these outcomes appear similar, differences in study design and patient populations prevent direct cross-study comparison of results.
Hepatitis C virus disproportionally affects the veteran population and the Department of Veterans Affairs (VA) is the largest US provider of healthcare to HCV-infected individuals caring for nearly 5% of all individuals in the US with HCV infection.[15, 16] Thus, ongoing evaluation of the effectiveness of HCV antiviral regimens remains a priority for VA.[17] With the rapid uptake of all-oral HCV regimens across the VA system and the diverse HCV-infected veteran population receiving these regimens, we examined SVR rates and comparative effectiveness of LDV/SOF ± ribavirin (RBV) vs. OPrD ± RBV in genotype 1 HCV-infected veterans treated in routine medical practice.

Materials and methods

This was an observational intent-to-treat cohort analysis of HCV-infected veterans receiving LDV/SOF ± RBV or OPrD ± RBV from VA. Data for this study were obtained from the VA's national Clinical Case Registry for HCV, an extract of the VA electronic medical record that contains demographics, laboratory results, pharmacy information and International Classification of Diseases diagnosis codes from inpatient hospitalisations, outpatient visits and problem lists of HCV-infected veterans seen at all VA medical facilities.[18]

Eligible subjects included all genotype 1 HCV-infected veterans from any VA facility nationwide who initiated 8 or 12 weeks of VA-prescribed LDV/SOF ± RBV or 12 weeks of OPrD ± RBV by 31 March 2015 with an end of treatment (EOT) by 14 July 2015 and a days supply less than or equal to 91 days. For patients who received multiple courses of therapy, only the first course was included. The choice of regimen and timing of follow-up visits and laboratory testing was at the discretion of the provider as patients were treated in routine practice. The present cohort includes 4356 treatment naïve patients treated with LDV/SOF ± RBV who were reported on previously.[19] Patients were excluded if they changed regimens without a treatment interruption (n = 64), had a baseline HCV RNA ≤1000 IU/mL (n = 218), had a liver transplant (n = 141), or had genotype subtype 1a and received OPrD without RBV (n = 16).

Treatment outcome

Patients were considered to have SVR if they had HCV RNA results below the limit of quantification on all HCV RNA tests after the EOT including at least one test 10 weeks or more after the EOT. The 10 week time point was chosen to account for variability of clinic visits and of laboratory testing draws in clinical practice. Patients were categorised as not achieving SVR if they had a HCV RNA above the limit of quantification after the EOT, had no HCV RNA testing after the EOT and a HCV RNA above the limit of quantification on their last HCV RNA test while on treatment or died while on treatment or within 10 weeks of the EOT. Patients with HCV RNA below the limit of quantification on their last HCV viral load test, either on treatment or after the EOT, but no test 10 weeks of more after the EOT were excluded from the SVR analysis. The EOT was calculated as the last day covered by prescriptions of LDV/SOF or OPrD using the dates the medication was dispensed and the days’ supply. HCV RNA was categorised as above or below the lower limit of quantification based on the locally reported HCV RNA result of which 98% utilised assays with a lower limit of quantification of 15 U/mL or less. Patients were followed from the initiation of LDV/SOF ± RBV or OPrD ± RBV through 29 February 2016, allowing for more than 32 weeks of follow-up after the EOT for all patients in the cohort.

Control variables

Demographic and other baseline variables were determined at the time of treatment initiation and included age, gender, race/ethnicity, diabetes, HIV coinfection, history of decompensated liver disease (defined by oesophageal variceal haemorrhage, hepatic coma, hepatorenal syndrome or spontaneous bacterial peritonitis), prescribed proton pump inhibitor use, prior HCV antiviral treatment experience and HCV genotype 1 subtype. Subtype 1a included patients with reported results of 1a, mixed 1a/1b or 1 with subtype unspecified. Prior virological response was based on the most recent VA course of HCV antiviral treatment and categorised as relapse, partial response, null response and not defined. Baseline values for height and weight used to calculate body mass index (BMI) and the laboratory tests for alanine aminotransferase, aspartate aminotransferase, platelets and baseline HCV RNA were defined as the value within 1 year before and closest to the treatment start date. A FIB-4 score >3.25 at the start of treatment using baseline laboratory values was used as a marker of advanced liver disease.[20, 21] Patients with FIB-4 ≤ 3.25 were considered to be ‘noncirrhotic’.

In VA, HCV antiviral prescriptions are frequently filled for quantities less than 28 days. Patients were considered to have completed 8 weeks of LDV/SOF if they had received between 49 and 63 days’ worth of medication and 12 weeks LDV/SOF ± RBV or OPrD ± RBV if they received between 77 and 91 days’ worth of medication.

Statistical analysis

Univariate comparisons used the Pearson chi-squared test with Yates’ continuity correction for categorical variables. Multivariate logistic regression models were constructed to model SVR. Models included age, gender, race/ethnicity, diabetes, history of decompensated liver disease, treatment experience, BMI, FIB-4, genotype 1 subtype, and regimen. In a sensitivity analysis proton pump inhibitor use was included in the model. A set of models with the above baseline variables was constructed with all patients and with only patients who completed 12 weeks of treatment.
For all comparisons, a P < 0.01 was considered statistically significant. All analyses were performed using R version 3.1 (R Foundation for Statistical Computing, Vienna, Austria).
The protocol was approved by the Stanford University Institutional Review Board and the VA Palo Alto Health Care System Research and Development Committee.

Results

In total, 6961 patients with HCV genotype 1 initiated LDV/SOF ± RBV (n = 5747) or OPrD ± RBV (n = 1214) at 126 VA facilities. The mean age for the cohort was 61.4 years, 96.3% were male, 36.0% were African-American, 31.5% had diabetes, 3.2% had a history of decompensated liver disease, 23.6% were treatment experienced, 35.4% had a BMI ≥30 kg/m², and 29.5% had a FIB-4 > 3.25.

Baseline characteristics for the cohort by regimen appear in Table 1. For the cohort, 64.3% (n = 4478) received LDV/SOF, 18.2% (n = 1269) received LDV/SOF + RBV, 4.3% (n = 297) received OPrD and 13.2% (n = 917) received OPrD + RBV. Patients who received LDV/SOF+RBV were most likely to be treatment-experienced and to have markers of advanced liver disease including a history of decompensated liver disease, lower mean platelet count, higher mean FIB-4 score, and FIB-4 > 3.25.

Table 1. Baseline characteristics and 4 week on-treatment response of genotype 1 patients receiving ledipasvir/sofosbuvir- or ombitasvir/paritaprevir/ritonavir plus dasabuvir-based regimens with durations of 12 weeks or less

	Genotype 1 cohort (N = 6961)	LDV/SOF (N = 4478)	LDV/SOF + RBV (N = 1269)	OPrD (N = 297)	OPrD + RBV (N = 917)
Continuous variables reported as mean ± s.d. (range). Categorical variables reported as % (n). ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; DAA, direct-acting antiviral; LDV/SOF, ledipasvir/sofosbuvir; OPrD, ombitasvir/paritaprevir/ritonavir + dasabuvir; PEG, pegylated interferon; SOF, sofosbuvir; RBV, ribavirin. *Some patients received more than one prior DAA regimen and are included in the count for each regimen they received.
Age (years)	61.4 ± 6.2 (24.5–90.8)	61.2 ± 6.5 (25.3–90.8)	61.9 ± 5.2 (24.5–86.2)	62.3 ± 5.9 (28.5–77.2)	61.5 ± 6.0 (26.7–85.3)
Gender, male	96.3 (6703)	95.9 (4295)	97.2 (1233)	96.3 (286)	96.9 (889)
Race/ethnicity
African-American	36.0 (2506)	38.2 (1712)	29.0 (368)	46.8 (139)	31.3 (287)
Caucasian	51.6 (3591)	50.5 (2263)	54.5 (692)	43.4 (129)	55.3 (507)
Hispanic	5.4 (376)	4.5 (304)	8.0 (102)	4.0 (12)	6.4 (59)
Other/multiple	7.0 (488)	6.7 (300)	8.4 (107)	5.7 (17)	7.0 (64)
Diabetes	31.5 (2195)	30.3 (1357)	37.7 (479)	33.3 (99)	28.4 (260)
Proton pump inhibitor	27.7 (1927)	26.3 (1178)	35.4 (449)	25.3 (75)	24.5 (225)
HIV coinfected	4.5 (310)	5.3 (237)	3.7 (47)	2.4 (7)	2.1 (19)
Decompensated liver disease	3.2 (224)	1.9 (87)	8.6 (109)	0.7 (2)	2.8 (26)
Any treatment experience	23.6 (1645)	16.0 (718)	53.0 (673)	19.2 (57)	21.5 (197)
DAA experience (% of treatment experienced)	44.1 (726)	39.1 (281)	62.4 (420)	7.0 (4)	10.7 (21)
Prior SOF + simeprevir (n)*	71	12	57	0	2
Prior SOF + PEG + RBV or SOF + RBV (n)*	131	29	96	0	6
Prior boceprevir (n)*	494	222	253	4	15
Prior telaprevir (n)*	74	21	53	0	0
Prior treatment response	N = 1645	N = 718	N = 673	N = 57	N = 197
Relapse	29.9 (492)	24.0 (172)	39.2 (264)	14.0 (8)	24.4 (48)
Partial	10.2 (167)	9.1 (65)	10.1 (68)	21.1 (12)	11.2 (22)
Null	11.3 (186)	9.6 (69)	11.1 (75)	12.3 (7)	17.8 (35)
Unknown	48.6 (800)	57.4 (412)	39.5 (266)	52.6 (30)	46.7 (92)
BMI (kg/m²)	28.8 ± 5.3 (15.8–65.2)	28.5 ± 5.2 (15.8–65.2)	30.0 ± 5.5 (16.4–60.1)	28.2 ± 5.0 (16.0–53.7)	28.8 ± 5.3 (17.6–58.5)
BMI (kg/m²)
<25	23.1 (1605)	24.8 (1109)	17.9 (227)	24.2 (72)	21.5 (197)
25–29	41.6 (2893)	41.6 (1863)	37.6 (477)	49.8 (148)	44.2 (405)
≥30	35.4 (2463)	33.6 (1506)	44.5 (565)	25.9 (77)	34.4 (315)
ALT (U/L)	74.1 ± 56.5 (8–659)	71.4 ± 55.9 (8–659)	80.3 ± 52.3 (13–445)	62.6 ± 50.7 (13–552)	82.4 ± 64.3 (11–560)
AST (U/L)	64.4 ± 45.5 (6–614)	60.5 ± 43 (6–614)	76.6 ± 48.2 (11–503)	50.6 ± 34.8 (14–322)	70.4 ± 52.1 (13–499)
Platelets (Κ/μL)	185.6 ± 69.9 (6–759)	194.4 ± 68.2 (6–661)	150.3 ± 67.9 (22–759)	214.6 ± 59.6 (81–421)	181.8 ± 66.7 (32–470)
FIB-4	3.2 ± 3.7 (0.1–185.0)	2.8 ± 3.8 (0.1–185.0)	4.7 ± 4.1 (0.5–34.7)	2.0 ± 1.2 (0.3–10.0)	3.3 ± 2.9 (0.4–27.3)
FIB-4	N = 6936	N = 4460	N = 1267	N = 296	N = 913
≤3.25	70.5 (4889)	76.4 (3406)	47.8 (605)	89.5 (265)	67.1 (613)
>3.25	29.5 (2047)	23.6 (1054)	52.2 (662)	10.5 (31)	32.9 (300)
HCV RNA (log IU/mL)	6.2 ± 0.7 (3.0–7.9)	6.2 ± 0.7 (3.1–7.9)	6.2 ± 0.7 (3.0–7.8)	6.3 ± 0.6 (3.9–7.6)	6.3 ± 0.7 (3.0–7.8)
HCV RNA (IU/mL)
<6 000 000	82.0 (5705)	82.7 (3705)	84.6 (1073)	76.8 (228)	76.2 (699)
≥6 000 000	18.0 (1256)	17.3 (773)	15.4 (196)	23.2 (69)	23.8 (218)
HCV subtype 1b	27.3 (1897)	24.2 (1085)	23.4 (297)	100.0 (297)	23.8 (218)
IL28B polymorphism	N = 989	N = 598	N = 204	N = 33	N = 154
CC	20.3 (201)	22.6 (135)	15.2 (31)	9.1 (3)	20.8 (32)
CT	54.0 (534)	52.7 (315)	58.3 (119)	51.5 (17)	53.9 (83)
TT	25.7 (254)	24.7 (148)	26.5 (54)	39.4 (13)	25.3 (39)

Among patients who received LDV/SOF, 3.6% (n = 159) discontinued treatment before 8 weeks, 32.7% (n = 1464) received 8 weeks, 1.7% (n = 77) discontinued treatment between 8 and 12 weeks and 62.0% (n = 2778) received 12 weeks. In total, 94.7% completed either an 8 or 12 week course. Among people who received LDV/SOF + RBV, 8.1% (103/1269) discontinued treatment prior to completing 12 weeks. Among patients who received OPrD or OPrD+RBV, 11.4% (34/297) and 15.2% (140/917) of patients, respectively, discontinued treatment prior to completing a 12 week course. Significantly more patients receiving OPrD + RBV discontinued treatment prior to completing a 12-week course compared to those receiving LDV/SOF + RBV (P < 0.001).

Sustained virological response results were available for 94.0% (n = 6542) of patients in the cohort, including 24 patients who died while on treatment or shortly after who were categorised as no SVR. Four hundred nineteen patients whose last HCV RNA was undetectable, but occurred while still on treatment (n = 123) or less than 10 weeks after the EOT (n = 296), were excluded from the SVR analysis. Three hundred five patients had an undetectable HCV RNA obtained 10–11 weeks after the EOT and were included in the SVR analysis for reasons described previously.

Among 4170 LDV/SOF patients 91.4% achieved SVR; among 1220 LDV/SOF + RBV patients 90.0% achieved SVR; among 283 OPrD patients 95.1% achieved SVR and among 869 OPrD + RBV patients 85.8% achieved SVR (Table 2). For patients who received LDV/SOF, the SVR rates differed statistically based on categories of race/ethnicity, BMI, and FIB-4. For patients who received LDV/SOF + RBV, the SVR rates differed statistically based on proton pump inhibitor use and FIB-4. No statistically significant differences in SVR were observed according to baseline patient characteristics among patients receiving either OPrD or OPrD + RBV, and responses were generally similar to that observed in the overall population. SVR data for treatment naïve and experienced patients by subgroup can be found in Table S1A and B.

(Table 2). SVR rates by regimen for genotype 1 patients receiving ledipasvir/sofosbuvir- or ombitasvir/paritaprevir/ritonavir plus dasabuvir-based regimens with durations of 12 weeks or less

Click On Image To Enlarge

For patients who completed an 8 week course of LDV/SOF or a 12 week course of LDV/SOF ± RBV or OPrD ± RBV, SVR rates were consistently higher overall and among subgroups when compared to the intention-to-treat SVR rates (Table 3). With regard to the impact of treatment duration among patients who received LDV/SOF, the SVR rate in those who received 8 weeks was 91.7% (1223/1333) and 94.6% (2475/2615) in those who received 12 weeks. An SVR rate of 92.2% (1033/1120) was achieved in patients completing 12 weeks of LDV/SOF + RBV and 95.5% (705/738) in those completing 12 weeks of OPrD+RBV. In genotype 1b patients who received 12 weeks of OPrD, an SVR rate of 98.0% (248/253) was achieved. In 1098 patients who met the Food and Drug Administration (FDA) labelling considerations for a shortened LDV/SOF course consisting of treatment-naïve, without cirrhosis (defined as FIB-4 ≤ 3.25), and a baseline HCV RNA <6 000 000 IU/mL and who completed 8 weeks of LDV/SOF therapy, the SVR rate was 93.2% (1023/1098). In 905 patients who also met the FDA considerations for a shortened LDV/SOF course but nevertheless received 12 weeks of LDV/SOF therapy, the SVR rate was 96.6% (874/905)(P = 0.001 compared to 8 week course).

Table 3. SVR rates by regimen for genotype 1 patients receiving ledipasvir/sofosbuvir- or ombitasvir/paritaprevir/ritonavir plus dasabuvir-based regimens who received 8 or 12 weeks of LDV/SOF and 12 weeks of all other regimens

Click On Image To Enlarge

In multivariate analysis, significant independent predictors of decreased odds of SVR were African American race (OR 0.71, 95% CI 0.59–0.86, P < 0.001), BMI ≥30 kg/m² (OR 0.73, 95% CI 0.60–0.89, P = 0.002), FIB-4 > 3.25 (OR 0.60, 95% CI 0.49–0.72, P < 0.001) and use of OPrD + RBV compared to LDV/SOF (OR 0.60, 95% CI 0.48–0.76, P < 0.001) (Table 4). Genotype subtype 1b was an independent predictor of increased odds of SVR (OR 1.38, 95% CI 1.11–1.71, P = 0.003). Age, gender, diabetes, history of decompensated liver disease and treatment experience did not predict SVR. In the sensitivity analysis proton pump inhibitor use was not associated with a difference in the odds of achieving SVR (0.85, 95% CI 0.71–1.03, P = 0.09). In models limited to patients receiving 12 weeks of treatment, only BMI ≥30 kg/m² (OR 0.66, 95% CI 0.49–0.88, P = 0.004) and FIB4 > 3.25 remained significant (OR 0.46, 95% CI 0.35–0.60, P < 0.001).

Table 4. Odds ratios for sustained virological response in multivariate model for genotype 1 patients treated with ledipasvir/sofosbuvir- or ombitasvir/paritaprevir/ritonavir plus dasabuvir-based regimens

	Intention-to-treat OR (95% CI), N = 6525	Received 12 weeks OR (95% CI), N = 4720
BMI, body mass index; CI, confidence interval; LDV/SOF, ledipasvir/sofosbuvir; OPrD, ombitasvir/paritaprevir/ritonavir+dasabuvir; OR, odds ratio; RBV, ribavirin; ref., reference; SVR, sustained virological response. †Subtype 1a includes 1a, mixed 1a/1b and 1 with subtype unspecified. P < 0.01, *P < 0.001.
Age <55 years (ref. 55–64)	1.37 (0.98–1.94)	1.36 (0.83–2.37)
Age ≥65 years (ref. 55–64)	1.17 (0.96–1.43)	1.26 (0.94–1.70)
Female (ref. Male)	2.23 (1.26–4.38)	2.51 (1.04–8.23)
African American (ref. Caucasian)	0.71 (0.59–0.86)***	0.86 (0.64–1.14)
Hispanic (ref. Caucasian)	0.77 (0.54–1.12)	1.00 (0.59–1.81)
Other/multiple (ref. Caucasian)	0.87 (0.62–1.23)	0.81 (0.51–1.34)
Diabetes (ref. no diabetes)	1.01 (0.83–1.22)	1.08 (0.82–1.42)
Decompensated liver disease (ref. no)	0.60 (0.41–0.90)	0.87 (0.51–1.54)
Treatment experienced (ref. naïve)	0.90 (0.73–1.11)	0.90 (0.67–1.21)
BMI <25 kg/m² (ref. 25–29 kg/m²)	0.77 (0.61–0.96)	0.99 (0.69–1.44)
BMI ≥30 kg/m² (ref. 25–29 kg/m²)	0.73 (0.60–0.89)**	0.66 (0.49–0.88)**
FIB-4 > 3.25 (ref. ≤3.25)	0.60 (0.49–0.72)***	0.46 (0.35–0.60)***
HCV subtype 1b (ref. 1a†)	1.38 (1.11–1.71)**	1.44 (1.04–2.02)
LDV/SOF + RBV (ref. LDV/SOF)	1.07 (0.84–1.37)	0.87 (0.64–1.19)
OPrD (ref. LDV/SOF)	1.27 (0.74–2.37)	1.68 (0.71–4.93)
OPrD+RBV (ref. LDV/SOF)	0.60 (0.48–0.76)***	1.22 (0.83–1.84)

Discussion

In this robust comparative effectiveness analysis of LDV/SOF ± RBV vs. OPrD ± RBV in genotype 1 HCV-infected veterans treated in routine medical practice, high SVR rates were achieved overall (86–95%) and within subgroups (83–100%). In multivariate models, OPrD + RBV was found to be less effective than LDV/SOF and patients receiving the former were 40% less likely to achieve SVR. However, in patients who completed a 12-week treatment course there was no difference in effectiveness. Similar to clinical trials, curative all-oral treatment has become a reality for over 90% of patients treated in the real-world, even in those with characteristics previously associated with poorer outcomes. This analysis demonstrates the real-world comparative effectiveness of all-oral DAA regimens in individuals with genotype 1 HCV infection that clinicians, patients and payers have anticipated.

The current HCV treatment landscape remains complex despite increasingly more effective HCV regimens, with variability in outcomes for patients with previous treatment experience, genotype subtype, race, degree of underlying liver disease and other comorbid conditions.[7, 8, 13, 14, 22-24] Because of the large sample size in this cohort, we were able to do robust subgroup analyses to examine differences among these characteristics and identify where challenges remain.
Despite SVR rates higher than any previously reported among veterans with advanced liver disease, the presence of advanced liver disease as indicated by a FIB-4 score greater than 3.25 remained a significant negative predictor of response with an apparent impact for treatment naïve and treatment experienced patients and across all regimens.[5, 23, 25] Over 2000 patients with advanced liver disease were included in this cohort. In multivariate models, the presence of advanced liver disease predicted reduced odds of achieving SVR by 40% independent of treatment experience and regimen. Absolute SVR rates in treatment naïve patients were generally four to five percent lower in those with advanced liver disease compared to those without advanced liver disease for patients who received LDV/SOF (87.6% vs. 92.6%), who received LDV/SOF + RBV (90.0% vs. 94.7%), and who received OPrD (91.7% vs. 96.1%). Current AASLD/IDSA treatment guidelines and FDA labelling recommend LDV/SOF for 12 weeks in treatment naïve patients with cirrhosis based largely on data from 34 patients in the ION-1 trial.[7, 26, 27] However, our observation of SVR rate of 87.6% with LDV/SOF in 889 treatment naïve patients with FIB4 scores >3.25 indicate SVR rates with this regimen may be below the 90% bar for which all-oral regimen expectations have been set and other treatment options might need to be considered in such patients.

In treatment experienced patients with and without advanced liver disease, reductions of 5–8% in SVR rates were seen in patients who received LDV/SOF (85.5% vs. 93.5%), who received LDV/SOF + RBV (85.4% vs. 90.9%), and who received OPrD + RBV (82.1% vs. 89.6%). The reduced SVR rates in the low to mid-80s in treatment experienced patients with advanced liver disease in this study mirror the 86% and 82% SVR rates observed in ION-2 in treatment-experienced cirrhotic patients receiving 12 weeks of LDV/SOF and LDV/SOF + RBV respectively.[8] In the TURQUOISE-II study SVR rates were 87% and 95% in treatment experienced cirrhotic null responders treated for 12 and 24 weeks respectively with OPrD+RBV.[14] The large number of patients included in our study coupled with the similar results obtained from ION-2 and TURQUOISE-II suggest that lower SVR rates may be expected in cirrhotic patients and particularly treatment-experienced cirrhotic patients treated in routine clinical practice. Extended treatment of 24 weeks in such patients may be warranted to achieve higher SVR rates.

In this cohort, SVR data were available for over 2300 African Americans. Multivariate modelling indicated African American race was associated with a 29% reduction in the odds of SVR. This effect was observed in multivariate models of the overall cohort but not in models limited to patients completing a 12 week treatment course suggesting that the reduced odds of SVR for African Americans arose in large part from excess early treatment discontinuations and from diminished effectiveness of 8-week LDV/SOF in African Americans, which has also been observed in retrospective analyses of the ION clinical trials.[22] Numerically lower SVR rates were observed in African Americans compared to Caucasians treated with LDV/SOF, OPrD and OPrD+RBV. In patients who received a full 12 weeks of treatment, SVR rates in African Americans were higher than in the intention-to-treat analysis and the numeric differences in SVR rates between African Americans and Caucasians were diminished.

This study included over 2300 patients with a BMI at or above 30 kg/m², and in the overall cohort those with high BMI were 27% less likely to achieve SVR. As one might expect, the effect of BMI on SVR was not dependent on whether the patient completed therapy and, as such, high BMI remained a negative predictor of response in those who completed a 12-week treatment course. For such patients, additional treatment options may need to be considered to optimise SVR rates.
Shorter 8 week regimens were widely used in treatment-naïve patients with baseline HCV RNA below 6 000 000 IU/mL without cirrhosis. We could only assess the use of 8 week LDV/SOF regimens in patients who completed therapy because we were unable to otherwise determine if the original provider intent was to treat for 8 or 12 weeks using the available electronic data. Although the difference in SVR rates between those who completed 8 weeks and those who completed 12 weeks was numerically small at 3.4% it was statistically significant suggesting that to optimise a patient's likelihood of SVR the 12-week duration may be preferred.

Real-world SVR rates achieved with these treatment regimens were remarkably high. The large differences between real-world effectiveness and clinical trial efficacy previously observed with HCV antiviral treatment have now been almost eliminated with the use of potent all-oral regimens. Most of the small decrement in observed effectiveness in this real-world cohort may be explained in large part by higher early discontinuation rates. Early discontinuations rates were highest in those receiving OPrD + RBV (15.2%), followed by OPrD (11.4%), LDV/SOF + RBV (8.1%) and LDV/SOF (5.3%). Clinical trials tend to have early discontinuation rates of less than 3%.[7-14] Higher early discontinuation rates had the greatest impact on SVR rates in those receiving OPrD + RBV with a nearly 10% difference in SVR rates comparing intention-to-treat (85.8%) to those who completed 12 weeks (95.5%). While we did not examine reasons for early discontinuation, adverse effects and adherence are often recognised as contributing factors. Setting appropriate expectations about potential medication side effects and continued emphasis on adherence and persistence will remain important elements in maximising treatment success. Any remaining decrement in clinical effectiveness compared to clinical trial efficacy may be explained by differences in patient populations. For example, higher BMI in our cohort was identified as a significant negative predictor of SVR.

Given the high SVR rates achieved in clinical practice even among subgroups, regimen selection will depend increasingly upon nuanced considerations. Genotype subtype, presence of cirrhosis, prior treatment regimen or presence of pre-existing resistance associated polymorphisms currently determines the need for RBV and subsequent length of treatment for certain regimens. Potential for drug interactions and comorbidities may limit use of a particular agent. Enough options presently exist to allow providers some flexibility in selecting regimens tailored to meet individual patient characteristics or needs without sacrificing effectiveness. Expectations for high SVRs have been set and now validated in real-world cohorts, thus regimen subtleties together with cost considerations and insurance coverage will be key determinants for utilisation.

While this study includes one of the largest cohorts of diverse HCV-infected patients treated in clinical practice published to date, there are limitations. Specific reasons for early discontinuation (i.e. adverse events, poor tolerability, social or behavioural issues) could not be determined from the electronic data. Duration of treatment and early treatment discontinuation rates were determined based on the cumulative dispensed days’ supply which may overestimate the treatment duration as patients may have discontinued treatment even with medication in their possession. In VA, many prescriptions are filled for small quantities (e.g. 2-week supplies) which would limit the extent of the overestimation. Baseline resistance testing was not performed thus we were unable to assess the impact of this factor.

Conclusions

In this large real-world cohort of genotype 1 HCV-infected veterans treated with LDV/SOF-based or OPrD-based therapy, high SVR rates comparable to clinical trials were observed and were consistently high across all subgroups evaluated. Odds of SVR were reduced in African Americans compared to Caucasians, those receiving OPrD + RBV compared to LDV/SOF, those with advanced liver disease and those with BMI ≥30 kg/m² compared to those with lower BMI. Reduced odds of SVR for African Americans and those receiving OPrD + RBV arose in large part from early discontinuation as these predictors no longer had a significant impact on odds of SVR in those who completed a 12-week course. Advanced liver disease and higher BMI, however, persisted as significant negative predictors of SVR even when considering only those patients who completed a 12-week course. For patients with advanced liver disease and high BMI longer durations of therapy or additional treatment options may still be needed to increase SVR rates. Real-world experience from large diverse cohorts such as this is necessary to better inform and refine HCV management strategies.

Authorship

Guarantor of the article: Lisa I. Backus.
Author contributions: Drs Backus, Belperio, Loomis and Mole: Study concept and design. Drs Backus, Belperio, Shahoumian, Loomis and Mole: Analysis and interpretation of data; Drs Backus, Belperio: drafting of the manuscript, Drs Backus, Belperio and Mole: Critical revision of the manuscript for important intellectual content; Dr Shahoumian: Statistical analysis. This statement acknowledges that all authors approved the final version of the article, including the authorship list.

Acknowledgement

Declaration of personal and financial interests: None.

Source http://onlinelibrary.wiley.com/enhanced/doi/10.1111/apt.13696

Risk Of Developing Liver Cancer After HCV Treatment