Adverse Events Common With Triple Therapy in HCV Cirrhosis

Reuters Health Information

May 22, 2013

By David Douglas

NEW YORK (Reuters Health) May 22 - In cirrhotic patients, triple-therapy against hepatitis C virus (HCV) produces a high virological response rate, but at the cost of a high rate of serious adverse events, French researchers say.

In the French CUPIC cohort, four in ten cirrhotic patients on triple therapy with pegylated interferon and ribavirin plus boceprevir or telaprevir suffered a serious complication (death, severe infection, or hepatic decompensation).

This cohort, Dr. Christophe Hézode told Reuters Health by email, consisted of "HCV genotype 1 treatment-experienced patients with compensated cirrhosis."

In a May 13th online paper in The Journal of Hepatology, Dr. Hézode of Universite Paris-Est, Creteil and colleagues say phase III trials have yielded similar results in treatment-experienced cirrhotics and non-cirrhotics, but patients were highly selected.

To evaluate the effect in "real-world" patients, the team analyzed 497 patients who reached at least week 16 in a 48-week triple therapy early access program. All had previously received interferon.

Forty percent (199 patients) had serious adverse events, with 58 patients stopping their treatment as a result. Refractory anemia was also common. Six patients died and another 32 (6.4%) had severe infection or hepatic decompensation or another serious event.

Death or severe complications were related to platelet counts at or below 100,000/mm3 (odds ratio 3.11) and albumin <35 g/dL (OR 6.33).

In patients with both of these risk factors, who accounted for 7.9% of the cohort, the rate of severe complications was 44.1%, "suggesting that they should not be treated with the triple therapy." In the remaining 92.1%, the risk was at or below 7.1%.

In an intention-to-treat analysis in the 292 patients treated with the telaprevir combination, HCV RNA was undetectable in 78.8% at week 12 and 67.1% at week 16. In the 205 given boceprevir, the corresponding proportions were 54.6% and 58.0%.

Although the safety profile of triple therapy is poor in a real-life setting, the approach "was associated with high rates of on-treatment virological response," the authors report.

Overall, they say "Serum albumin level and platelet count should be evaluated to determine the risk/benefit ratio of triple therapy in cirrhotic patients and to decide treatment."

"Patients combining a platelet count of less 100,000 /mm3 and serum albumin below 35 g/L should not be treated with a triple combination," Dr. Hézode stressed.

"The other patients," the team concludes, "could be treated cautiously and carefully monitored."

Commenting on the findings by email, Dr. Savino Bruno of A. O. Fatebenefratelli e Oftalmico, Milan, Italy told Reuters Health that "risk overcame benefit" in a number of patients. However, "a more reliable on-treatment stopping rule... may maximize benefit and minimize risk."

Other research on the CUPIC cohort that was recently presented at the 48th annual meeting of European Association for the Study of the Liver, sheds more light on a related strategy. In that study, by investigators including Dr. Hézode found that independently of cirrhosis severity, baseline concentration of apolipoprotein H was associated with early virological response.

SOURCE: http://bit.ly/14S1CwV

J Hepatol 2013.

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Significant Progress in the Treatment of Hepatitis C

By: Badar Muneer, MD
Wednesday, May 22, 2013

Hepatitis C (HCV) is a common cause of liver disease and cirrhosis in the United States. It is the most common indication for liver transplantation, and the cause of more than 50% of hepatocellular carcinoma in the U.S.

Most patients with HCV are asymptomatic, and are thus not tested. Diagnosing and treating patients at earlier stages of HCV would be beneficial, and could prevent the development of cirrhosis and its associated complications. The Centers for Disease Control and Prevention (CDC) estimates that without diagnosis and treatment, about 1.7 million HCV patients will develop cirrhosis, more than 400,000 will develop hepatocellular carcinoma, and almost 1 million will die from HCV-related complications. Another benefit of early diagnosis is that patients with less fibrosis respond better to HCV therapy.

Testing everyone born between 1945 and 1965 would find an estimated 800,000 undiagnosed HCV cases.

The CDC now recommends one-time HCV antibody testing for all individuals born between 1945 and 1965, also known as “Baby Boomers.” The prevalence of HCV antibody in this group is five times higher than people born before or after. In fact, 75% of adults with HCV were born in these years. Testing everyone born between 1945 through 1965 would find an estimated 800,000 undiagnosed HCV cases.

The standard of care for the treatment of HCV had been combination therapy with pegylated interferon and ribavirin. This therapy had suboptimal sustained virologic response (SVR or cure) rates. In 2011, the Food and Drug Administration approved the first generation of direct-acting antiviral agents (DAAs) for the treatment of genotype 1 HCV. These protease inhibitors (Boceprevir and Telaprevir) in combination with pegylated interferon and ribavirin significantly increased the SVR rates to 68-75% in treatment-naïve white patients, 52-63% in treatment-naïve black patients, and 29-83% in treatment-experienced patients. In addition, these regimens allowed shortening therapy in certain subgroups of patients to only 24 weeks (compared to the standard 48 weeks).

However, there are still many limitations and challenges with Telaprevir and Boceprevir. The discontinuation rate due to severe adverse events is about 10-12%, and even higher in cirrhotic patients (20-25%). Anemia is a major side effect with both Telaprevir and Boceprevir. More than 40% of patients develop anemia requiring dose adjustment of ribavirin with or without the use of erythropoietin. Skin rash is also common with Telaprevir and about 10% of patients stop treatment due to severe skin rash. These side effects are more common in patients with cirrhosis. Drug-drug interactions are also major problems with Telaprevir and Boceprevir. In addition, DAAs are not yet approved for HCV patients co-infected with HIV or hepatitis B, post-liver transplant patients, or patients infected with non-genotype 1 HCV.

The most exciting research ongoing for HCV is the use of interferon-free (and often, ribavirin-free) regimens. The goal of such therapies will be simpler and more effective treatment options for HCV. These will have higher SVR rates, less side effects, purely oral regimens, shorter duration, and will be effective against all HCV genotypes. Currently, there are a multitude of such phase 2 and phase 3 trials being performed. The preliminary data has been excellent with SVR rates as high as 100% with treatment durations as short as 12 weeks.

In summary, significant progress has been made in the treatment of HCV. Although somewhat limited by toxicity and the continued need for interferon, the currently-approved medications are able to cure a majority of patients with HCV. However, in the next 2-5 years, we will likely reach a point of being able to cure almost all patients with shorter, interferon-free, well-tolerated regime.

Dr. Badar Muneer is a transplant hepatologist at University Hospitals Digestive Health Institute and an instructor at Case Western Reserve University School of Medicine. For more information, visit www.uhhospitals.org/transplant.

Source: MD News June/July 2013, Northeastern Ohio/Western PA Edition

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Spleen stiffness predicted risk for large, bleeding esophageal varices in cirrhotic patients

Provided by Healio

Sharma P. Am J Gastroenterol. 2013;doi:10.1038/ajg.2013.119.

May 23, 2013

Measuring spleen stiffness in patients with cirrhosis was an effective, noninvasive method of predicting and differentiating large and small esophageal varices and determining those at risk for bleeding, according to recent study results.

Using transient elastography (FibroScan), researchers measured spleen stiffness (SS) and liver stiffness (LS) in 200 consecutive patients with cirrhosis between September 2011 and March 2012. Other measurements conducted in some of the cohort included hepatic venous pressure gradient (HVPG), upper gastrointestinal endoscopy, LS-spleen diameter to platelet ratio score (LSPS) and platelet count to spleen diameter ratio (PSR).

Among 174 evaluable patients who met inclusion criteria and had valid LS and SS measurements, 124 (71%) had esophageal varices (EV). Seventy-eight patients had large EV (more than 5 mm); 46 had small varices (less than 5 mm). Patients with EV displayed a significant difference in median SS (54 kPa compared with 32 kPa), LS (51.4 kPa vs. 23.9 kPa), LSPS (6.1 vs. 2.5) and PSR (812 vs. 1,165) compared with patients without EV (P=.001 for all differences).

Although LS could not be used to differentiate between large and small varices (53 kPa vs. 45.3 kPa; P=.57), SS was greater and indicative of patients with large varices (56 kPa vs. 49 kPa; P=.001) compared with small varices. Patients who had variceal bleed (n=46) also had greater SS than nonbleeder (n=78) patients (58 kPa vs. 50.2 kPa; P=.001).

Among only patients who submitted to HVPG (n=52), a significant correlation was observed with SS (P=.001) and LSPS (P=.01), but not LS (P=.207).

“Given the need to screen patients with cirrhosis, noninvasive tests, such as SS, may help to identify patients at risk of having EVs, particularly large, and those at risk of bleeding,” the researchers concluded. “Spleen stiffness, along with liver stiffness measurement, could select patients with cirrhosis, who should undergo upper gastrointestinal endoscopy to decrease burden upon endoscopy units.”

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The Majority of Physicians that Treat Hepatitis C Virus (HCV) Have Begun "Warehousing" and Preparing Their HCV Patients for the Next Generation of HCV Treatments

Sixty Percent of Surveyed Physicians Agree That They Are Beginning To Warehouse HCV Patients Until New Interferon-Free Regimens Are Available, According to a Recently Published BioTrends Report

EXTON, Pa., May 23, 2013 /PRNewswire/ -- BioTrends Research Group, one of the world's leading research and advisory firms for specialized biopharmaceutical issues, finds that, unaided, one in five surveyed gastroenterologists, hepatologists, and infectious disease specialists reported that in the past six months, they have begun warehousing patients (e.g., intentionally delaying treatment) in anticipation of the next generation of HCV treatments—notably more physicians than six months ago, when only 6 percent reported that they had begun warehousing patients.

(Logo: http://photos.prnewswire.com/prnh/20130103/MM36805LOGO )

Furthermore, only one in five physicians agrees that they are satisfied with currently available treatment options, underscoring the high unmet need for alternatives to treat chronic HCV infections. The trending analyses of physician-reported anticipated prescribing in TreatmentTrends^®: Hepatitis C Virus (US), Wave 1 also finds that, for the first time in a year, surveyed physicians are expecting to treat a greater proportion of their genotype 1 (3 percent) and 2/3 (3 percent) patients in the next six months with regimens that are not currently available. Unaided responses from most physicians who expect to be using other treatments suggest they are expecting products in development, potentially interferon-free regimens, to be available for use in the next six months.

In aided physician responses, Gilead's sofosbuvir and Janssen/Medivir's simeprevir garnered the highest degree of familiarity for use in HCV treatment, followed closely by Bristol-Myers Squibb's daclatasvir and asunaprevir. Additionally, 20 percent of the surveyed physicians believe that Gilead's sofosbuvir is the most promising product in development, primarily due to its favorable tolerability, oral dosing, pan-genotypic activity, and its possibility to be utilized as an interferon-free regimen.

"The protease inhibitors, Vertex's Incivek and Merck's Victrelis, were very important advances in the management of HCV infections," said BioTrends Research Group Associate Director, Lynn Price . "However, there is still a clear unmet need for alternative HCV therapies and the recent NDA filings for simeprevir and sofosbuvir have physicians hopeful for new treatment options that are highly efficacious and more tolerable than the currently available protease inhibitors."

TreatmentTrends^®: Hepatitis C Virus (US), Wave 1 is a report that covers the use of agents for the treatment of HCV infections. This bi-annual study focuses on current and future use of leading HCV treatment regimens, patient market share, perceived strengths and weaknesses of the key brands, barriers to broader usage, sales force performance, and perceived value of manufacturers' patient assistance programs. In addition, this report assesses potential impact of regimens in development, including Abbott's ABT-267, ABT-333, and ABT-450, Boehringer Ingelheim's BI-207127 and faldaprevir, Bristol-Myers Squibb's asunaprevir and daclatasvir, Janssen's simeprevir, and Gilead's sofosbuvir and ledipasvir. In the current wave of research, BioTrends surveyed 101 U.S. gastroenterologists, hepatologists, and infectious disease specialists in March 2013.

About BioTrends Research Group
BioTrends Research Group provides syndicated and custom primary market research to pharmaceutical manufacturers competing in clinically evolving, specialty pharmaceutical markets. For information on BioTrends publications and research capabilities, please contact us at www.bio-trends.com. BioTrends is a Decision Resources Group company.

About Decision Resources Group
Decision Resources Group is a cohesive portfolio of companies that offers best-in-class, high-value information and insights on important sectors of the healthcare industry. Clients rely on this analysis and data to make informed decisions. Please visit Decision Resources Group at www.DecisionResourcesGroup.com.

All company, brand, or product names contained in this document may be trademarks of their respective holders.

For more information, contact:

Decision Resources Group
Christopher Comfort
781-993-2597
ccomfort@dresources.com

SOURCE BioTrends Research Group

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Assessment of motivating factors associated with the initiation and completion of treatment for chronic hepatitis C virus (HCV) infection

Published on: 2013-05-23

Infection with hepatitis C virus (HCV) is associated with high morbidity and increased mortality but many patients avoid initiation of treatment or report challenges with treatment completion. The study objective was to identify motivators and barriers for treatment initiation and completion in a community sample of HCV-infected patients in the United States.

Methods: Survey methods were employed to identify factors reported by patients as important in their decision to start or complete HCV treatment.

Study participants included 120 HCV-infected individuals: 30 had previously completed treatment with pegylated interferon/ribavirin (PR), 30 had discontinued PR, 30 were treated with PR at the time of the survey, and 30 were treatment-naive. Telephone interviews occurred between May and August of 2011 and employed a standardized guide.

Participants assigned factors a rating from 1 (not at all important) to 5 (extremely important). Trained researchers coded and analyzed interview transcripts.

Results: Of 33 factors, expected health problems from not treating HCV infection was reported as most encouraging for treatment initiation and completion, while treatment side effects was most discouraging.

Sixty-nine percent of participants reported that the ability to obtain information during treatment on the likelihood of treatment success (i.e ., results of viral load testing) would motivate them to initiate therapy. Median preferred timing for learning about test results was 5 weeks (range: 1--23 weeks). Conclusion: Understanding challenges and expectations from patients is important in identifying opportunities for education to optimize patient adherence to their HCV treatment regimen.

Author: Lauren FusfeldJyoti AggarwalCarly DougherMontserrat Vera-LlonchStephen BubbMrudula DonepudiThomas F Goss
Credits/Source: BMC Infectious Diseases 2013, 13:234

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AASLD members at forefront to raise awareness of hepatitis B and C

Published on May 23, 2013 at 2:26 AM

Viral hepatitis is an asymptomatic disease affecting more than 5.3 million Americans. More than 75 percent of those with hepatitis C are unaware they have the virus.

Hepatitis B and C Testing and Awareness Day in the U.S. House of Representatives will take place at 10:00 am - 2:00 pm in the Rayburn Foyer of the Rayburn House Office Building in Washington, D.C.

The American Association for the Study of Liver Diseases (AASLD) is pleased to participate with the Congressional Hepatitis Caucus, the National Viral Hepatitis Roundtable, the Community Education Group, Hepatitis B Initiative of Washington DC, Caring Ambassadors Program, the National Alliance of State and Territorial AIDS Directors, the Association of Chinese American Physicians, and private industry to provide testing for hepatitis B and C.

In May 2011, the United States Department of Health and Human Services (HHS) released "Combating the Silent Epidemic of Viral Hepatitis: Action Plan for the Prevention, Care & Treatment of Viral Hepatitis." The plan runs through 2013, and AASLD -- the leading organization of scientists and healthcare professionals committed to preventing and curing liver disease -- welcomes the HHS announcement that it intends to update and renew the plan for 2014-2016.

Access to care and support of liver disease research are at the center of AASLD's advocacy efforts and Hepatitis Awareness Month and hepatitis testing events are necessary to make Americans aware that they can now be tested and treated for hepatitis C.

Research in the area of hepatitis C has led to FDA approval of two direct acting antiviral drugs for the treatment of hepatitis C, and numerous other direct acting antiviral drugs are in the development pipeline. AASLD looks forward to -- and its members work diligently to realize -- the day when an all-oral, interferon-free, shortened treatment can be used to eradicate the virus from patients with hepatitis C.

As research in hepatitis C continues, the fight against hepatitis B does so too, and AASLD members are at the forefront of these battles. We are proud to partner with the Centers for Disease Control and Prevention and others at HHS wherever there is an opportunity to raise awareness of both hepatitis B and C.

• May is Hepatitis Awareness Month.
• May 2013 is the second anniversary of the National Viral Hepatitis Action Plan.
• May 19, 2013, was the second annual Hepatitis Testing Day.
• May 23, 2013, is Hepatitis B and C Testing and Awareness Day in the U.S. House of Representatives.

SOURCE American Association for the Study of Liver Diseases

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