TheraSphere® Recommended by the National Institute for Health and Care Excellence (NICE) for the Treatment of Primary and Secondary Liver Cancer

LONDON, July 30, 2013 /PRNewswire/ --

BTG plc (LSE: BTG), the specialist healthcare company, today announces that the National Institute for Health and Care Excellence (NICE) has issued guidance recommending the use of Selective Internal Radiation Therapy (SIRT)⁽¹⁾, which includes TheraSphere^®, for patients with liver cancer across the NHS. The guidance supports the use of this innovative treatment for patients with primary hepatocellular carcinoma as well as for those with intrahepatic cholangiocarcinoma⁽²⁾ and follows the previous recommendation for its use in patients with colorectal cancer liver metastases⁽³⁾.

The NHS in England is currently preparing guidelines on how SIRT should be used as a treatment option for patients with liver cancer, including those with colorectal cancer liver metastases and cholangiocarcinoma, after recently issuing an interim policy on how this therapy should be funded⁽⁴⁾. It is anticipated that this latest NICE guidance will result in a similar evaluation for patients with primary liver cancer. "NICE's guidance further highlights the growing acceptance and understanding of radioembolization in the treatment of liver cancer," said Peter Pattison, General Manager TheraSphere^®. "With over 4,000 new liver cancer cases diagnosed annually in the UK⁽⁵⁾, this new guidance will potentially provide patients with access to a broader range of treatment options."

Pattison added: "With many countries looking to the UK for direction on their own reimbursement decisions and processes, this guidance should lead to greater awareness amongst physicians and patients and may also prompt similar guidance in other geographies. In addition to increasing liver cancer treatment options for physicians and patients in the UK, this guidance will assist BTG as we continue to explore other reimbursement opportunities in various regions across the world."

About TheraSphere®

TheraSphere is a form of radioembolization therapy that consists of millions of small glass beads (20 to 30 micrometers in diameter) containing radioactive yttrium-90 (Y-90). The product is injected by physicians into the artery of the patient's liver through a catheter, which allows for a high dose of radiation to be delivered directly to the tumour via blood flow thereby limiting the damage to surrounding healthy tissue and side effects to the patients.

TheraSphere is used in the European Union and in Canada for the treatment of hepatic neoplasia in patients who have appropriately positioned arterial catheters. Since its introduction in Europe, more than 1,000 patients have been treated with TheraSphere.

Common side effects include mild to moderate fatigue, pain and nausea for about a week. Physicians describe these symptoms as similar to those of the flu. Some patients experience some loss of appetite and temporary changes in several blood tests. For details on rare or more severe side effects, please refer to the TheraSphere package insert/instructions for use at http://www.nordion.com/therasphere.

1. National Institute of Care Excellence. IPG460 Selective internal radiation therapy for primary hepatocellular carcinoma: guidance. London. 24 July 2013.
2. National Institute of Care Excellence. IPG459. Selective internal radiation therapy for primary cholangiocarcinoma. London.  24 July 2013.
3. National Institute of Care Excellence. IPG401. Selective internal radiation therapy for non-resectable colorectal metastases of the liver: guidance. London. July 2012 (updates May 2013).
4. NHS England. Interim Clinical Commissioning Policy Statement: Selective Internal Radiotherapy (SIRT). June 2013.
5. http://www.cancerresearchuk.org/cancer-info/cancerstats/types/liver/

About BTG

BTG is an international specialist healthcare company that is developing and commercialising products targeting critical care, cancer and varicose veins. The company has diversified revenues from sales of its own marketed products and from royalties on partnered products, and is seeking to acquire new programmes and products to develop and market to specialist physicians. For further information about BTG please visit our website at http://www.btgplc.com.

For further information please contact:

BTG
Andy Burrows, Director of Investor Relations
+44(0)20-7575-1741; Mobile: +44(0)7990-530605

FTI Consulting
Ben Atwell/Simon Conway
+44(0)20-7831-3113

SOURCE BTG plc

Source

Getting hepatitis on the policy agenda in Asia

For Vietnam, where 15-17% of the population have hepatitis B or C, the global health burden has been heavy. Photograph: Hemis/Alamy

For health ministries trying to tackle hepatitis, the advice is: know your epidemic, get government on board to find a solution, educate the population and have the right policy in place

Guardian Professional, Sunday 28 July 2013 03.00 EDT

Viral hepatitis causes 1 million deaths a year in the Asia Pacific region, the equivalent of one death every 30 seconds and more than three times as many as HIV. Of the 350 million people in the world living with hepatitis B, 74% of them live in Asia, but getting the disease on the health policy agenda of some of the worst affected countries has not been easy.

"We have a vaccine for hepatitis B and new treatments for chronic hepatitis C that could save millions of lives, but none of these matter if governments fail to tackle viral hepatitis," says professor Stephen Locarnini, director of the WHO Regional Reference Laboratory for Hepatitis B at the Victorian Infectious Diseases Reference Laboratory in Melbourne and joint secretary of the Coalition to Eradicate Viral Hepatitis in Asia Pacific (Cevhap).

"What we need is for governments across the region to approach viral hepatitis in the same way that most have HIV/Aids, TB and malaria. This starts with the development of a national action plan and our expert members are ready and willing to help governments in the development of these, following the framework for global action blueprint provided by WHO."

Dr Robert Gish, Cvevhap's co-founder has been doing just that with the government in Vietnam, where an estimated 15-17% of the country's 100 million people have hepatitis B or C. "It's clear that the country needs a policy for liver health," he said.

Gish, together with colleagues in Vietnam and from UN and other international agencies has been working to get hepatitis and liver health on the Vietnamese government's health agenda.

A white paper published in 2011 in the Journal of Gastroenterology and Hepatology spelt out the rationale for a dedicated policy for liver health in Vietnam: 12% estimated prevalence of chronic hepatitis B, at least 2% prevalence of chronic hepatitis C and heavy alcohol use by men, adding up to liver cancer as the most common cause of cancer death in the country. Despite the sizeable liver cancer wards in all of Vietnam's major hospitals, a general lack of understanding of liver disease both among the public and health professionals and no systematic screening for those at risk has left the epidemic unchecked.

The white paper advocated liver disease education for the public and healthcare workers and an expansion of countrywide screening, hepatitis B vaccination and treatment of chronic hepatitis. These measures coupled with long-term surveillance for liver cancer, enhanced infection control to prevent transmission in health care settings and ongoing prevalence data analysis can help bring the epidemic of liver disease under control.

The message fell on fertile ground: in December 2012 the ministry of health set up a technical action group and by the end of this year is likely to have a draft policy in place.

Vietnam currently vaccinates approximately 60% of babies within 24 hours of birth and, says Gish, has the rural healthcare system in place to reach the WHO's revised target of 90% coverage (up from 80%).

Vaccination for adults is far less widespread but Gish and his colleagues are currently running pilot projects to test and vaccinate 20,000 adults, recruited from medical, dental pharmacology and nursing schools. "They are easy to reach and can carry the message forward to their patients, but they can only do so effectively if they themselves have been tested and vaccinated," says Gish.

But progress is stunted in parts of Asia, such as the Philippines, where hepatitis is accompanied by discrimination. Prevalence estimates range from 8% to 20% across different segments of the 96 million population and the stigma attached to hepatitis B is severe. Pre-employment tests for the disease screen out those who test positive. Overseas workers from the Philippines face similar discrimination notably in Middle Eastern countries. People with hepatitis are blatantly discriminated against," says Gish. "Workplace discrimination is a huge problem that deters people from getting voluntarily tested."

Gish has also been working with the Hepatology Society of the Philippines, which is leading the effort in the country, and also with hepatitis activist group Yellow Warriors Society Philippines to get hepatitis on the health policy agenda but, he says the contrast with Vietnam at government level has been "like night and day. The department of health has sat on a draft hepatitis policy for three years, so we're trying to revitalise a lot of activity. In Vietnam we were starting from scratch, but now the Vietnamese ministry of health is moving forward quite aggressively on its own."

Having become interested in hepatitis in Asia when treating Asian patients in his practice in San Francisco, Gish decided he could make a bigger impact on the disease by supporting colleagues to get it more widely recognised in Asia. His interest has spread to central Asia, another hepatitis hotspot, with a regional project underway in Armenia.

"Every country I've worked with has different customs and problems, but what they have in common is a need to know their hepatitis epidemic, get government on board to find a solution, educate the population and have the right policy in place."

Source

CHMP OKs Eltrombopag for HCV Patients With Thrombocytopenia

International Approvals > Medscape Medical News

Troy Brown

Jul 30, 2013

The indications for eltrombopag (Revolade, GlaxoSmithKline Trading Services) should be extended to include adults with chronic hepatitis C virus (HCV) infection who have thrombocytopenia severe enough to prevent the initiation of interferon-based therapy or limit the maintenance of optimal therapy, according to a July 25 recommendation by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA).

"Treatment with pegylated interferon and ribavirin is the current standard of care for patients with HCV, however both the European Association for the Study of the Liver guidelines and the American Association for the Study of Liver Diseases report the presence of thrombocytopenia among the relative contraindications to antiviral therapy," according to a GlaxoSmithKline statement.

"A sustained virologic response is the goal for treatment of hepatitis C infection and our clinical study, the largest ever in cirrhotic patients with low platelet counts and chronic hepatitis C infection, demonstrated that eltrombopag in combination with interferon-based therapy, allowed more cirrhotic patients with low platelet counts to reach this goal," Rafael Amado, MD, head of oncology research and development at GlaxoSmithKline said in the statement.

The committee's opinion was based on data from 2 randomized, double-blind, placebo controlled, multicenter phase 3 studies with a total of 1521 patients with platelet counts below 75000 µl, the ENABLE 1 and 2 (Eltrombopag to INitiate and Maintain Interferon Antiviral Treatment to Benefit Subjects with Hepatitis C related Liver DiseasE) trials. Patients in ENABLE 1 received peginterferon alfa-2a (Pegasys, Genentech) plus ribavirin for antiviral treatment and patients in ENABLE 2 received peginterferon alfa-2b (Pegintron, Merck) plus ribavirin.

Eltrombopag was previously approved in the European Union to treat thrombocytopenia in adult splenectomized patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who haven't responded to other treatments including corticosteroids and immunoglobulins. It can be considered as a second-line treatment for adult nonsplenectomized patients in whom surgery is contraindicated.

Eltromopag is marketed in the US under the trade name Promacta (GlaxoSmithKline) and is approved for both indications there.

Limitations to the use of eltrombopag include:

• Eltrombopag should not be used to normalize platelet counts;
• Eltrombopag should only be used in patients with chronic HCV whose thrombocytopenia is severe enough to prevent initiation of interferon therapy or maintenance of optimal interferon therapy; and
• The safety and efficacy of eltrombopag have not been established in combination with direct-acting antiviral agents that are approved to treat chronic hepatitis C genotype 1 infection.

Eltrombopag can cause hepatotoxicity, and hepatic enzymes should be measured before beginning therapy. When used in combination with interferon-based antiviral therapy, eltrombopag can increase the risk for hepatic decompensation, so patients should be monitored closely.

Venous and arterial thrombotic and thromboembolic events have occurred in patients receiving eltrombopag, with portal vein thrombosis reported most frequently. Patients with poor baseline liver function are at increased risk and should be monitored closely.

At least 10% of patients in both trials experienced headache, anemia, decreased appetite, insomnia, cough, nausea, diarrhea, alopecia, pruritus, myalgia, pyrexia, fatigue, influenza-like illness, muscle weakness, chills, and peripheral edema.

The European public assessment report (EPAR) will be revised to include the updated summary of product characteristics (SmPC) after the European Commission grants marketing authorization for this indication.

The European Commission generally follows the recommendations of the CHMP and usually delivers its final decision within 3 months of the CHMP recommendation.

European Medicines Agency statement, July 25, 2013. Overview

Source

HBV vaccine birth dose practices in Laos need more improvement

Provided by Healio

CDC. MMWR. 2013;62:587-590.

July 31, 2013

The median hepatitis B vaccine birth dose coverage at facility-based births was 74% in Laos, where hepatitis B virus is highly endemic, according to data published in Morbidity and Mortality Weekly Report.

From December 2011 to February 2012, the Laos Ministry of Health and WHO staff members evaluated coverage at 37 health facilities. At 18 of the facilities (49%), the HBV vaccine was not in stock. Among the 17 facilities that assisted with home births, seven included the vaccination in the services. Twenty-three facilities conducted postnatal visits, and only 15 of these provided the vaccine in the visit.

“Administration of the hepatitis B vaccine birth dose followed by timely completion of the hepatitis B vaccine series is 70% to 95% effective in preventing mother-to-child HBV transmission,” the researchers wrote. “During 2006 to 2011, the reported coverage in Laos increased from 3% to 34%. Despite this increase, the country continues to have the lowest coverage in the region, largely because only 37% of women in Laos give birth with the assistance of a skilled birth attendant.”

The study was conducted in five of the 24 provinces of Laos and included provincial or central hospitals, as well as two district hospitals and four health centers. Staff members at each facility participated in an in-person interview, answering questions about the HBV vaccine birth dose procedures.

Among the 31 facilities that provided birthing services onsite, all reported proving the vaccine to newborns. There were 5,072 onsite births recorded during the 3-month study period, of which 70% received the vaccine. Four additional facilities that did not provide onsite birthing services also reported providing newborns with the vaccine.

“Laos has shown a strong commitment toward the Western Pacific Region goal of reducing chronic HBV infection prevalence in children aged 5 years and younger to less than 1%,” the researchers wrote. “Such a reduction in HBV prevalence will require prevention of both perinatal and early childhood infections.”

Disclosure: The researchers report no relevant financial disclosures.

Source

Labeling for HBV medication updated following new safety, efficacy data

Provided by Healio

July 31, 2013

The FDA has approved changes to the labeling for Viread, a treatment for chronic hepatitis B, following the results of a 96-week study.

Updated labeling for tenofovir disoproxil fumarate (Viread, Gilead Sciences) reflects that the indication was the product of trials of treatment-experienced, lamivudine-resistant adult patients with chronic HBV and chronic liver disease who were naive to nucleoside-based therapy. Adverse events observed among these patients during treatment were similar to those observed in other HBV-related clinical trials.

In a randomized, double blind, active-controlled study, 141 patients with chronic HBV, HBV DNA of 1,000 IU/mL (mean 6.4 log₁₀ copies/mL) or more and resistance to lamivudine received Viread for 96 weeks. Forty-six percent of the cohort were HBeAg-positive, and 56% had abnormal serum ALT levels at baseline (mean 71 U/L).

Upon completion of treatment, 89% had HBV DNA below 400 copies/mL, and 62% of those with abnormal ALT had normalized. HBeAg loss occurred in 15% of the HBeAg-positive patients, and 11% experienced anti-HBe seroconversion through the final treatment week.

The labeling also indicates a potentially significant drug-drug interaction between Viread and didanosine. A didanosine dose reduction is recommended upon coadministration with Viread: to 250 mg once daily among patients weighing more than 60 kg and 200 mg among those weighing less than 60 kg. The drugs should be taken under fasting conditions or with a light meal containing fewer than 400 kcal and 20% fat.

Source

Turmoil for AIDS Conference Organizers

FLICKR, NIAID

Conflict between former conference organizers has shuttered a website that has come to serve as a resource for the HIV/AIDS community.

By Kate Yandell | July 30, 2013

The website for the annual Conference on Retroviruses and Opportunistic Infections (CROI), a major US HIV/AIDS meeting, is currently offline following a conflict between the two groups that formerly organized the event, ScienceInsider reported.

CROI, which has taken place annually for the past 20 years, has been the site of many important announcements in the history of HIV/AIDS research. The conference website was host to years’ worth of conference abstracts and other resources for AIDS researchers and the public.

The nonprofit CROI Foundation and the for-profit CROI LLC have previously been responsible for organizing the conference each year. But the two groups appear to have had a falling out. “I’m not allowed by our confidentially agreement to divulge anything,” Constance Benson, CROI Foundation board president and a professor at the University of California, San Diego, told ScienceInsider. “We reached an impasse this past couple of years over several issues and decided we needed to go in a different direction.”

Melissa Sordyl, head of CROI LLC, told ScienceInsider, “CROI LLC is no longer the conference secretariat and that is why the site is no longer active.”

Benson told The Scientist in an email that anyone seeking information on the 2014 conference, which will take place in Boston in March, should go to a new website: www.CROI2014.org. “We have no further update on the old website at this time,” Benson said. She added that Sordyl owned and maintained the old website and that it does not belong to the CROI Foundation.

The CROI Foundation is partnering with the International Antiviral Society-USA to put on the 2014 conference, according to the new website.

Simon Collins, head of HIV i-Base, a website for HIV treatment activism and information, wrote on his site that the loss of the CROI website was a frustrating one: “CROI is established as the most important HIV scientific meeting,” he wrote, adding that  “the website is a vital resource not only as a record of previous meetings but as a free open-access research tool.”

Benson told The Scientist that the conference organizers are “working on a solution for the old content from past meetings.”

Source

Engineered mice act as hepatitis C model

Hepatitis C particles (yellow) infect liver cells, causing disease and cancer.

THOMAS DEERINCK, NCMIR/SPL

Nature | News

Rodents may eventually replace chimpanzees in vaccine research.

Beth Mole

31 July 2013

Researchers have created the first strain of mouse that is completely vulnerable to hepatitis C. The advance, reported today in Nature¹, promises to aid efforts to develop a vaccine against the virus, which causes liver disease and cancer.

Chimpanzees have been the primary animal model for studying hepatitis C infection over the last several decades. But in the past few years scientists have begun phasing out chimp experiments, a process accelerated by the US government’s decision to retire most of its research chimps. That has created a need for alternative models to test potential drugs and vaccines.

Enter the mouse, which is naturally immune to hepatitis C. To transform the rodent into a model organism for studying infections with the virus, researchers genetically altered the animals to hamper their natural immune response. The team also engineered the animals to produce proteins found on the outside of human liver cells.

“It has been very difficult to get to this point,” says Alexander Ploss, a virologist at Princeton University in New Jersey and lead author of the study.

In 2011, Ploss — then at Rockefeller University in New York — and his colleagues showed that hepatitis C could infect mice engineered to produce the two human proteins². But the virus did not replicate well in those animals, making them a poor model for human infections. So the team created another strain by breeding the human-protein-containing mice with animals that carried a broken version of a gene involved in antiviral responses. The result, they report, is mice in which hepatitis C can take root and flourish, creating new viral particles to spread the disease.

“For the first time you can study the whole spectrum of hepatitis C replication” in a mouse model, says Lishan Su, an immunologist at the University of North Carolina at Chapel Hill, who was not involved with the study.

Strong immune system

Researchers have previously tested candidate hepatitis C drugs using a mouse containing human liver cells, developed in 2010 by Karl-Dimiter Bissig, a virologist at Baylor College of Medicine in Houston, Texas, and his colleagues³. But that mouse model had no immune system. Su says that Ploss and colleagues' strain may be more useful for testing vaccines, because most of the mouse's immune system is intact.

Michael Houghton, a hepatitis C researcher at the University of Alberta in Edmonton, Canada, says that scientists should still be careful when interpreting results from tests with the latest mouse model. The mouse's immune system is still partially damaged, so the response to vaccines may be altered — which could cause falsely negative results when testing vaccines that are actually effective.

“This model still cannot replace chimpanzees,” says Ploss, who is working with his colleagues to improve the mouse strain. “It gives us a first glimpse of what may be possible with mice in coming years.”

Nature doi:10.1038/nature.2013.13477

Source

‘HCC-4 risk score’ IDs hepatitis C patients likely to develop HCC

^{Courtesy US. Dept of Veterans Affairs}

A new risk score may help identify the patients with chronic hepatitis C who are most at risk for developing hepatocellular carcinoma.

By: MARY ANN MOON, Family Practice News Digital Network

07/31/13

Vitals

Major finding: The annual incidence of HCC was 0.06% in the group designated as low risk, 0.5% in the group designated as medium risk, and 2.6% in the group designated as high risk, indicating that the HCC-4 risk score was highly predictive of actual outcomes.

Data source: A retrospective study of data collected in a 17-year longitudinal cohort study involving 829 adults with chronic hepatitis C, of whom 58 developed HCC.

Disclosures: There was no external funding source for this study, and no financial conflicts of interest were reported.

A risk score derived from four simple test results readily obtained during routine care may help identify the patients with chronic hepatitis C who are most at risk for developing hepatocellular carcinoma, according to a retrospective study published online July 12 in the European Journal of Internal Medicine.

The score could enable physicians to target only the highest-risk patients for annual surveillance for malignant hepatic nodules, which is crucial because current screening methods are too invasive, too expensive, and too low-yield to be applied broadly across all risk groups.

The new risk score also may help identify patients with chronic hepatitis C who are at lowest risk for developing HCC, who can then be reassured that they can safely forgo invasive and expensive surveillance, reported Dr. Juan Carlos Gavilan and his associates at University Hospital Virgin de la Victoria, Malaga (Spain).

The investigators reviewed data from a 17-year longitudinal cohort study involving 829 patients with chronic hepatitis C. These subjects were assessed every 6 months for the development of HCC using serum alpha-fetoprotein (AFP) levels and ultrasound imaging to detect new focal hepatic lesions.

A total of 58 subjects (7%) developed HCC during follow-up.

An initial univariate analysis identified numerous clinical and epidemiologic factors associated with elevated risk for HCC. The researchers constructed a formula for predicting risk using the four independent factors that were most predictive of HCC in this cohort: patient age, platelet count, gamma-globulin level, and AFP level at baseline.

By dividing the study population into tertiles, Dr. Gavilan and his colleagues established cutoff ranges for low, medium, and high risk. They then classified each study participant as belonging to one of these three categories, to see how well this risk score correlated with the actual rates of HCC.

The annual incidence of HCC was 0.06% in the group designated as low risk, 0.5% in the group designated as medium risk, and 2.6% in the group designated as high risk, indicating that this "HCC-4 risk score" was indeed highly predictive, Dr. Gavilan and his associates said (Eur. J. Intern. Med. 2013 July 12 [doi: 10.1016/j.ejim.2013.06.010]).

In fact, the score was more accurate at predicting HCC than was the commonly used fibrosis index, they noted.

According to recently published recommendations, surveillance is only justified in populations with an HCC incidence of 1.5% or more per year. Thus, patients found to be high risk using this HCC-4 risk score would be appropriate for such surveillance, while those at medium or low risk would not be.

"These results must be confirmed in other studies," the investigators said.

There was no external funding source for this study, and no financial conflicts of interest were reported.

Source

Hepatitis C genotype 1 virus with low viral load and rapid virologic response to peginterferon/ribavirin obviates a protease inhibitor

Hepatology

Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)

Viral Hepatitis

Brian L. Pearlman^1,2,3,4,*, Carole Ehleben²

DOI: 10.1002/hep.26624

© 2013 by the American Association for the Study of Liver Diseases

Publication History Accepted manuscript online: 19 JUL 2013 10:11AM EST, Manuscript Accepted: 3 JUL 2013, Manuscript Revised: 12 JUN 2013 , Manuscript Received: 6 MAY 2013

Abstract

Keywords: Sustained virologic response; rapid virologic response; African American; IL-28B; boceprevir

The new standard of care for treatment-naïve patients with hepatitis C virus (HCV) genotype 1 includes triple therapy with peginterferon, ribavirin, and a protease inhibitor. However, patients who achieve a rapid virologic response after 4 weeks of peginterferon and ribavirin therapy are likely to achieve a sustained virologic response (SVR), and we hypothesized that protease inhibitor therapy may be unnecessary in these patients. Treatment-naïve, noncirrhosis patients infected with genotype-1 HCV and a low viral load at baseline were considered for inclusion (n = 233). After 4 weeks of lead-in therapy with peginterferon α-2b and ribavirin, 101 patients (48%) had a rapid virologic response (defined as undetectable levels of hepatitis C virus RNA at 4 weeks) and were eligible to participate. Patients were randomized 1:1 to 20 weeks of additional therapy with peginterferon α-2b and ribavirin (double therapy) or to 24 weeks of peginterferon α-2b, ribavirin, and boceprevir (triple therapy). There was no significant difference in rates of SVR-12 in patients treated with double versus triple therapy. This similarity persisted regardless of viral subtype (genotype 1a or 1b), interleukin (IL)−28b genotype (CC or non-CC), or ethnicity (African American versus non-Hispanic white). Conclusion: Protease inhibitor therapy could be obviated in genotype 1-infected treatment-naïve patients with low viral load at baseline who achieve undetectable viremia after 4 weeks of peginterferon/ribavirin. (Hepatology 2013;)

Source

Interferon-free treatment for genotype-1b hepatitis C patients: an interview with Professor Wulf Boecher, Boehringer Ingelheim

Published on July 30, 2013 at 6:32 AM

Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)

Please can you give a brief introduction to genotype-1b hepatitis C and how it differs from subtype 1a?

Genotype 1 is, worldwide, the most prevalent genotype of the hepatitis C virus. It accounts for around seventy percent of all hepatitis C infections.

With the introduction of protease inhibitors, it became known that the subtypes 1a and 1b make a difference in terms of treatment response.

Subtypes 1a and 1b are genetically closely related. They share seventy to eighty percent of their genome. However, 1a turned out to be more difficult to treat than 1b, which is easier to treat.

That was also the case with the already approved protease inhibitors, and still is the case with the second generation of protease inhibitors (PIs) like faldaprevir or other second generation PIs that are in late stage development. And it applies for interferon based as well as interferon-free treatments.

Faldaprevir's target in viral polyprotein processing.

*Please note faldaprevir (BI 201335) is an investigational compound and not yet approved. Its safety and efficacy has not yet been fully established.

Source: Boehringer Ingelheim

Do genotypes 1a and 1b affect equal numbers of people, or is one more common than the other?

It is regionally very different. In the US, genotype 1a is more prevalent where it accounts for roughly seventy percent of genotype 1 infections.

In Europe, there is slightly more genotype 1b. So there’s roughly a sixty-forty split, with sixty percent being genotype 1b, forty percent 1a.

If you go further East the prevalence of 1b becomes nearly the only genotype 1. So in Japan, in China, and in large parts of Asia, genotype 1b is basically the vastly prevailing or the only genotype 1 subtype.

Hepatitis C virus travelling in the bloodstream.

Source: Boehringer Ingelheim

Why is eliminating injectable interferon from HCV treatment regimens highly desirable?

I have been working on hepatitis C treatment for many years and it is not only subcutaneous injections that make patients uncomfortable. Interferon really makes patients sick for the whole course of treatment and with current treatments this can be as long as twenty four or forty eight weeks, so nearly one year.

Patients feel like they have the flu, with fever, myalgia, chills, and many other symptoms. Also their neuro-cognitive function is reduced. They have low blood cell count that can lead to infections and to severe bleedings. They suffer from psychiatric side effects like severe depression. There are suicides associated with treatment with interferon.

So interferon is really a trouble-maker for patients; it makes patients sick for the duration of their treatment and it is less effective than the oral treatments that are to come. Treatment lasts longer and there is a high chance patients won’t be cured at the end. In contrast, current triple therapies the next generation triple therapies, as well as the future interferon-free treatments, offer shorter treatment duration and higher cure rates.

Faldaprevir* Protease Inhibitior Mode of Action.

*Please note faldaprevir (BI 201335) is an investigational compound and not yet approved. Its safety and efficacy has not yet been fully established.

Source: Boehringer Ingelheim

How did your interferon-free combination treatment originate and what stage of development is it currently at?

It’s actually based on the knowledge of HIV and tuberculosis treatment; where by combining different oral drugs with a different mode of action it is possible to control or eliminate the virus or mycobacteria.

In HCV, we had two different mode-of-action drugs in late stage development that we combined. We had actually thought we may possibly have a forty-five percent cure rate, which would still have been a very attractive cure rate for patients without any treatment options.

Up to fifty percent of hepatitis c patients right now do not tolerate interferon or have contra-indications against interferon.

But then in our phase two studies we found out that by focusing on the easier-to-treat genotype 1b patients, eighty five to ninety five percent of patients can be cured. This makes this combination very attractive as an alternative to replace interferon-based treatments.

And with this interferon-free treatment, we are currently in phase III development.

Please can you tell us about the recent Phase IIb study into the efficacy and safety of this combination treatment?

This is our second phase IIb trial. Initially (in the SOUND-C2 trial) we tested our interferon-free treatment regimen of faldaprevir, deleobuvir and ribavirin in a large study. We had 362 patients, including patients with liver cirrhosis and all stages of liver disease.

We found that genotype 1a patients are indeed difficult to treat, achieving lower cure rates. That would have been attractive maybe three, four years ago, but not nowadays.

But in this study genotype 1b patients had a cure rate of eighty-five percent.

Then we modified the regimen. We shortened treatment from twenty eight to sixteen weeks in SOUND-C3, which is the study we just published at the Asian Pacific Liver Conference (APASL) in June.

We also dropped a so-called induction dose. So in the old regimen, we had a high dose of our polymerase inhibitor and this was not so well tolerated, as we found out.

So we dropped this, we shortened treatment and we found in genotype 1b patients ninety five percent achieved viral cure. But it turned out that in the more difficult to treat population of genotype 1a patients, only two of seventeen patients were cured. And that confirmed our decision to focus on genotype 1b patients with this regimen.

Progression of liver damage caused by infection with hepatitis C.

Source: Boehringer Ingelheim

What were the results of this study and what do they indicate?

The very high cure rates of ninety five percent confirm our decision to focus on genotype 1b patients with this regimen.

We dropped genotype 1a patients from this regimen. However we are currently investigating a third compound in combination with our interferon free combination with which we strive to address genotype 1a patients.

The tolerability was very good. This was as expected from interferon-free treatment. We saw only minor effects on the red blood cells, which was due to the ribavirin component of the regimen, but we didn’t see any effects on white blood cells or platelets.

We did see mostly mild adverse events like mild rashes or nausea, which were the most common side effects.

Did any patients experience serious adverse events during the trial?

Only two patients had to discontinue treatment for adverse events and only one patient reported a serious adverse event (SAE). So overall, I think we can say that this is very good tolerability.

What serious adverse event did the patient experience?

The SAE patient was a patient who had severe dehydration. He was hospitalized to get some infusions and discontinued HCV treatment early after 6 weeks of treatment. However the condition was managed and resolved and the patient recovered completely from the event but also from his hepatitis C.

What are your plans for the future?

For genotype 1b patients we are in the middle of our phase III evaluations. We are expecting results early next year.

We have three on-going phase III trials:-

• One in treatment-naive genotype 1b patients.
• One in a treatment-naive population that includes interferon ineligible patients, which are patients who have contra indications to interferon based treatments. So these patients have currently no treatment option at all.
• We have a third trial that goes to the highest unmet medical need population, which are patients with decompensated liver cirrhosis.

The first two trials also include patients with compensated liver cirrhosis, but the third trial really addresses the late stage liver cirrhosis, or decompensated liver cirrhosis. These are patients that will die if they do not receive a liver transplant. All studies are on-going as we speak.

Our trials are comprehensively designed and address the real-world patients that physicians see every day in clinical practice. Through robust science, our goal is to provide a safe and highly effective interferon-free treatment for genotype-1b patients.

How do you think the future of genotype-1b hepatitis C treatments will progress?

From a patient and a prescriber or physician’s perspective, the future is very bright.

There are several companies and there will be several regimens available to physicians to pick the best treatment option for a given patient.

There are many factors that need to be considered when prescribing HCV treatments, so there will be no one-size-fits-all approach. In the future individualized treatment will become a reality. Physicians will be able to pick the best treatment option for a given patient depending on:-

• the virus genotype and patient genetics
• on individual patient conditions
• age
• gender
• co-morbidities
• co-medications

Everything will play into this and there will be several interferon-free treatment options that can be really tailored individually to a given patient.

It is exactly our strategy to provide tailored therapy which is optimal for specific patient populations. I think this is where we believe we will excel in.

The treatment landscape will become more complex. In the past, we had only to pick between prescribing pegylated interferon for twenty four, or forty eight weeks, and ribavirin in eight hundred, one thousand or twelve hundred milligrams. This was very easy, no drug-drug interactions.

The future looks like it will be more individualized, with physicians choosing which regimen to provide based on the individual patient’s profile. But this is in fact a luxury situation and a great opportunity.

Where can readers find more information?

Readers can find more information on Boehringer Ingelheim at: http://www.boehringer-ingelheim.com/

Readers can also find more information on HCV at: http://www.newshome.com/

About Professor Wulf Boecher

Wulf trained and worked more than 15 years at Mainz University Hospital in Germany as a Gastroenterologist/ Hepatologist and Infectious Diseases Specialist, where he lectures as an Associate Professor for Internal Medicine.

His main scientific focus has been immune pathogenesis and new treatments of HBV, HCV and HIV infection.

Wulf joined Boehringer Ingelheim for the clinical development of new HCV treatments in 2007 and currently holds the position of Associate Therapeutic Area Head Virology.

Source

Sign-on letter to Gilead about sofosbuvir/ Pétition adressée a Gilead sur le sofosbuvir

Request for sign-ons/ Appel à signatures

Sign-on letter to Gilead about sofosbuvir/ Pétition adressée a Gilead sur le sofosbuvir

publication: 28 juillet 2013

The TRT-5 and the CHV are requesting individual and organizational sign-ons to a letter urging Gilead to provide early access to sofosbuvir for people with the most urgent need / Le TRT-5 et le CHV sollicitent des signatures individuelles ou d’organisations pour une pétition demandant à Gilead de donner un accès précoce au sofosbuvir aux personnes qui en ont le besoin le plus urgent.

SIGN-ON LETTER TO GILEAD - 26th JULY 2013

Version française ci-dessous

GILEAD REFUSES ACCESS TO TREATMENT TO SERIOUSLY ILL HEPATITIS C PATIENTS

People living with HCV who are in an urgent need of new treatments should get an early access to compounds that are in nearing approval, and therefore not yet on the market. In France, there is an early access system, called ATU (Temporary Authorization of Use), to allow for early access to potentially life-saving drugs.

The French national regulation agency ANSM (Agence Nationale de Sécurité du Médicament) has granted many name-based temporary authorizations of use (ATU) for sofosbuvir, a compound from Gilead that is nearing approval, for transplanted people, people awaiting a liver transplant and cirrhotic patients with no other treatment options since the drug appears to be safe and effective for these populations.

But Gilead has refused to provide sofosbuvir to some of the people with the most urgent need : patients with late-stage cirrhosis (Child-Pugh B or C).

For their refusal, Gilead argued that it would be unfair to provide access only to patients in France. We do not accept this reason.

Gilead filed a European marketing application for sofosbuvir in April 2013. Although there are patients throughout Europe who need early access to sofosbuvir, many other countries do not have the legal or regulatory framework to provide early access. If Gilead provides sofosbuvir in France, where the system already exists, it will pave the way for desperately ill patients and their advocates in other countries to gain access. A European initiative could allow early access programs without delaying the provision of sofosbuvir in the countries with adequate regulatory and medical agencies.

It is cruel to withhold potentially life-saving treatment from the patients who meet the clinical criteria for being most likely to benefit from it, or die without it.

In addition, Gilead has much to gain by providing sofosbuvir through early access programs. Scientific data can be collected in patients with the most urgent need, who are also likely to be the first to receive the drug when it will be approved. Data from early access programs can be used to determine the safest and most effective way to treat HCV in people who need it most. For example, the CUPIC study (French ANRS) provided critical information on which cirrhotic patients were most likely to benefit—or be harmed by —boceprevir or telaprevir-based regimens.

If Gilead refuses to study sofosbuvir in « real life » cohorts, the opportunity to minimize harm and maximize benefits is lost.

Therefore, we ask Gilead to provide sofosbuvir NOW, for the people with urgent need, including patients with late-stage cirrhosis (Child-Pugh B or C), among whom people living with HIV or other illnesses.

To sign the letter, please go to change.org

PÉTITION ADRESSÉE À GILEAD - 26 JUILLET 2013

GILEAD REFUSE DE DONNER UN TRAITEMENT A DES PERSONNES GRAVEMENT MALADES DE L’HÉPATITE C

Les personnes vivant avec une hépatite C et dont l’état de santé présente une urgence doivent pouvoir bénéficier des médicaments en cours de développement et proches de leur mise sur le marché. Pour cela, il existe en France un dispositif appelé Autorisations Temporaires d’Utilisation (ATU), qui permet l’accès précoce à des médicaments susceptible de sauver des vies.

L’Agence Nationale de Sécurité du Médicament (ANSM) a accordé des ATU de sofosbuvir, une molécule développée par Gilead proche de sa mise sur le marché, à des personnes transplantées, des personnes en attente de transplantation et des personnes cirrhotiques en impasse thérapeutique. Le sofosbuvir apparaît comme sûr et efficace chez ces populations de patients.

Mais Gilead refuse de donner la molécule à certains des patients qui en ont un besoin urgent : les patients avec une cirrhose avancée (score Child-Pugh B ou C). Cet antiviral du virus de l’hépatite C leur est refusé par Gilead au motif de l’équité entre les pays européens. Nous n’acceptons pas cette justification.

Gilead a déposé une demande européenne de mise sur le marché pour le sofosbuvir en avril 2013. Bien que des patients aient besoin d’un accès précoce au sofobuvir partout en Europe, de nombreux autres pays ne possèdent pas le cadre légal ou réglementaire nécessaire. Si Gilead met le sofosbuvir à disposition en France, où le système existe déjà, cela ouvrira une voie pour obtenir l’accès précoce aux malades très avancés et aux associations de défense des patients d’autres pays d’Europe. Une initiative européenne pourrait permettre la mise en place de programmes d’accès précoce à l’échelle européenne, sans retarder la mise à disposition du sofosbuvir dans les pays ayant déjà les structures médicales et administratives adéquates.

Il est cruel de bloquer des traitements susceptibles de sauver des vies lorsque les personnes auxquelles ils sont refusés présentent des critères cliniques qui montrent qu’elles ont une très forte probabilité d’en retirer un bénéfice, ou de mourir sans.

De plus, Gilead a beaucoup à gagner en fournissant le sofosbuvir par le biais de programmes d’accès précoce. Des données scientifiques peuvent ainsi être collectées chez des patients qui en ont un besoin urgent, dont il est probable qu’ils seront aussi les premiers à recevoir le produit quand il sera approuvé.

Les données issues de programmes d’accès précoce (ou compassionnel) peuvent être utilisées pour déterminer les façons les plus sûres et les plus efficaces de traiter le VHC chez les personnes qui ont le plus besoin d’un traitement. Par exemple, la cohorte ANRS CUPIC a fourni des informations essentielles pour comprendre quels patients cirrhotiques étaient les plus susceptibles d’aller mieux- ou moins bien – avec des traitements basés sur le boceprevir ou le telaprevir.

Si Gilead refuse d’étudier le sofosbuvir « dans la vraie vie », l’occasion est perdue de minimiser les dommages et de maximiser les bénéfices.

C’est pourquoi nous demandons à Gilead de donner le sofosbuvir MAINTENANT aux personnes qui en ont le besoin le plus urgent, y compris celles avec une cirrhose avancée (Child-Pugh B ou C), parmi lesquelles certaines vivent avec le VIH ou une autre maladie.

Pour signer la pétition, merci d’aller sur change.org

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TRT-5 : Actions Traitements, Act Up-Paris, Act Up-Sud Ouest, AIDES, ARCAT, Dessine-Moi Un Mouton, Nova Dona, Sida Info Service, SolEnSi

CHV : Actif Santé, Actions Traitements, ARCAT, Association Française des Hémophiles (AFH), ASUD, CIGaLes, Nova Dona, Sida Info Service / Hépatites Info Service, SOS Hépatites, Transhépate

Source

Activists demand cheaper Hepatitis C drugs

The Jakarta Post, Jakarta | National | Tue, July 30 2013, 2:24 PM

A group of 14 non-governmental organizations running a campaign titled “People living with HIV/AIDS (ODHA) have a right to health” signed an online petition urging a drug manufacturer to offer Hepatitis C drugs at lower prices.

The petition launched via public campaign platform change.org is aimed at urging Roche Indonesia to immediately cut the prices of Hepatitis C drugs, the patent of which belongs to it parent Swiss multinational pharmaceuticals company.

In Indonesia, the official figure of people with Hepatitis C is estimated at 7 million, although the actual figure is likely higher due to low the awareness of the need to have a Hepatitis C test. The high cost of the test aggravates the problem.

For people living with HIV/AIDS, Hepatitis C infection has become a particular source of concern because co-infection of HIV and hepatitis C virus (HCV) exacerbates their condition and can lead to death.

The campaign’s public campaigner, Ayu Oktariani, said many ODHA managed to survive and were still healthy because the government provided HIV-infected people with anti-retroviral drugs for free.

“But ODHA co-infected with Hepatitis C makes their life expectancy lower because in Indonesia, Hepatitis C medication is costly,” said Ayu in a statement made available to The Jakarta Post, on Tuesday.

Currently, Hepatitis C medication costs around Rp 25 million (US$2,425) per month, with medication until recovery costing more than Rp 250 million per patient.

“The role of our government in regulating the trade of pharmaceuticals is still very weak. As a result, multinational companies can set the prices of drugs as they like,” said Indonesia AIDS Coalition executive director Aditya Wardhana. (ebf)

Source

Prices of treatment are killing patients with hepatitis C - a protest action in Russia

29/07/2013

On 24 July 2013 a protest action was carried out in Moscow in front of the Ministry of health of Russia. Activists of the "Patients’ control" came to officials with the requirement to force manufacturers of hepatitis C drugs to decrease prices. The protest took place under the slogans: "There are 5 million people with hepatitis C in Russia", "Treatment costs 500,000 rubles", "Prices Roche and Merck are killing us", "Force Roche and Merck to lower prices".

The same day activists of the "Patients’ control" held pickets at the offices of pharmaceutical companies Roche and Merck and sent letters to them demanding price reductions for hepatitis C treatment.

The prices of the main component of HCV treatment - pegylated interferon – are constantly high for the last 15 years. There are only two major manufacturers of pegylated interferons in the world - Roche and Merck.

“As for today 5 million people are affected by hepatitis C in Russia. Not everyone can afford Hepatitis C treatment. People are getting into debt, sometimes they are forced to sell their homes to buy treatment. We have repeatedly asked the manufacturers to lower prices, but haven’t received any reply. Our last hope - that the new composition of the Ministry of Health will hear us and will take drastic measures to ensure affordable treatment - namely, force companies to decrease prices”, - says Andrey Skvortsov, leader of “Patients’ control” movement.

"Hepatitis C is curable", - says Alexei Mikhailov, activist. "If we cure all people the epidemic would stop. If prices are reduced the state could provide treatment to more people, save the budget and, thus, more people could afford to buy life-saving drugs".

Russia is not the only country where activists call on the manufacturers of pegylated interferon to cut prices. In anticipation the International Hepatitis Day similar events take place or will take place in Ukraine, Georgia, Armenia, India, Thailand, Moldova, Latvia, the United States and other countries.

For information:

The average price of hepatitis C treatment (48 weeks of pegylated interferon in combination with ribavirin) in the commercial market in Russia is more than half a million of rubles (~$15.000) while the drugs do not always allow the patient to fully recover from a virus and have a number of serious side effects.

Because of the very high cost of HCV treatment the state provides with treatment an extremely small number of patients: according to the independent patients monitoring, the federal program in 2012 covered less than 4,000 patients.

Source

Assessment of health-related quality of life predicts the outcome of pegylated interferon and ribavirin therapy for chronic hepatitis C

J Gastroenterol Hepatol. 2013 Jul 22. doi: 10.1111/jgh.12337. [Epub ahead of print]

Matsushita H, Ikeda F, Iwasaki Y, Seki H, Nanba S, Takeuchi Y, Moritou Y, Yasunaka T, Onishi H, Miyake Y, Takaki A, Nouso K, Yamamoto K.

Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama.

Abstract

BACKGROUND: Chronic infection with hepatitis C virus (HCV) decreases health-related quality of life (HRQOL). The present study was planned to investigate the impact of HRQOL of patients with chronic hepatitis C (CHC) on the outcomes of therapy with pegylated interferon and ribavirin, in addition to IL28B polymorphisms.

METHODS: The present study enrolled 228 CHC patients, and assessed their HRQOLs prospectively with the 36-item short-form health survey.

RESULTS: The patients with chronic hepatitis C have lower physical HRQOL status than the general population (P = 0.037, the Z test). The patients with advanced liver diseases exhibited further decreases in HRQOL (P = 0.036, Spearman's rank correlation coefficient). The score of total HRQOL was significantly lower in the group with sustained virological response (SVR) to the therapy with pegylated interferon and ribavirin than the non-SVR group (P = 0.031, the Mann-Whitney U test), with significantly lower scores of mental component and its comprising subscales in the SVR group. Stepwise multivariate logistic regression analysis showed that low HRQOL score ≤400 points was significantly associated with SVR (odds ratio = 2.4, P = 0.013), independently from high platelet counts, low HCV RNA, favorable SNP type of IL28B, and HCV serotype 2. The patients with low HRQOL score will had significantly less decrease in HRQOL score by 4 weeks of the treatment than those with high HRQOL score at baseline (P = 0.0045).

CONCLUSIONS: HRQOL is one of the significant predictor of the outcomes of therapy with pegylated interferon and ribavirin independently from IL28B polymorphism.

This article is protected by copyright. All rights reserved.

KEYWORDS: Interferon, QOL, and HCV

PMID: 23869873 [PubMed - as supplied by publisher]

Source

Telaprevir safe, effective among older patients with chronic HCV

Provided by Healio

Furusyo N. J Hepatol. 2013;59:205-212.

July 30, 2013

Advanced age did not impact the efficacy of triple therapy with pegylated interferon, ribavirin and telaprevir among patients with hepatitis C genotype 1b in a recent study.

In a prospective study, researchers evaluated 120 patients with chronic hepatitis C genotype 1b, including 64 participants aged older than 60 years. All patients received peginterferon alfa-2b, ribavirin and telaprevir for 12 weeks, then 12 weeks of peginterferon and ribavirin. During prior therapy 53.3% of participants had relapsed, 22.5% were treatment-naive, 20.8% were prior nonresponders and 3.3% had an unknown prior response.

Undetectable HCV RNA (rapid virological response) was observed at 4 weeks in 73.4% of older patients and 73.2% of patients aged younger than 60 years. Sustained virological response at 24 weeks post-treatment occurred similarly between groups: 76.6% of older patients vs. 83.9% of younger patients (P=.314 for difference). Investigators said SVR was more common among all patients with the IL28B TT allele (89.4% of older and 91.9% of younger patients vs. 41.2% and 68.4% among those without; P<.05 for both comparisons).

Multivariate analysis indicated associations between SVR and RVR (OR=7.498; 95% CI, 1.014-65.42) and IL28B TT genotype (OR=14.93; 95% CI, 1.6-142.9), as well as prior nonresponse (OR=8.403; 95% CI, 1.025-66.667), among older patients. Independent associations with RVR and TT genotype also were noted among younger patients.

Treatment discontinuation for adverse events occurred in 12.5% of all cases. Hemoglobin decreases for levels of 100 g/L or more were observed in 41.1% of younger and 9.4% of older patients; between 85 g/L and 100 g/L in 25% and 40.6%, and less than 85 g/L was present in 33.9% and 50% of younger and older patients, respectively (P=.0006).

“This study shows there is no impact by age on the virological outcome of TVR-based triple therapy for HCV genotype 1b chronic hepatitis C,” the researchers concluded. “We found that older patients achieve a better virological outcome by TVR-based triple therapy than with the traditional dual therapy. IL28B genotyping and EVR indicate the potential to achieve an SVR in these difficult-to-treat older patients.”

Disclosure: The researchers report no relevant financial disclosures.

Source

Future directions in hepatitis C treatment - closing in on a cure for the vast majority

Updated policy brief: Future directions in hepatitis C treatment - closing in on a cure for the vast majority

Professor Gregory Dore

July 2013

Policy Brief 1

Key Messages

• Hepatitis C is a viral infection that is curable with pegylated interferon and ribavirin (PEG-IFN/RBV) in around 60% of people, but has considerable side effects and requires relatively prolonged treatment duration (24-48 weeks). 
• The initial direct-acting antiviral (DAA) agents - HCV protease inhibitors, telaprevir and boceprevir, were recently listed on the Australian PBS for treatment of chronic hepatitis C genotype 1.                                           

• When combined with PEG-IFN/RBV in triple therapy regimens these initial DAA agents improve cure rates (by 20-25%), and shorten treatment duration from 48 to 24 weeks for around half of patients.

• Although increasing cure rates, there are several concerns with these initial two DAA agents: not effective against genotype 2/3; additional toxicity (e.g. rash, anaemia); problematic dosing (three times per day with food); and complex monitoring schedules and stopping rules.
• Several other DAA agents in development appear to be as potent (and possibly more potent), have reduced toxicity, and better dosing schedules (some are once daily), and should become available in 3-4 years.
• Several studies of combination DAA treatment (without PEG-IFN/RBV) have been extremely encouraging in demonstrating cure of hepatitis C in 90%.
  The first available IFN-free DAA regimen is likely to be sofosbuvir (Nucleotide analogue) and ribavirin with a treatment cure (called a sustained virological response - SVR) of 90% for genotype 2 and 60% for genotype 3.
• The future of hepatitis C treatment with DAA therapy is extremely promising - with the potential to cure the vast majority of people commenced on therapy. The challenge now and into the future is to increase access to treatment as currently only one to two per cent of Australians with chronic hepatitis C commence treatment each year.
• As people who inject drugs are the group at greatest risk of hepatitis C, further research and specifically developed treatment programs will be crucial.

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What is the issue?

Hepatitis C is somewhat unusual among chronic diseases generally and chronic liver disease specifically – it is eminently curable. Around 60% of people commenced on current standard of care (PEG-IFN/RBV) will be cured of their chronic hepatitis C infection, with most people also having reversal of underlying liver damage. However, current treatment  remains problematic due to the considerable side effects, the requirement for contraception during and for six months following treatment (due to RBV causing foetal malformation), the relatively prolonged treatment duration (24-48 weeks), and the restrictive settings in which most treatment is provided (tertiary clinics in large hospitals). As such, only 1-2% of people with chronic hepatitis C are commenced on treatment each year in Australia.

The landscape of hepatitis C treatment will alter enormously over the coming decade following the development of direct acting antiviral (DAA) agents that enhance treatment efficacy (that is more people will be cured of their hepatitis C). The duration of therapy will be shortened with treatment demonstrated to be curative without interferon-based therapy. As new treatments become available, there will be a need to evaluate them among current injecting drug users, the group at greatest risk of hepatitis C infection who have to date been excluded from clinical trials developing these agents. It will also be crucial to improve access through specifically developed treatment programs. 

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What is the evidence?

Over the last 12 months several major milestones have been reached in the clinical development of DAA therapy for chronic HCV infection. The initial HCV protease inhibitors, telaprevir and boceprevir, have been approved in Australia for use in combination with PEG-IFN/RBV for people with HCV genotype 1 who  have never previously been treated for hepatitis C (treatment naïve) and people previously treated for hepatitis C (treatment experienced).

In treatment naïve populations, telaprevir or boceprevir when added to PEG-IFN/RBV improved the chance of a treatment cure (called a sustained virological response - SVR) from 40-45% to 65-75% and enabled the length of treatment to be shortened from 48 weeks to 24-28 weeks for around half of patients. In treatment experienced populations, telaprevir and boceprevir both provided considerably enhanced but variable SVR when combined with PEG-IFN/RBV (from 30% to 85%).

Although telaprevir and boceprevir are now listed on the Pharmaceutical Benefits Scheme, several concerns remain regarding these two agents, including:

• Problematic dosing schedule of three times per day with a meal (fatty for telaprevir), and large pill burden (boceprevir, 12 pills per day; telaprevir, 6 pills per day);
• Low level of treatment response (efficacy) in patients who had a minimal reduction in the level of the virus when treated with PEG-IFN/RBV in the past, particularly those with advanced fibrosis (15-20% SVR);
• The potential for drug resistance;
• Increased side effects – in particular rash (telapravir) and anaemia (bocepravir and telapravir);
• Potential for a large number of drug interactions due to the way that telapravir and bocepravir are broken down in the liver (they impact on the cytochrome P450 (CYP) 3A4 pathways);
• The strategies for administering telapravir and bocepravir in particular vary (they have different “start” and “stop” rules) and can be confusing for both patients and doctors.
• Telaprevir and boceprevir are only approved for HCV genotype 1.

There are several important pathways for future DAA clinical development, with many studies recently releasing promising findings. Some of the major areas for development will include:

• Shortened PEG-IFN/RBV/DAA therapy durations: a phase III study demonstrated 90% SVR rate for people with HCV genotype 1 (treatment naïve) treated with PEG/RBV and sofosbuvir (nucleotide analogue) with total treatment duration of only 12 weeks.
• IFN-free DAA regimens: There are several promising regimens in development. Sofosbuvir and ribavirin should be licensed by the US Food and Drug Administration in late 2013 for HCV genotype 2 (12 weeks) and HCV genotype 3 (16 weeks), based on SVR rates of around 90% for genotype 2 and 60% for genotype 3. Subsequent regimens will combine at least 2 DAA agents, possibly without the need for ribavirin, and possibly with activity against all HCV genotypes. 
• Over the next five to ten years there will be major improvements in hepatitis C therapy, with  simplified, short duration, probably once daily single combination pill dosing. Side effects and pill-burden (the number of tablets the person needs to take each day) will also reduce.

Preliminary evidence that IFN-free regimens are curative and the development of other promising once-daily agents shines a bright light on the way forward.

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What resources are useful?

Dore GJ. The changing therapeutic landscape for hepatitis C. MJA 2012; 196: 629-632.

Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368: 1878-87.

Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 2013; 368: 1867-77.

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Website

The Treatment Action Group in New York produces excellent community-based reports on hepatitis C treatment developments in their Pipeline Report series. See the chapter titled ‘Hepatitis C drug development goes from pony ride to rocket launch’ by Swan and Kaplan in the most recent report - HIV, Hepatitis C Virus (HCV), and Tuberculosis (TB) Drugs, Diagnostics, Vaccines, and Preventive Technologies in Development(Clayden et al. 2012) Go to the website for Pipeline Reports and updates

Source

Women With Chronic Hepatitis C Virus Infection

Southern Medical Journal

Recommendations for Clinical Practice

Mary Jane Burton, MD, James B. Brock, MD, Stephen A. Geraci, MD

South Med J. 2013;106(7):422-426.

Abstract and Introduction

Abstract

The natural history of hepatitis C virus infection differs between women and men. Women demonstrate a slow rate of disease progression until menopause. Older women are more likely to develop fibrosis and are less responsive than younger women to pegylated interferon and ribavirin. Women of childbearing age have higher rates of sustained virologic response, but current therapies are contraindicated during pregnancy. Vertical transmission of hepatitis C virus occurs, but data supporting recommendations for prevention of mother-to-infant transmission are limited.

Introduction

Approximately 3 million people in the United States are chronically infected with the hepatitis C virus (HCV),^[1] which is transmitted primarily through contact with the blood of an infected person. Acute infection resolves in approximately 20% of cases and the rest develop chronic infection.^[2] The major sequelae of chronic HCV infection are cirrhosis and hepatocellular carcinoma.^[2] The clinical course varies widely among individuals, with sex influencing the natural history and clinical outcomes. Understanding the unique features in women will assist clinicians in managing female patients with chronic HCV infection.

Prevalence and Natural History of HCV in Women

Since the implementation of blood product screening, injection drug use (IDU) has become the most common mode of HCV acquisition.^[1] Sex does not affect the risk of acquiring HCV. Although women in the United States historically have demonstrated a lower prevalence of HCV infection,^[3] their sex likely reflected their lower rate of IDU^[4] because sex differences in HCV prevalence are not seen in other cultures.^[5] In addition, a meta-analysis of 30 studies reported that female prison inmates are 40% more likely than are male prison inmates to be infected with HCV.^[6] Female injection drug users also exhibit higher rates of HCV infection than their male counterparts,^[7,8] a difference that is related to behavior rather than biology: Female injection drug users frequently share injection equipment and engage in unsafe sex practices,^[7,9] including having intercourse with people with whom they also inject drugs.^[10,11]

Although sex does not appear to affect the risk of HCV infection, it does influence its outcome. A systematic review of 31 longitudinal studies found that 40% of women versus 19% of men will resolve acute HCV infection.^[12] Genome-wide association studies have reported that genetic variation surrounding the interleukin-28B (IL-28B) locus is associated with enhanced response to interferon-based therapies and spontaneous resolution of HCV infection.^[13] A cohort study of Danish injection drug users noted that women with favorable IL-28B genotypes were six times as likely as women with unfavorable genotypes to spontaneously clear HCV infection;^[14] however, even when controlling for the IL-28B genotype, women remain more likely than men to spontaneously clear HCV infection.^[15]

Women also manifest slower progression to two major chronic HCV infection complications, cirrhosis and hepatocellular carcinoma. In a cohort of 376 Irish women chronically infected with HCV from contaminated anti-D immunoglobulin, only 1.9% had progressed to histological cirrhosis after a mean of 17 years following exposure.^[16] The low rate of fibrosis progression was confirmed in a 25-year follow-up study of 167 women, of whom 1.2% developed histological cirrhosis.^[17] Male sex was identified as an independent risk factor for developing hepatocellular carcinoma in several studies.^[18,19] This sex-specific predilection for complications of liver disease is not completely understood. Some experts posit that higher estrogen states exert a protective effect on the liver.^[20] Animal models suggest that estrogen suppresses hepatic fibrosis,^[21–23] and a recent in vitro study proposed that estrogen inhibits the production of HCV virions.^[24] Multiparous women exhibit lower stages of fibrosis than nulliparous women, and fibrosis progression accelerates after menopause.^[25,26] In observational studies, women who received hormone therapy (HT) appeared to have a slower progression to fibrosis;^[20] however, the benefits of HT in women with HCV have not been established. HT appears to be safe in women with liver disease when indicated for other reasons.^[20]

Modifiable Risks for Progression of Liver Disease

Excessive alcohol intake accelerates the progression to HCV-related cirrhosis. Studies demonstrate consumption of >30 g/day increases the risk for cirrhosis in hepatitis C threefold.^[27] Current guidelines stress the importance of abstinence from alcohol for all patients with HCV.^[28] Accumulating evidence suggests that women infected with HCV are more vulnerable than their male counterparts to the effects of alcohol.^[20] A prospective study illustrated that women who consumed >20 g/day doubled their risk for increased fibrosis, whereas men required >30 g/day to reach a similar risk increment.^[29] Healthcare providers should encourage women with chronic HCV to abstain from alcohol or, alternatively, to limit intake to an equivalent of 12 g/day of ethanol.

Increased body mass index (BMI) also appears to accelerate disease progression, regardless of sex. Multiple studies have illustrated an increased risk for progression of liver disease in patients who are overweight (BMI ≥ 25 kg/m²) or obese (BMI ≥ 30 kg/m²).^[30–32] In a small prospective study of patients with chronic hepatitis C, a mean body weight reduction of 5.9 (±3) kg resulted in lower alanine aminotransferase levels and reduced levels of fibrosis on liver biopsy;^[33] thus, even modest weight loss may reduce the risk of the progression of liver disease.

Effect of Sex and Age on Treatment Response

The primary goal of treatment of HCV is the prevention of cirrhosis and hepatocellular carcinoma by eradicating the virus. The surrogate marker for viral eradication is a sustained virologic response (SVR), defined as an undetectable serum HCV viral load 6 months after completing therapy. Studies of hepatic C therapeutics that examined SVR rates by sex reported conflicting findings. Overall, men and women appear to have equal responses to pegylated interferon and ribavirin.^[34,35] When stratified by age, however, SVR rates for women dramatically decline with older age, a phenomenon that has not been observed in men^[36–38] (). Similar to their protective effects on the progression of liver disease, higher estrogen states are hypothesized to promote SVR.^[37] Studies of telaprevir or boceprevir in combination with pegylated interferon and ribavirin illustrate equivalent response rates among men and women with genotype 1 HCV^[39–42] (). These studies did not further stratify women by age, although in some studies older age was associated with overall lower rates of SVR.^[35,43]

Table 1.  Studies that stratified sustained virologic response to interferon-based therapies by sex and age

Study	Women		P	Men		P
	Age group, y	SVR, %		Age group, y	SVR, %
Hayashi et al36	<40	75	<0.0001	<40	33	<0.001
	≥40	16		≥40	25
Sezaki et al37	<50	71	0.03	<50	69	0.41
	≥50	32		≥50	63
Villa et al38	Premenopausal	68	<0.0001	<45	59	0.114
	Postmenopausal	46		≥55	50

SVR, sustained virologic response.

Table 2.  Summary of SVR rates by sex for phase III studies examining the addition of telaprevir or boceprevir to pegylated interferon and ribavirin

Study	Drug	SVR rate, women (%)	SVR rate, men (%)
Treatment naïve
ILLUMINATE39	Telaprevir	77/89 (87)	169/197 (86)
SPRINT-240	Boceprevir	181/284 (64)	294/450 (65)
Treatment experienced
REALIZE39,41	Telaprevir	103/158 (65)	247/372 (66)
RESPOND-242	Boceprevir	68/118 (60)	134/210 (63)

ILLUMINATE, Illustrating the Effects of Combination Therapy with Telaprevir; REALIZE, Retreatment of Patients with Telaprevir-based Regimen to Optimize Outcomes; RESPOND-2, Retreatment with HCV Serine Protease Inhibitor and PegIntron/Rebetol 2; SPRINT-2, Serine Protease Inhibitor Therapy-2; SVR, sustained virologic response.

Pregnancy and Breast-feeding

Women with advanced liver disease are at increased risk for complications during pregnancy, but the effects of maternal HCV infection on natal outcomes are less well defined.^[44] Recent evidence suggests that HCV infection may increase the risks for gestational diabetes, low birth weight, and neonatal intensive care unit admission.^[45,46] Modifiable risk factors, such as IDU and limited prenatal care, may be more prevalent in patients with HCV,^[41] which could confound data on maternal and fetal outcomes.

Pregnancy may improve the natural course of HCV infection. In the second and third trimesters, alanine aminotransferase levels decrease, whereas serum levels of HCV RNA increase.^[47] This could imply that decreased hepatocyte damage, possibly related to increased estrogen levels and/or placental interferon production, occurs during pregnancy. Although alanine aminotransferase and HCV RNA serum concentrations return to prepregnancy levels within several months of delivery, women with multiple gestations do exhibit slower disease progression.^[21]

Vertical transmission is the major cause of HCV infection in children.^[45] Maternal–infant transmission occurs in roughly 5% of cases in which the mother is infected with HCV,^[48] but recommendations regarding prevention are limited by insufficient high-quality data. The timing of transmission also is poorly understood; evidence exists for both in utero and transvaginal transmission.^[49] Frequently identified risk factors for vertical transmission are high maternal HCV viral load and human immunodeficiency virus (HIV) co-infection.^[50,51] Prolonged rupture of membranes (>6 hours) has been associated with more frequent perinatal transmission.^[50] In addition, some experts recommend avoiding invasive procedures that promote fetal exposure to maternal blood, such as fetal scalp monitoring.^[50,52] Elective cesarean section has been proposed to reduce the risk of vertical transmission;^[53] however, this practice is not recommended for women infected with HCV unless they are co-infected with HIV.^[52] Some studies have reported that because an elevated serum viral load increases the risk of transmission,^[50,51] women who achieve remission from HCV before conception may reduce their risk of transmitting the virus to their fetuses.

Although HCV RNA has been detected in breast milk and colostrum,^[54] breast-feeding does not appear to be a primary route of maternal–infant HCV transmission.^[50,55] Some experts believe that the quantity of virions in these bodily fluids is insufficient to result in infection and that gastric acid exerts a protective effect.^[52] Mothers infected with HCV are encouraged to breast-feed in the absence of other contraindications, such as HIV-1 co-infection, but they should be counseled that there is limited study on this topic.^[56] The Centers for Disease Control and Prevention propose temporary interruption of breast-feeding when the mother has cracked, bleeding, or traumatized nipples, which could increase exposure of the infant to HCV.^[57]

Antiviral Therapy in Women

Choosing when to initiate HCV therapy in women can be challenging, particularly with regard to maternal age and family planning. There is evidence that advanced age decreases the likelihood of an SVR in women more so than in men.^[29,30] Given the risk of vertical transmission, it may be preferable to complete treatment in women of reproductive age before they conceive. Because use of ribavirin is contraindicated in pregnancy, women of childbearing age who are considering therapy for HCV require careful counseling regarding the potential danger to a child conceived during the treatment period.

Although ribavirin has not been studied formally in human gestation, several animal studies have demonstrated significant embryocidal and teratogenic effects; as a result, ribavirin is contraindicated during pregnancy (pregnancy category X).^[58] The serum half-life of ribavirin is 12 days; the drug also is pooled in erythrocyte populations, which can result in prolonged postadministration exposure.^[59] Two forms of effective contraception are required during and 6 months following therapy with ribavirin in women capable of conception.^[58] Women who are capable of conception should be aware that if their male partners are receiving ribavirin, then the use of two forms of contraception during and 6 months after treatment is recommended. In addition, women of childbearing age should take a pregnancy test before treatment initiation and submit to monthly pregnancy tests during the treatment period.^[58] Because ribavirin has not been studied in human pregnancy, women inadvertently exposed to ribavirin 6 months before or during pregnancy should consider enrollment in the Ribavirin Pregnancy Registry (www.ribavirinpregnancyregistry.com).

The effects of interferon on the fetus are uncertain (pregnancy category C). Interferon-[alpha] does not appear to cross the placental barrier or demonstrate teratogenic effects.^[60] Case studies of pregnant women with leukemia have not demonstrated fetal malformation associated with interferon use, but intrauterine growth retardation has been observed in this setting.^[61]

Boceprevir and telaprevir have been assigned to pregnancy category B by the Food and Drug Administration; however, these medications are administered exclusively with ribavirin and pegylated interferon-[alpha], precluding any use during pregnancy. Both drugs are potent CYP3A4 substrates and inhibitors, resulting in many potentially dangerous interactions with other drugs, including oral contraceptives. Telaprevir and boceprevir may cause systemic hormonal contraceptives to be unreliable during concurrent administration.^[62,63] Drosperinone concentrations double in the presence of boceprevir, contraindicating coadministration because of concern for potentiating hyperkalemia.^[63] Barrier methods and intrauterine devices are the preferred methods of contraception in women receiving boceprevir or telaprevir in combination with pegylated interferon-[alpha] and ribavirin.^[55,56] Given the wide range of drug–drug interactions involving these agents, close review of package inserts or consultation with a clinical pharmacist is recommended in patients receiving concomitant medications during therapy.^[64]

Conclusions

The natural history of HCV infection differs between women and men. Women are more likely than men to clear acute HCV infection. With chronic HCV infection, women experience a slower progression to cirrhosis and are less likely than men to develop hepatocellular carcinoma. Accelerated disease progression occurs in postmenopausal women; older women also have lower rates than younger women of SVR to pegylated interferon and ribavirin. Infected women of childbearing age should be educated about the risks of perinatal HCV transmission and the potential teratogenicity of current treatment regimens. All women with HCV should be counseled on the effects of alcohol and obesity on the progression of liver disease.

Sidebar

Key Points

• In the absence of comorbid conditions, women with hepatitis C virus (HCV) infection experience a slower progression to cirrhosis and a lower risk of hepatocellular carcinoma.
• Following menopause, the incidence of liver damage increases and women become less responsive to interferon-based therapies for chronic HCV infection.
• Abstinence from alcohol and maintenance of a healthy weight reduce the risk of liver disease progression in patients with chronic HCV.
• Achieving a sustained virologic response before conception may reduce substantially the risk of vertical HCV transmission; however, current therapies carry risks of fetal malformation.
• Fertile women who receive pegylated interferon and ribavirin should be counseled to use two forms of contraception. Because of drug–drug interactions with estrogen-based oral contraceptives, this form of birth control is unreliable in women receiving telaprevir or boceprevir.

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