March 4, 2014

Chronic hepatitis C virus infection: it is not only about the liver

Eur J Gastroenterol Hepatol. 2014 Mar;26(3):313-8. doi: 10.1097/MEG.0b013e328362dbff.

Vigani AG1, Tozzo R, Quezada A, Diaz AC, Mendes L, Lopes I, Riberio E, Espindola GM, Lopes FP, Petoilho EC, Queiroz JL, Castro HM.

Abstract

BACKGROUND AND AIMS: Although hepatitis B virus (HBV) and hepatitis C virus (HCV) are both hepatotropic and quite similar in terms of clinical manifestations and histopathology, their respective infections are distinct in terms of epidemiology and prognosis. Recognizing the differences between patients with HBV and HCV infection with respect to demographic characteristics, prevalence of comorbidities, and presence of lifestyle factors aids the proper treatment of these patients. We aimed to compare two populations with chronic viral liver disease (chronic HCV and chronic HBV), each of them with resolved hepatitis C.

PATIENTS AND METHODS: We included patients referred to a municipal reference clinic from March 2009 through May 2012. Patient data were collected using standardized questionnaires at the patients' first visit to clinic. Questionnaires included epidemiological information, presence of comorbidities, and lifestyle.

RESULTS: A total of 756 patients were included in the study, 348 (46.0%) with chronic HCV infection, 176 (23.3%) with chronic HBV infection, and 232 (30.7%) with resolved HCV infection. Multivariate analysis including patients with chronic HCV infection and chronic HBV infection indicated that age [adjusted odds ratio (AOR)=1.06; 95% confidence interval (CI): 1.03-1.08], alcohol abuse (AOR=1.58; 95% CI: 1.01-2.49), smoking (AOR=1.64; 95% CI: 1.00-2.17), and illicit drug (AOR=2.92; 95% CI: 1.69-5.02) use were associated independently with chronic HCV infection. Multivariate analyses including patients with chronic HCV infection and those patients with resolved HCV infection, presence of at least one comorbidity (AOR=1.94; 95% CI: 1.12-3.3), illicit drug use (AOR=3.24; 95% CI: 1.90-5.54), and age (AOR=1.03; 95% CI: 1.01-1.05) were independently associated with chronic HCV infection. Age (AOR=0.98; 95% CI: 0.96-0.99) and male sex (AOR=1.93; 95% CI: 1.26-2.95) were the only variables associated significantly with chronic HBV infection in the multivariate analysis between patients with chronic HBV infection and resolved HCV infection.

CONCLUSION: Our results highlight that patients with chronic HCV infection are complex and require a multidisciplinary approach during patient follow-up and clinical management.

PMID: 23719563 [PubMed - in process]

Source

Dig Dis Sci. 2014 Feb 27. [Epub ahead of print]

Liu G1, Holmberg SD, Kamili S, Xu F.

Abstract

BACKGROUND: The hepatitis C virus (HCV) antibody test alone does not distinguish current from resolved infections.

AIM: The study aimed to describe the percentage of current HCV infection, defined by HCV RNA positivity, among those tested positive for anti-HCV, and to examine characteristics of those with current infection.

METHODS: Using nationally representative data from the 2003 to 2010 National Health and Nutrition Examination Surveys, descriptive analyses and regressions were performed on data from anti-HCV-positive adults aged ≥40 years.

RESULTS: Of 13,909 participants examined, 304 were anti-HCV-positive. Of these, 238 or 75.3 % [95 % confidence interval (CI) 67.5-81.8 %] had detectable viral RNA. The percentage of current, unresolved HCV infection was highest among non-Hispanic Blacks (91.1 %) and lowest among those with a college education (57.3 %). In multivariate analyses, non-Hispanic Blacks were more likely to have current HCV infection compared to non-Hispanic Whites (adjusted odds ratio 3.9, 95 % CI 1.6-9.2). Among persons with current HCV infection, most had elevated alanine aminotransferase (56.5 %) or aspartate aminotransferase (71.8 %) levels, but only 35.3 % reported having been diagnosed with any abnormal liver conditions. Excessive alcohol drinking was reported by 27.3 % of participants with current HCV infection.

CONCLUSIONS: Among adults aged ≥40 years who had ever been infected with HCV, approximately three-quarters had current, unresolved HCV infection. Non-Hispanic Blacks were more likely to have current infection than non-Hispanic Whites. The majority of those with current infection had abnormal liver function tests but had not received appropriate diagnoses. Many currently infected persons would benefit from lifestyle modifications to avoid the multiplicative effect of alcohol on HCV infection.

PMID: 24573716 [PubMed - as supplied by publisher]

Source

21st Conference on Retroviruses and
Opportunistic Infections
Boston MA
March 3 - 6, 2014

Reported by Jules Levin

(All links open into new windows)

Source NATAP

Enanta Pharmaceuticals Announces New Data Presented on Protease Inhibitor ABT-493 at the 21st Conference on Retroviruses and Opportunistic Infections (CROI)

WATERTOWN, Mass.--(BUSINESS WIRE)--Mar. 4, 2014-- Enanta Pharmaceuticals, Inc., (NASDAQ: ENTA) a research and development-focused biotechnology company dedicated to creating small molecule drugs in the infectious disease field, today announced that new in vitro data on ABT-493, a potent NS3/4 protease inhibitor, was presented today during a poster session at the 21st Conference on Retroviruses and Opportunistic Infections (CROI) in Boston.

ABT-493 is a next-generation HCV NS3/4A protease inhibitor identified within the Enanta-AbbVie collaboration. Designed to enable once-daily dosing without ritonavir, ABT-493 is expected to be co-formulated with AbbVie’s next-generation NS5A inhibitor, ABT-530.

Data from poster number 636 titled “ABT-493, a Potent HCV NS3/4 Protease Inhibitor with Broad Genotypic Coverage”, demonstrates that ABT-493 has a substantially improved in vitro profile compared to earlier generation HCV NS3/4A protease inhibitors and displays potent and broad genotypic activity in genotypes 1a, 1b, 2a, 3a, 4a and 6a, against which many other HCV NS3/4A protease inhibitors have significantly lower potency.In vitro ABT-493 retains potency against most of the clinically important resistance-associated variants in genotype 1 and is fully active against variants resistant to NS5A or NS5B inhibitors. It demonstrates additive to synergistic antiviral activity in vitro when combined with next-generation NS5A inhibitor ABT-530.

About Enanta

Enanta Pharmaceuticals is a research and development-focused biotechnology company that uses its robust chemistry-driven approach and drug discovery capabilities to create small molecule drugs in the infectious disease field. Enanta is discovering, and in some cases developing, novel inhibitors designed for use against the hepatitis C virus (HCV). These inhibitors include members of the direct acting antiviral (DAA) inhibitor classes – protease (partnered with AbbVie), NS5A (partnered with Novartis) and nucleotide polymerase – as well as a host-targeted antiviral (HTA) inhibitor class targeted against cyclophilin. Additionally, Enanta has created a new class of antibiotics, called Bicyclolides, for the treatment of multi-drug resistant bacteria, with a focus on developing an intravenous and oral treatment for hospital and community MRSA (methicillin-resistantStaphylococcus aureus) infections.

Forward Looking Statement

This press release contains forward-looking statements, including with respect to our expectation regarding how ABT-493 will be co-formulated with ABT-530 and the prospects for ABT-493’s activity against multiple genotypes of HCV. Statements that are not historical facts are based on our management’s current expectations, estimates, forecasts and projections about our business and the industry in which we operate and our management’s beliefs and assumptions. The statements contained in this release are not guarantees of future performance and involve certain risks, uncertainties and assumptions, which are difficult to predict. Therefore, actual outcomes and results may differ materially from what is expressed in such forward-looking statements. Important factors that may affect actual results include results of further preclinical and clinical studies of ABT-493-containing regimens, the development, regulatory and marketing efforts of AbbVie (our collaborator on ABT-493 and on our collaboration’s initial protease inhibitor, ABT-450), and clinical development and marketing efforts of others for competitive product candidates. Enanta cautions investors not to place undue reliance on the forward-looking statements contained in this release. These statements speak only as of the date of this release, and Enanta undertakes no obligation to update or revise these statements, except as may be required by law.

Source: Enanta Pharmaceuticals, Inc.

Investor Contact
Enanta Pharmaceuticals, Inc.
Carol Miceli, 617-607-0710
cmiceli@enanta.com
or
Media Contact
MacDougall Biomedical Communications
Kari Watson, 781-235-3060
kwatson@macbiocom.com

Source

NATURE MEDICINE | SPOONFUL OF MEDICINE

04 Mar 2014 | 16:01 EST | Posted by Nicholette Zeliadt | Category: Policy

Bioethicists have long known about a potential regulatory loophole that excludes certain types of clinical trials from federal regulations designed to protect the safety of human research subjects in the US. However, the number of clinical trials that fell into this gap remained unknown. Now, a letter published online today in the Journal of the American Medical Association reveals just how many trials may fall outside federal government supervision at present.

In the US, two federal policies provide oversight for research involving people. One is the so-called Common Rule, which applies to the majority of human studies that are performed or funded by the federal government. The other is the set of regulations issued by the US Food and Drug Administration (FDA) that apply to human tests of drugs, devices and biological products such as vaccines regardless of funding source. Some clinical trials are subject to only one of these regulations; others are governed by both. However, some privately funded trials are neither subject to oversight by the FDA nor the Common Rule.

A team led by Deborah Zarin, director of the site ClinicalTrials.gov—a federal registry of publicly and privately funded human trials—decided to find out just how many active trials fall into each of the various categories of oversight. The researchers compiled a list of some 24,000 US-based clinical trials that were listed as active in that database as of 13 September 2013, and estimated that at least 19% of the sampled trials were covered by both policies. Furthermore, between 1,285 and 3,696 trials, or approximately 5%–16%, were not subject to the Common Rule or the FDA, because they weren’t federally funded and didn’t involve drugs, devices or biologics. “That might include things like surgical interventions,” Zarin says.

The unregulated trials raise concerns for human safety, says Robert Califf, vice chancellor for clinical research at Duke University in Durham, North Carolina. “Put yourself in the shoes of a person that volunteers for a study,” he says. “I think most people would agree it would be good to make sure that there’s an encompassing system so you can be assured that the institution that’s conducting the trial has agreed to a common set of rules about how human studies should be done.”

At the same time that Zarin voices concern about studies falling outside the regulatory domain of both the FDA and Common Rule, she says it’s not ideal for trials to be subject to oversight by both rules. This double oversight, according to Zarin, could create a potential burden to researchers due to differences in reporting requirements and extra paperwork: “When people consider possible changes to the regulatory framework, these are the kinds of things that should be thought about.”

Source

Insurers, Medicaid fear multibillion-dollar hepatitis C drug tab

BY CAROLINE HUMER
Tue Mar 4, 2014 10:58pm GMT

(Reuters) - U.S. health insurers are seeking help from state health officials to foot the bill for a new generation of hepatitis C treatments that could cost the nation $200 billion or more in the next five years.

Several insurers, including Molina Healthcare, which administer health plans for California's Medicaid program for the poor are asking states to step in and pay for Gilead Sciences Inc's Sovaldi, a drug that costs $84,000 per patient. The wrangling has reopened a national debate on how much the United States can afford to spend on the newest, costliest medications.

California, home to more than 9 million of the 62 million people who receive Medicaid benefits nationally, said it is still considering policies on how to reimburse for these new drugs. It is looking both at Sovaldi and a combination of the drug with Olysio from Johnson & Johnson.

Gilead and some health experts argue that the high price represents a worthwhile tradeoff, since the new treatments for the first time can cure nearly all patients who adhere to the 12-week course of drugs. That can help millions of Americans avoid repeated treatment with other therapies, as well as the more serious consequences of liver disease.

"Government systems ... will bear the long-term medical costs of liver cancer, liver failure and transplant, and therefore are the systems that will benefit most from the availability of new therapies for (hepatitis C)," Gregg Alton, executive vice president of corporate and medical affairs at Gilead, said in a statement.

At the same time, state and federally funded Medicaid programs have been straining under a slow economic recovery, repeated budget cuts and rising public-sector costs.

"The challenge is providing the most appropriate treatment for medical members that is also fiscally sound," said Tony Cava, a spokesman with the California Department of Healthcare Services in Sacramento. Cava said in a phone interview that the department received requests to separate, or carve out, the medication from several insurers' plans. Instead, patients would be reimbursed directly by the state for any drug costs.

As many as 3.2 million U.S. patients have hepatitis C. It can take 20 to 30 years for the virus to develop into more serious health problems such as cirrhosis or liver cancer and is the main cause of liver transplants.

Sovaldi was approved in December by the U.S. Food and Drug Administration. AbbVie Inc and Bristol-Myers Squibb Co have developed oral treatments for hepatitis C with cure rates in excess of 90 percent. They are expected on the market over the next year, while Merck & Co and Vertex Pharmaceuticals are also working on new therapies.

Sovaldi's price tag has made headlines, but the actual cost can be higher in many cases. Some patients must take the drug for longer than 12 weeks or require a combination of other drugs for it to be most effective.

Many doctors are requesting a $150,000 combination of Sovaldi (sofosbuvir) and Olysio (simeprevir). The FDA is expected to decide later this year on a Gilead combination drug that will have a similar effect.

A METEOR OUT OF THE SKY

Camilla Graham, co-director of the viral hepatitis center at Beth Israel Deaconess Medical Center at Harvard Medical School, fears that insurers will restrict the treatments.

"There is probably some price point where we as a society say we can afford to treat everyone with hepatitis C, like currently we say everyone needs to be treated with HIV," she said in a phone interview.

Graham estimates that treating two-thirds of U.S. hepatitis C patients at about $100,000 each would cost the country $200 billion. Doctors expect the disease to peak in 2019 or 2020.

Insurers that manage Medicaid plans, including HealthNet Inc, WellPoint Inc and Aetna Inc, say they are talking to the state-based agencies about how to manage these costs. The fear is that the true number of people infected with the virus is not known, making it hard to gauge whether they will lose money by covering the new drug costs.

Molina is based in California and has nearly 2 million Medicaid members nationwide. It has asked for carve-outs, or direct government reimbursements outside of its contracts in all of its 11 states, which also include Texas and Florida.

"The drug was approved in December and it was not factored into our rates for 2014. We are going back to the states and saying, 'How do you want us to handle this?'" said Chief Executive J. Mario Molina in a phone interview.

Medicaid programs nationwide are so far holding off on deciding. They are more likely to allow insurers to renegotiate contracts or build in additional payments based on the risk profiles of Medicaid recipients than turn to carve-outs, Matt Salo, executive director of the National Association of Medicaid directors said in a phone interview.

"We are sensitive to the potential that this is a meteor falling out of the sky and devastating a business model (for insurers) ... but I don't think we are there yet," Salo said.

WellPoint spokeswoman Jill Becher said in a statement that the Sovaldi approval was not included when it negotiated its Medicaid contracts or set rates in its commercial business. The company is covering the Sovaldi and Olysio combination for members with advanced liver disease.

Aetna is paying claims now on Sovaldi and said it will adjust guidelines as the other new drugs come onto the market. It is negotiating Medicaid coverage of the drug on a state-by-state basis.

Ed Pezalla, Aetna's national medical director of pharmaceutical policy, said in a phone interview that insurers are facing a deluge of hepatitis C patients as screening efforts for the disease ramp up, while people already diagnosed had been waiting for an easier-to-tolerate treatment.

Richard Esnard, a 73-year old retired policeman who lives in Rockland County, New York, is part of the early wave of patients who waited for Sovaldi after having failed to be cured in a clinical trial several years ago.

"After the clinical trial ended, there was a long period of time for me to recuperate and then in the interim these drugs became approved," Esnard said in a phone interview. He has a $15 co-pay for each of the three drugs he takes in combination: Sovaldi, Olysio and older drug ribavarin. The rest is covered by his primary and secondary Medicare plans as treatment for his advanced liver disease. "I'm lucky in that way," he said.

U.S. health officials have recommended that all baby boomers born between 1945 and 1965 be screened for the virus, estimating that more than 2 million of them may be infected.

(Reporting by Caroline Humer; Editing by Michele Gershberg and Jonathan Oatis)

Source

Your Liver Delivers Protect It From Harm

Provided by NIH News in Health

March 2014

feature1

Your liver works hard to protect your health. It’s a rugged, strong organ. But certain things—like alcohol, drugs, viruses, and excess weight—can damage it. You may not even realize when your liver is struggling, because liver disease usually has no symptoms until the problem becomes severe. Help your liver to guard your health by avoiding the things that might cause it harm.

The liver is the largest organ inside your body. It’s about the size of a football, and rests just under your ribs against the right side of your stomach.

“The liver performs an amazing set of functions that keep you healthy,” says Dr. Jake Liang, a liver specialist and researcher at NIH.

Your liver helps fight infections. It cleans your blood by getting rid of your body’s natural waste products and other harmful substances, including alcohol and drugs. “The liver also transforms the foods you eat into energy and nutrients your body can use, and it regulates how nutrients flow to different parts of the body when needed,” Liang says.

Your liver can keep working even if part of it is damaged or removed. But if it starts to shut down completely—a condition known as liver failure—you can survive for only a day or 2 unless you get emergency treatment.

Many things can affect liver function. Some liver problems are inherited from your parents, some are caused by viruses (certain kinds of hepatitis), and some are related to your behavior. Certain liver diseases go away on their own. Others can last a lifetime and cause serious illness.

Although liver disease often has no symptoms, warning signs can include a swollen abdomen, nausea, itching, or jaundice (having a yellow tint to the skin and the whites of the eyes).

NIH supports large research networks across the country to learn more about liver disease. For instance, teams of scientists nationwide have joined forces to study rare and often-deadly liver disorders that strike newborns and older children.

“Research networks are important because no single medical center has enough patients with rare diseases to do a rigorous study or test new treatments,” says Dr. Edward Doo, a liver disease expert at NIH. “With this large pediatric network, we can combine the efforts and expertise of many clinical centers that specialize in rare childhood liver diseases.”

Other NIH studies are focusing on an increasingly common type of liver disorder—known as fatty liver disease—that affects both children and adults. A healthy liver contains just a little fat or none at all. But too much fat buildup in liver cells can cause swelling and damage. Over time, the excess fat can lead to cirrhosis, liver cancer, and even liver failure.

“Estimates vary, but 2 different studies in the past decade suggest that about 30% to 45% of Americans have excess fat in the liver,” says Dr. Yaron Rotman, an NIH specialist in fatty liver disease. “It’s also becoming a huge problem for children and teens.”

Drinking too much alcohol can cause fatty liver. But a growing number of people who drink little or no alcohol are also being diagnosed with fatty liver. “The rise seems to be tied to the nation’s obesity epidemic,” says Doo.

Studies suggest that fatty liver disease now also affects about 1 in 10 children nationwide. As with adults, most children with fatty liver disease are overweight and resistant to insulin, a critical hormone that regulates energy.

In its early stages, fatty liver disease usually has no symptoms. It’s often first detected by blood tests for liver function. But these tests can’t tell the difference between mild fatty buildup and more serious damage. And some people with fatty liver disease can have normal blood tests. The only sure way to diagnose the severity of fatty liver disease is by getting a liver biopsy. For this test, a doctor inserts a thin needle through the skin and into the liver to remove a small piece of tissue for analysis.

NIH-funded scientists have been searching for simpler ways to measure the severity of fatty liver disease. They’re also conducting clinical studies to assess possible treatments. There are currently no approved medications for fatty liver or its more severe form called NASH, or non-alcoholic steato-hepatitis.

“To treat fatty liver disease, we recommend lifestyle changes: Weight loss for people who are overweight, and exercise and a healthy diet to help reduce fat,” Rotman says. “In many patients, just a 5-8% reduction in body weight will translate into a large improvement to liver damage.” For people with alcohol-related fatty liver, stopping alcohol use can reverse or prevent further liver injury.

Another common type of liver disease—known as viral hepatitis—can be caused by at least 5 different viruses, named hepatitis A, B, C, D, and E. These infections can injure your liver and keep it from working properly.

“Collectively, about 20% of people worldwide may be affected by a hepatitis virus infection,” Liang says. “It’s a major public health problem.” The most common types in the United States are hepatitis A, B, and C.

Each hepatitis virus causes a different form of liver disease. All the viruses can trigger acute, or short-term, hepatitis. Hepatitis B, C, and D can also cause chronic hepatitis, in which the infection lasts a long time, sometimes for your whole life.

People are often exposed to hepatitis A and E viruses through contaminated food or water. “The other hepatitis viruses often pass through some type of break in the skin barrier, sometimes by injections or by close contact with blood or other body fluids,” Liang adds. Hepatitis B, C, and D can spread through sexual contact.

Because many infected people have few symptoms, they may not realize they have viral hepatitis. They can spread the infection to others without even knowing it.

Viral hepatitis is often treated with antiviral medications. Hepatitis A, B, and D infections can be prevented by vaccines. Practicing good hygiene—such as washing your hands and avoiding contact with infected blood—can also help block the spread of viral hepatitis.

Another potentially dangerous type of liver disease can be caused by taking certain drugs or supplements. “It’s important to be aware that a lot of drugs can cause liver injury,” Liang says. “This especially can be a problem for people who are taking several different medications.”

Taking too much acetaminophen (Tylenol) is the most common cause of sudden liver failure. “It’s particularly dangerous if you mix alcohol with acetaminophen or certain other drugs,” Liang adds. Talk with your doctor or pharmacist about all the medications you take and how they might affect your liver.

Maintain a healthy weight, stay physically active, and limit your alcohol use. Keep your liver healthy, and it will protect you for a lifetime.

Source

Published: Mar 4, 2014
By Ed Susman , Contributing Writer, MedPage Today

BOSTON -- An all-oral, 12-week regimen appears to successfully treat hepatitis C virus (HCV) infection in about 90% of patients, researchers reported here.

Of the 166 treatment-naive patients in the study, 92% achieved a sustained virologic response at 12 weeks (SVR-12) on the combination of the investigative NS5A inhibitor daclatasvir, the protease inhibitor asunaprevir and the non-nucleoside BMS-791325, said Trevor Hawkins, MD, chief medical officer at Southwest CARE Center and professor of medicine at the University of New Mexico in Santa Fe.

"The observed analysis showed a 92% SVR12, and in the modified intent-to-treat analysis -- wherein data at week 12 is counted as failure if it is missing -- [it] was 89%," Hawkins toldMedPage Today at the annual Conference on Retroviruses and Opportunistic Infections.

A cure in the context of HCV is a sustained virologic response (SVR) -- defined as undetectable viral RNA at some prespecified point after ending therapy, usually 12 or 24 weeks.

At the end of treatment in Hawkins' study, 97.5% of those in the low-dose BMS-971325 group showed a complete viral response compared with 94.2% of those taking the high dose; the SVR4 was 92.4% in the low-dose group and 91.7% in the high-dose-treated patients. The SVR12was achieved by 92.2% in the low-dose treatment group and by 91.7% of those taking high-dose BMS-791325, the researchers reported.

In the trial, Hawkins said that 9% of the patients were diagnosed with cirrhosis. He said that there did not appear to be a difference in outcome among the cirrhotic patients compared with those who were not cirrhotic -- 13 of the 15 cirrhotic patients achieved an SVR12.

Hawkins said that the next trials -- called UNITY 1 and UNITY 2 -- will separate cirrhotic and noncirrhotic patients to examine if there are differences in outcomes depending on the extent of liver disease. These trials will use the 75-mg dose of BMS-791325.

The trial he reported here showed that patients were able to tolerate the regimen. "There were two discontinuations due to adverse events in the entire 166-patient cohort," he said at a press conference.

The patients diagnosed with HCV genotype 1 were randomly assigned to receive a twice-daily regimen of daclatasvir 30 mg, asunaprevir 200 mg and BMS-791325 at 75 mg or 150 mg for 12 weeks. Hawkins said outcomes were similar for the 80 patients on BMS-791325 given 75 mg twice daily and the 86 patients given BMS-791325 at a dose of 150 mg twice daily.

"There were 11 virologic failures and we attempted to find out if there were any predictors of failure," he said. "The only thing that appeared to predict failure was being of genotype 1a. We tried to determine if there were any polymorphisms at baseline that would predict virologic failure, but we were unable to do that. There really was no obvious correlation."

In pilot studies, the 24-week SVR was 94% and the 12-week SVR was 94% with use of the 75-mg dose of BMS-791325; with the 150-mg dose, the 24-week SVR was 94% and the 12- week SVR was 89%.

The patients were about 54 years old, 67% were men, 83% were white, 82% were genotype 1a, and 15 patients in the study -- 9% -- were diagnosed with cirrhosis.

"This looks good," press conference moderator Jean-Michel Pawlotsky, MD, of the Hôpital Henri Mondor Creteil/University of Paris-Est, told MedPage Today. "There are several potential combinations that are going to work in patients with HCV. This combination with three drugs has good potency and a high barrier to resistance. This is promising."

The study was sponsored by Bristol-Myers Squibb.

Hawkins disclosed commercial interests with Gilead, Janssen, AbbVie, Bristol-Myers Squibb, BMS, Vertex, GlaxoSmithKline, Sangamo, Salix, Merck and ViiV. Co-authors include Bristol-Myers Squibb employees.

Pawlotsky had no disclosures.

Source

HIV No Bar to HCV Therapy With New Agents

Published: Mar 4, 2014

By Michael Smith, North American Correspondent, MedPage Today

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BOSTON -- New drugs for hepatitis C mean HIV co-infection is no longer a barrier to successful HCV treatment, researchers said here.

Three studies using different medications in co-infected patients all found cure rates similar to the same drugs in people who had only HCV, according to Douglas Dieterich, MD, of Mount Sinai Hospital in New York City.

"All of these drugs work remarkably well in co-infection," Dieterich told reporters at the annual Conference on Retroviruses and Opportunistic Infections.

Dieterich presented some details of phase III studies of faldaprevir, an investigational HCV protease inhibitor used with pegylated interferon-alfa and ribavirin; simeprevir (Olysio), a protease inhibitor approved for use with interferon and ribavirin; and sofosbuvir, an HCV NS5B inhibitor used with ribavirin.

All three medications are "direct-acting agents" -- they target aspects of viral replication, in contrast to interferon, which boosts the patient's immune system, and ribavirin, which is a general antiviral drug.

In all three studies, Dieterich said, the rate of cure was "exactly the same in co-infected patients as they are in mono-infected patients." A cure in the context of HCV is a sustained virologic response (SVR) -- defined as undetectable viral RNA at some prespecified point after ending therapy, usually 12 or 24 weeks.

The results of the trials are "good news" but not entirely surprising, commented Jean-Michel Pawlotsky, MD, PhD, of Henri Mondor University Hospital in Créteil, France, who moderated a press conference at which some details were presented.

Investigators had been seeing similar results with the first approved direct-acting agents, the protease inhibitors telaprevir (Incivek) and boceprevir (Victrelis), Pawlotsky told MedPage Today.

But treatment just with peginterferon and ribavirin -- for years the only available HCV therapy -- was more difficult for people who also had HIV. "The main difference was due to interferon," Pawlotsky said. "These patients were not responding well to interferon."

One implication, he said, is that in the future, separate trials in co-infected patients might not be needed in order to get approval for new direct-acting agents.

"A trial in mono-infected patients might lead to approval for co-infected patients as well," he said.

Dieterich said the so-called STARTVerso4 was intended to test the efficacy and safety of two different doses of faldaprevir, in combination with peginterferon and ribavirin, in 308 patients with genotype 1 of HCV.

Almost all the patients -- 96% -- were also on highly active antiretroviral therapy for HIV.

The overall SVR rate 12 weeks after the end of treatment (SVR12), he said, was 72% and did not differ significantly between the two doses; phase III results in mono-infected patients were about 80%.

The simeprevir trial (dubbed Study C212) was also investigating the safety and efficacy of the drug among 108 HIV patients with genotype 1 HCV. The drug is approved for mono-infected patients.

In the trials used to support approval, the SVR rates were about 80% in treatment-naive and previously treated but relapsed patients, although they were lower -- 53% to 65% -- among patients who responded either partly or not at all to therapy with peginterferon and ribavirin.

In the co-infected cohort, Dieterich said, the SVR12 rate was 74%. Interestingly, a mutation that usually predicts poor response to interferon -- the Q80K polymorphism -- had no effect, he said, although its presence made a significant difference among mono-infected patients.

In both studies, the drugs were well-tolerated, he said, and the safety profile was similar to what has been seen in mono-infected patients, with most of the adverse events related to interferon.

The final study, dubbed PHOTON-1, looked at sofosbuvir and ribavirin in 223 co-infected patients with several HCV genotypes and differing treatment status.

But overall, he said, SVR12 rates ranged from 70% to 90%, depending on genotype, and in most cases were "exactly the same as in mono-infected patients." SVR24 rates did not change, except for one patient with genotype 1 who appeared to be re-infected after achieving SVR12.

The regimen, he noted, is the first interferon-free regimen to be tested in HIV/HCV co-infected patients.

The regimen was well-tolerated, he said, with only a handful of patients stopping treatment owing to adverse events.

Source

Stockholm, Sweden — Medivir AB (OMX: MVIR) today announced that study results from a phase IIa trial evaluating simeprevir, a once-daily protease inhibitor jointly developed by Janssen R&D Ireland and Medivir AB, in combination with daclatasvir, an investigational once-daily NS5A inhibitor developed by Bristol-Myers Squibb (NYSE: BMY), with and without ribavirin, in patients with hepatitis C (HCV) genotype 1 infection, have been presented at the 21th Conference on Retroviruses and Opportunistic Infections (CROI) on March 4th in Boston, USA. The study was conducted by Bristol-Myers Squibb.

Data from the study demonstrate that sustained virologic response 12 weeks after the end of treatment (SVR12) was reached in 75 to 85 percent of treatment-naïve patients and 65 to 95 percent of prior null responders with HCV genotype 1b after 12 or 24 weeks of treatment.

“We are pleased to report on the successfully completed exploratory phase IIa clinical trial of simeprevir and daclatasvir. The results are promising, but further studies would be required in order to fully assess the potential of the simeprevir/daclatasvir combination.” says Charlotte Edenius, EVP Development, Medivir AB.

Study Design
In this phase IIa open-label study, HCV genotype 1b treatment-naive patients (N=104) and prior null responders (N=43) were randomly assigned (1:1) to receive daclatasvir 30mg QD + simeprevir 150mg QD with or without ribavirin. Two treatment durations were evaluated: patients who completed 12 weeks treatment were re-randomized (1:1) to stop at Week 12 orcontinue treatment through Week 24.

In an exploratory evaluation of HCV genotype 1a patients, treatment naive (N=12) and prior null responder patients (N=9) received daclatasvir + simeprevir + ribavirin for 24 weeks.

Summary – Efficacy
In treatment-naïve HCV genotype 1b patients SVR12 was achieved by 75% (38/51) and 85% (45/53) when treated with simeprevir and daclatasvir, with or without ribavirin, respectively. In HCV genotype 1b prior null responders SVR12 was achieved by 95% (19/20) and 65% (15/23) with or without ribavirin, respectively. Estimated SVR12 rates in HCV genotype 1b patients (adjusted for pre-Week 12 discontinuations) were similar after 12 or 24 weeks of treatment in naive patients but higher after 12 than 24 weeks in prior null responders.

In treatment-naïve HCV genotype 1a patients 67% (8/12) achieved SVR12. All HCV genotype 1a prior null responders were offered pegylated interferon alfa-2a in addition to ribavirin + daclatasvir + simeprevir as rescue therapy due to frequent on-treatment breakthroughs and were counted as treatment failures.

Overall, patients were 92% white, 49% male, 21% cirrhotic, and 76% IL28B non-CC genotype and were well-balanced across treatment groups.

Summary - Safety
The all-oral combination of daclatasvir plus simeprevir, with and without ribavirin, was generally well tolerated. There were two treatment-related serious adverse events (neurotoxicity, liver disorder) and one on-treatment death (unrelated trauma-associated intracranial hematoma). Three patients experienced treatment-related adverse events leading to discontinuation. Seventeen patients experienced grade 3/4 total bilirubin elevations without concurrent transaminase elevations, mostly in patients receiving ribavirin (14/17), consistent with ribavirin-induced hemolysis and known effects of simeprevir on bilirubin transporters.

For more information please contact:
Rein Piir, EVP Corporate Affairs & IR, mobile: +46 708 537 292

Medivir is required under the Securities Markets Act to make the information in this press release public. The information was submitted for publication at 18.15 CET on 4 March 2014.

About Simeprevir
Simeprevir is an NS3/4A protease inhibitor jointly developed by Medivir and Janssen R&D Ireland for the treatment of chronic hepatitis C infection in combination with other antivirals in hepatitis C genotype 1 and 4 infected patients with compensated liver disease, including cirrhosis.

Simeprevir was approved for the treatment of genotype 1 hepatitis C in September 2013 in Japan and in the USA and Canada in November. A Marketing Authorisation Application was submitted to the European Medicines Agency (EMA) in April 2013 by Janssen-Cilag International NV seeking approval of simeprevir for the treatment of genotype 1 and and genotype 4 chronic hepatitis C. To date, more than 3,700 patients have been treated with simeprevir in clinical trials.

About Daclatasvir
Daclatasvir is an investigational NS5A replication complex inhibitor that has been studied in more than 5,500 patients to date as a foundational agent for multiple direct-acting antiviral-based combination therapies and is currently in phase III development. Daclatasvir has shown antiviral potency and pan-genotypic activity across hepatitis C genotypes in vitro. Daclatasvir has a drug-drug interaction profile that supports its continued study in a variety of hepatitis C combination regimens. Daclatasvir-based regimens are currently under review by regulatory authorities in Japan and Europe.

About Medivir
Medivir is an emerging research-based pharmaceutical company focused on infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company’s key pipeline asset is simeprevir, a novel protease inhibitor for the treatment of hepatitis C that is being developed in collaboration with Janssen R&D Ireland. The company is also working with research and development in other areas, such as bone disorders and neuropathic pain. Medivir has also a broad product portfolio with prescription pharmaceuticals in the Nordics.

For more information about Medivir AB, please visit the Company’s website: www.medivir.com

Medivir is a collaborative and agile pharmaceutical company with an R&D focus on infectious diseases and a leading position in hepatitis C. We are passionate and uncompromising in our mission to develop and commercialize innovative pharmaceuticals that improve people’s lives.

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The face of liver disease could be your own

March 4, 2014 5:59 AM

Canadian Liver Foundation urges Canadians to 'face facts' and recognize own risk factors

TORONTO, March 4, 2014 /CNW/ - Most Canadians are oblivious to their own risks of developing liver disease. Unfortunately, this 'who me?' attitude is leading to a rise in complications and deaths due to advanced liver disease. To help change attitudes, the Canadian Liver Foundation is using Liver Health Month to urge Canadians to recognize that liver disease may have many faces - even their own or someone they love.

"If you were to ask people on the street if they thought they needed to worry about liver disease, the answer would typically be 'no'," says Gary Fagan, president of the Canadian Liver Foundation. "This is alarming because liver disease is a much bigger issue in this country than anyone realizes. Unfortunately people don't understand their own risk factors and few have ever been tested."

The Canadian Liver Foundation is launching a campaign called 'Face it' to promote the facts about liver disease and show Canadians that the 'face' of liver disease might be more familiar than they think. The 'Face It' campaign will use social media to promote liver disease facts under the hashtag #faceliverdisease and will encourage people to visit www.liver.ca/facefacts to learn how to protect themselves and their families.

Currently fatty liver disease, hepatitis B, hepatitis C, liver cancer and alcoholic liver disease are the most common forms of liver disease in Canada. According to the CLF's report, Liver Disease: A Crisis in the Making, deaths from liver disease have risen by almost 30% in a period of only eight years.

"Liver disease is often overlooked and yet every week there are children, teens and adults who are diagnosed with genetic, autoimmune, viral, toxin or obesity-related liver disease," says Mr. Fagan. "There are simple blood tests that can detect problems with the liver but we hear countless stories from people that were stunned to find out they had severe liver disease despite having few, if any, symptoms," says Mr. Fagan. "We want people to face the facts about liver disease before it's too late."

Throughout the month of March, several leading health and wellness experts -- Rose Reisman, Theresa Albert, Bryce Wylde, Stephanie Joanne and Tosca Reno -- will be lending their support to the campaign by helping to dispel the myths and offering liver health advice.

"People are always flabbergasted to learn how many different things can impact your liver health - not the least of which being what you eat," says Theresa Albert, nutritionist, author and member of the CLF's National Board. "One of the best ways to get people thinking beyond the stereotype is asking them 'have you ever'  or ' do you ever' questions about diet,  medication, body art, sex, travel and so on. Once people see how the liver plays a vital role in day-to-day life, they're a step closer to taking action to protect their liver health."

For more information on the Face It campaign and Liver Health Month activities, visit www.liver.ca/facefacts

About the Canadian Liver Foundation
Founded in 1969 by a group of doctors and business leaders concerned about the increasing incidence of liver disease, the Canadian Liver Foundation (CLF) was the first organization in the world devoted to providing support for research and education into the causes, diagnoses, prevention and treatment of all liver disease. Through its chapters across the country, the CLF strives to promote liver health, improve public awareness and understanding of liver disease, raise funds for research and provide support to individuals affected by liver disease.

SOURCE Canadian Liver Foundation

For further information:

Melanie Kearns
416-491-3353 ext. 4923
mkearns@liver.ca

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