Gilead Reports Interim Data From Phase 2 LONESTAR Study

-- Company Plans to Initiate Phase 3 Study Evaluating Eight and 12 Weeks of Therapy with Sofosbuvir and Ledipasvir for the Treatment of Chronic Hepatitis C --

FOSTER CITY, Calif.--(BUSINESS WIRE)--May. 2, 2013-- Gilead Sciences (Nasdaq: GILD) today announced plans to initiate a third Phase 3 clinical trial of the company’s investigational fixed-dose combination tablet of sofosbuvir and ledipasvir for the treatment of chronic hepatitis C virus (HCV) infection. The study, called ION-3, will evaluate the once-daily fixed-dose combination of sofosbuvir and ledipasvir for eight weeks with and without ribavirin (RBV) and for 12 weeks without RBV in 600 non-cirrhotic, treatment-naïve genotype 1 HCV-infected patients.

The design of ION-3 was based on interim results from the Phase 2 LONESTAR study, which evaluated eight- and 12-week courses of therapy with the once-daily fixed-dose combination of sofosbuvir and ledipasvir with and without RBV in 60 treatment-naïve, non-cirrhotic patients.

In this study, 19/19 patients in the 12-week arm had a sustained virologic response four weeks after completing therapy (SVR4) and 40/41 in the eight-week arms had a sustained virologic response eight weeks after stopping therapy (SVR8), with one relapse occurring in the arm receiving sofosbuvir/ledipasvir without RBV.

Two additional cohorts in the LONESTAR study evaluated a 12-week course of the fixed-dose combination of sofosbuvir and ledipasvir with or without RBV in 40 patients who had previously failed therapy with an HCV-specific protease inhibitor-based regimen. Half of these treatment-experienced patients have documented, compensated cirrhosis. Ninety-five percent of patients in both arms achieved SVR4, one cirrhotic patient in the sofosbuvir and ledipasvir arm relapsed and one patient in the sofosbuvir and ledipasvir plus RBV arm was lost to follow-up.

Interim results from LONESTAR are summarized in the table below. Further details from this study will be presented at a future scientific meeting.

 

Treatment		Treatment Duration		Population		Results
Sofosbuvir + ledipasvir		8 weeks		GT 1 treatment-naïve		95% (19/20) SVR 8
Sofosbuvir + ledipasvir + RBV		8 weeks		GT 1 treatment-naïve		100% (21/21) SVR 8
Sofosbuvir + ledipasvir		12 weeks		GT 1 treatment-naïve		100% (19/19) SVR 4
Sofosbuvir + ledipasvir		12 weeks		GT 1 treatment-experienced		95% (18/19) SVR 4
Sofosbuvir + ledipasvir + RBV		12 weeks		GT 1 treatment-experienced		95% (20/21) SVR 4

“The LONESTAR results suggest that once-daily all-oral therapy with the nucleotide NS5B inhibitor sofosbuvir and the NS5A inhibitor ledipasvir may have the potential to cure most genotype 1 HCV infected patients with a remarkably short treatment duration,” said Eric Lawitz, MD, President and Medical Director, The Texas Liver Institute, University of Texas Health Science Center, San Antonio, and Principal Investigator for the LONESTAR study.

Both sofosbuvir in combination with ledipasvir, and sofosbuvir in combination with ledipasvir and RBV were well tolerated in the LONESTAR study.

“Based upon the encouraging data derived from LONESTAR, we are continuing to advance our research evaluating new drug combinations and shorter durations of all-oral therapy that have the potential to simplify treatment for those living with hepatitis C,” commented Norbert Bischofberger, PhD, Executive Vice President, Research and Development and Chief Scientific Officer at Gilead Sciences.

About ION-3

ION-3 is a randomized, open label Phase 3 clinical trial evaluating the efficacy and safety of sofosbuvir and ledipasvir for the treatment of chronic HCV in non-cirrhotic, treatment-naïve genotype 1 infected patients. Participants will be randomized to receive sofosbuvir and ledipasvir for eight weeks (n=200), sofosbuvir and ledipasvir plus RBV for eight weeks (n=200), or sofosbuvir and ledipasvir for 12 weeks (n=200). The primary endpoint of the study is SVR12, defined as maintaining undetectable HCV RNA 12 weeks post-treatment and considered a cure for HCV infection. The study is designed to assess non-inferiority of the eight-week treatment duration arms to the 12-week treatment duration arm.

Two other ongoing Phase 3 studies are examining all-oral HCV therapy with sofosbuvir and ledipasvir. ION-1 and ION-2 are testing 12- and 24-week courses of the fixed-dose combination with and without RBV among treatment-naïve and treatment-experienced genotype 1 HCV patients, including those with compensated cirrhosis. Based on the results of the LONESTAR trial, Gilead has amended ION-2 to shorten the duration of therapy in one of the two fixed-dose combination arms without RBV from 24 to 12 weeks.

Additional information about ION-1, ION-2, ION-3 and LONESTAR can be found at www.clinicaltrials.gov.

Sofosbuvir, ledipasvir and the fixed-dose combination tablet are investigational products and their safety and efficacy have not yet been established.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North America, Europe and Asia Pacific.

Forward-Looking Statement

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the possibility of unfavorable results from the clinical studies evaluating sofosbuvir and the sofosbuvir and ledipasvir fixed-dose combination, including from the ION-1, ION-2 and ION-3 and LONESTAR studies. Gilead also faces risks related to its ability to enroll patients in the ION-3 study, the need to modify or delay the study and the risk of failing to obtain approval of sofosbuvir and/or the sofosbuvir and ledipasvir fixed-dose combination from regulatory authorities. As a result, sofosbuvir and the sofosbuvir and ledipasvir fixed-dose combination may never be successfully commercialized. In addition, Gilead may make a strategic decision to discontinue development of these products if, for example, Gilead believes commercialization will be difficult relative to other opportunities in its pipeline. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Annual Report on Form 10-K for the year ended December 31, 2012, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

For more information on Gilead Sciences, please visit the company’s website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-80-GILEAD-5 or 1-650-574-3000.

Source: Gilead Sciences

Gilead Sciences
Patrick O’Brien, 650-522-1936 (Investors)
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Beta-blockers reduced bacterial translocation, improved intestinal permeability in cirrhotic patients

May 1, 2013

Patients with cirrhosis treated with beta-blockers experienced improved intestinal permeability and reduced bacterial translocation, reducing the risk for variceal bleeding, in a study presented at The International Liver Congress in Amsterdam.

In a study of 50 patients with cirrhosis, participants’ portal pressure, gastroduodenal and intestinal permeability and LPS-binding protein (LBP) and interleukin-6 (IL-6) levels were measured before and after treatment with nonselective beta-blockers (NSBB). Rates of bleeding and mortality were determined during follow-up.

Severe portal hypertension, defined as hepatic venous pressure gradient (HPVG) of 20 mmHg or greater, was observed in 35 cases. These patients had significantly higher urine sucrose levels (P=.049), sucrose/mannitol ratios (P=.007) and intestinal permeability indices (P=.002), as well as increased LBP (P=.002) and IL-6 levels (P=.025) compared with those with an HPVG less than 20 mmHg. Patients treated with NSBB experienced significant reductions to HVPG, LBP (–16%; P=.018) and IL-6 (–41%; P<.0001).

Those with abnormal gastroduodenal or intestinal permeability, as indicated by sucrose-lactulose-mannitol test results, trended toward increased incidence of variceal bleeding (P=.066 for gastroduodenal and P=.084 for intestinal permeability), as did those with elevated LBP (P=.18) and/or IL-6 (P=.038). Despite the increased incidence rate, none of these conditions was associated with increased mortality (P=.87 for gastroduodenal and P=.994 for intestinal permeability, P=.571 for elevated LBP and P=.594 for elevated IL-6).

“Beta-blockers have been successfully used … as a standard treatment to control blood pressure in other disease areas,” Mauro Bernardi, MD, treasurer of the EASL, said in a press release. “In cirrhosis, they have been used for decades for primary and secondary prophylaxis of bleeding from esophageal varices. The results of this study show that besides improving portal hypertension … their beneficial effects are also due to their ability to reduce bacterial translocation, which may widen the indication for the use of these drugs in this setting.”

For more information:

Reiberger T. #84: Improvement of Intestinal Permeability and Reducing Bacterial Translocation by Betablocker Treatment is Associated with a Lower Risk of Variceal Bleeding. Presented at: the International Liver Congress 2013; April 24-28, Amsterdam.

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Probiotics Cut Risk for Hepatic Encephalopathy in Half

Daniel M. Keller, PhD

May 01, 2013

AMSTERDAM, the Netherlands — Probiotics were effective in helping to prevent a first episode of overt hepatic encephalopathy in patients with cirrhosis, compared with patients not receiving probiotics, according to a new study.

"The patients in the control group had 2 times the chance of developing overt hepatic encephalopathy in the follow-up period," lead author Manish Lunia, MD, from the G.B. Pant Hospital in New Delhi, India, told delegates here at the International Liver Congress 2013.

It is estimated that hepatic encephalopathy occurs in 30% to 45% of patients with cirrhosis, and the mortality rate is 20% to 30%. Because bacterial overgrowth in the small intestine leads to endotoxemia, the researchers reasoned that probiotics could prevent the condition.

For their open-label, prospective, randomized trial, they enrolled patients 18 to 80 years of age with cirrhosis and no history of overt hepatic encephalopathy. A battery of psychometric tests, the critical flicker frequency test, and the psychometric hepatic encephalopathy score were used to diagnose encephalopathy. Glucose hydrogen breath tests were used to identify small intestinal bacterial overgrowth and lactulose hydrogen breath tests were used to identify orocecal transit time.

Study participants were randomly assigned to the probiotic group (n = 86) or the control group (n = 74). The researchers used the commercially available VSL#3, which is a mixture of nonurease-producing organisms: Streptococcus thermophilus and various species of Bifidobacterium and Lactobacillus (110 billion colony-forming units, 3 times daily).

There were no significant differences between the probiotic and control groups in terms of baseline age (about 44 to 47 years), sex, cause of cirrhosis, proportion of Child–Turcotte–Pugh classes, and model for end-stage liver disease (MELD) score. The groups also did not differ in various baseline laboratory parameters, such as small intestinal bacterial overgrowth (38.4% vs 35.1%) and the proportion of patients with minimal hepatic encephalopathy, defined as a psychometric hepatic encephalopathy score of 5 or lower (48.8% and 44.6%).

Patients were followed monthly for signs of overt hepatic encephalopathy or death (mean follow-up time, 38 to 40 weeks). Every 3 months, they underwent psychometric, arterial ammonia level, critical flicker frequency, glucose hydrogen, and lactulose hydrogen breath tests. Six probiotic patients and 5 control subjects were lost to follow-up.

More patients in the probiotic group than in the control group developed overt hepatic encephalopathy (8.8% vs 20.3%). Kaplan–Meier analysis revealed a hazard ratio for developing overt hepatic encephalopathy of 2.1 (95% confidence interval, 1.31 - 6.53; P < .05). There were fewer deaths in the probiotic group than in the control group (7.5% vs 11.5%).

A significantly greater proportion of patients with Child class B and C cirrhosis than with class A cirrhosis developed overt hepatic encephalopathy, but patients with Child class A and Child class B did not differ from each other (P = .36).

Table. Child Class Effect on Development of Hepatic Encephalopathy

Child Class of Cirrhosis	Proportion, %	P value (vs class A)
A	8.3	—
B	13.0	<.05
C	16.5	<.01

In the probiotic group, there were significant improvements from baseline to 3 months in arterial ammonia (P = .04), small intestinal bacterial overgrowth (P = .006), orocecal transit time (P = .05), psychometric hepatic encephalopathy score (P = .01), critical flicker frequency test (P = .02), and minimal hepatic encephalopathy (P = .001). In the control group, there were no significant differences from baseline in any of these parameters.

Factors significantly associated with the development of overt hepatic encephalopathy were minimal hepatic encephalopathy (adjust odds ratio [aOR], 3.1), Child–Turcotte–Pugh score (aOR, 1.6), small intestinal bacterial overgrowth (aOR, 2.1), and critical flicker frequency (aOR, 1.44).

Dr. Lunia reported that 5 patients with minimal hepatic encephalopathy or 31 patients without minimal hepatic encephalopathy would need to be treated to prevent 1 case of overt hepatic encephalopathy.

This study involved patients with a low level of hepatic encephalopathy at worst, and was therefore for prevention, not treatment, session moderator Isabelle Colle, MD, from Gent University in Belgium, who was not involved with the study, told Medscape Medical News. She explained that the use of probiotics is "certainly not" standard for such patients at this point.

She also questioned whether the use of probiotics in these patients is completely benign. "The gut permeability...is increased, so you can imagine that these bacteria can go through the intestine and cause bacterial translocation.... Do you see infections with this treatment?" she asked. It was a short study, and Dr. Lunia did not present any data on infections, Dr. Colle pointed out.

Dr. Lunia and Dr. Colle have disclosed no relevant financial relationships.

International Liver Congress 2013: 48th Annual Meeting of the European Association for the Study of the Liver (EASL). Abstract 78. Presented April 26, 2013.

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Combination Drugs are the Future of the European Hepatitis B and C Therapeutics Markets, Says Frost & Sullivan

Benefits include improved drug efficiency, reduced pill burden, and lower dosage frequency

LONDON, May 1, 2013 /PRNewswire/ -- The limited efficacy and negative side-effects associated with current therapeutics for Hepatitis B and C are highlighting the urgent need for new, improved alternatives. Combination therapies offering better clinical outcomes are coming to the fore and look set to transform the European market for Hepatitis B and C.

New analysis from Frost & Sullivan (http://www.lifesciences.frost.com), Analysis of European Hepatitis B and C Therapeutics Markets, finds that the Hepatitis B market earned revenues of $1.26 billion in 2012 and estimates this to reach $1.89 billion in 2019, while the Hepatitis C market is projected to expand from $2.40 billion to $3.66 billion over the same time period. The therapeutic segments covered include interferons and nucleoside analogues for Hepatitis B, and Standard of Care (Peginterferon alfa and Ribavirin) and protease inhibitors for Hepatitis C.

The side-effects associated with interferon-based therapeutics – such as fever, headache, fatigue, muscle and joint pain, shivering, and the ineffective response to Hepatitis C Virus (HCV) genotype 1 patients – are motivating the development of combination therapies.

"Improved drug efficiency, reduced pill burden and lower dosage frequency are among the common advantages related to the use of combination drugs," notes Frost & Sullivan Healthcare Research Analyst Deepika Pramod Chopda . "For instance, the combined use of interferon and interferon-free treatments is expected to yield positive results among infected patients; ribavirin-long acting interferons combination is estimated to boost the therapeutic success rate by over 50-60%."

The market is responding swiftly to the demand for improved therapeutic offerings. There has been an increase in new classes of compounds such as protease inhibitors, NS5a inhibitors, and nucleotide polymerase inhibitors for interferon-free treatment of HCV and Hepatitis B Virus (HBV).

At the same time, wider access to personalised medical treatment is encouraging the uptake of novel, improved therapeutics. The availability of drugs that target viral hepatitis infections according to distinct genetic strains is promoting market development.

HBV and HCV are prevalent among illegal drug users and migrant populations across Europe. However, low awareness means that many affected patients remain untreated.

"Wider access to national counselling programmes and enhancing awareness among high-risk populations such as drug users, infected mothers, and migrants is critical," concludes Chopda. "Such initiatives, together with free screening and reduced treatment costs, will help limit the incidence and impact of Hepatitis B and C."

If you are interested in more information on this research, please send an email to Anna Zanchi , Corporate Communications, at anna.zanchi@frost.com

Analysis of the European Hepatitis B and C Therapeutics Market is part of the Life Sciences Growth Partnership Service programme. Frost & Sullivan's related research services include: European HIV Drugs Market, European Hepatitis B and C Diagnostics Market, U.S. Hepatitis C Market, and U.S HIV/AIDS Therapies Market. All research included in subscriptions provide detailed market opportunities and industry trends that have been evaluated following extensive interviews with market participants.

About Frost & Sullivan
Frost & Sullivan, the Growth Partnership Company, works in collaboration with clients to leverage visionary innovation that addresses the global challenges and related growth opportunities that will make or break today's market participants.

Our "Growth Partnership" supports clients by addressing these opportunities and incorporating two key elements driving visionary innovation: The Integrated Value Proposition and The Partnership Infrastructure.

• The Integrated Value Proposition provides support to our clients throughout all phases of their journey to visionary innovation including: research, analysis, strategy, vision, innovation and implementation.
• The Partnership Infrastructure is entirely unique as it constructs the foundation upon which visionary innovation becomes possible. This includes our 360 degree research, comprehensive industry coverage, career best practices as well as our global footprint of more than 40 offices.

For more than 50 years, we have been developing growth strategies for the global 1000, emerging businesses, the public sector and the investment community. Is your organisation prepared for the next profound wave of industry convergence, disruptive technologies, increasing competitive intensity, Mega Trends, breakthrough best practices, changing customer dynamics and emerging economies?

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Addition of simeprevir to peginterferon/ribavirin improves SVR rate among HCV patients

May 1, 2013

Simeprevir improves rates of sustained virologic response and may allow for a 24-week treatment duration when added to interferon-based therapy for chronic hepatitis C, according to data presented at the International Liver Congress in Amsterdam.

In the double blind, phase 3 QUEST-1 study, researchers randomly assigned 394 treatment-naive patients with HCV genotype 1 to either 150 mg oral HCV NS3/4A protease inhibitor simeprevir or placebo, for 12 weeks, plus 48 weeks of pegylated interferon alfa-2a with ribavirin (PR). Patients with HCV RNA below 25 IU/mL after 4 weeks of treatment and undetectable RNA at 12 weeks stopped treatment at 24 weeks. All placebo recipients received 48 weeks of PR therapy.

Rapid virologic response occurred in 80% of simeprevir recipients and 12% of the placebo group. Sustained virologic response at 12 weeks after treatment was achieved by 80% of the simeprevir group and 50% of placebo recipients (P<.001). Most simeprevir recipients (85%) stopped treatment at 24 weeks. Patients treated with simeprevir experienced less on-treatment failure (9% vs. 34% of cases) and less relapse (9% vs. 21%).

Similar results were observed in the QUEST-2 study, in which researchers randomly assigned 391 treatment-naive patients to simeprevir or placebo in addition to therapy with peginterferon alfa-2a or alfa-2b with ribavirin. In this trial, RVR occurred in 79% of simeprevir recipients and 13% of the placebo group, and SVR at 12 weeks occurred in 81% of the simeprevir group and 50% of placebo recipients (P<.001). Most patients in the simeprevir group (91%) were able to stop therapy after 24 weeks. Rates of on-treatment failure (7% vs. 32%) and relapse (13% vs. 24%) also were lower among simeprevir recipients.

In QUEST-1, commonly reported adverse events included headache, fatigue and pruritus, with 3% of simeprevir recipients discontinuing treatment due to adverse events. Common events in the QUEST-2 trial included headache, fatigue, pruritus and flu-like illness, with similar incidence rates of adverse events regardless of the type of peginterferon administered.

“Simeprevir 150 mg QD was well tolerated, leading to a high SVR 12 rate … when administered with either [peginterferon alfa-2a or -2b],” the researchers wrote. “The majority of patients receiving simeprevir [were] able to shorten therapy to 24 weeks.”

For more information:

Jacobson I. #1425: Simeprevir (TMC435) With Peginterferon/Ribavirin for Chronic HCV Genotype-1 Infection in Treatment-Naive Patients: Results from QUEST-1, a Phase III Trial. Presented at: The International Liver Congress 2013; April 24-28, Amsterdam.

Manns M. #1413: Simeprevir (TMC435) With Peginterferon/Ribavirin for Treatment of Chronic HCV Genotype-1 Infection in Treatment-Naive Patients: Results from QUEST-2, a Phase III Trial. Presented at: The International Liver Congress 2013; April 24-28, Amsterdam.

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Alicia Keys launching HIV campaign aimed at women

By Saundra Young, CNN

updated 12:03 PM EDT, Wed May 1, 2013

"We can't act like it's not happening," Alicia Keys says of HIV. "We have to make sure we know that we're all at risk."

(CNN) -- You know her best as a multi-platinum recording artist and a 14-time Grammy award-winning singer, songwriter and producer.

But Alicia Keys has also made quite a name for herself as a philanthropist and AIDS advocate.

It was in 2003, on her first trip to Africa, when Keys witnessed firsthand the disease's devastation.

When she returned to the United States, she co-founded "Keep a Child Alive," an organization that has raised millions to care for HIV/AIDS patients in Africa and India.

"So, as I've grown, you know, I think one of the things that I've realized is that there are not the headlines about the AIDS pandemic here in America that there should be, and it is shocking, and it is unacceptable," Keys told CNN last month.

CDC: Half of young people with HIV don't know it

"Yet we're not speaking about it, and so that's what's kind of brought me around to really becoming a part of what I like to say, 'bridging the conversation' so that there's not only an international conversation, there's not only a domestic conversation, there's a global conversation that we can all be a part of."

Keys brought that conversation to Washington, where she met with women being treated at the United Medical Center's Infectious Diseases Clinic. She also teamed up with Greater Than AIDS, a national public information group founded by the Kaiser Family Foundation and the Black AIDS Institute, to launch her latest initiative -- a campaign aimed at reaching out specifically to American women.

It's called "Empowered" and phase one features a video of Keys and five women who are HIV-positive from all walks of life.

They include Stephanie, a college graduate diagnosed at 19; and Kym, diagnosed three years ago after her new husband got sick and died of the disease (she did not know he'd been HIV-positive for a decade).

Also included are Cristina, a graduate student born with the virus; Jen, a wife and mother who was diagnosed at 18; and Eva, a wife, mother, grandmother and home health care professional who found out she was HIV-positive when she was just 17 -- and pregnant.

The women share their stories and their determination to change the course -- and the face -- of HIV/AIDS.

Keys said she wants all women to know the facts about HIV and its impact on women; to be able to speak openly about the disease with family and friends; to protect themselves and their loved ones; to get tested without shame; and to live rich, healthy lives by getting and staying on treatment.

Why youths aren't getting tested for HIV

"We can't act like it's not happening. We have to make sure we know that we're all at risk. This is all of our issues, you know. This doesn't make you bad. ... You shouldn't feel like you're ashamed. We have to make sure that we are demanding access to being tested. We have to demand access to treatment with dignity."

She found an ally in senior White House adviser Valerie Jarrett, whose passion about the epidemic inspired her. Part of that passion, Jarrett said, comes from losing her sister-in-law nearly 20 years ago to the disease.

"She was married with a young child and didn't really get the testing that she should have had early on in her illness because it never occurred to anyone that a married mom would actually ... be HIV positive," Jarrett told CNN.

"Losing her was just devastating for our family and so that's where I began to realize, of course, this could happen to anybody's family."

More than 1.1 million Americans are HIV positive, according to the Centers for Disease Control and Prevention. One in five don't know they're infected. One in four people living with HIV is a woman.

In Washington, one of the hardest-hit areas in the country, rates among African-American women have skyrocketed -- more than 92% of women living with HIV there are black. It was here, last year, that Keys and Jarrett came together and decided to support each other's efforts.

President Barack Obama is committed to the goal of an AIDS-free generation and will do everything in his power to eradicate the disease, according to Jarrett. That includes $23 billion for HIV in next year's proposed budget. But, said Jarrett, HIV still has to be brought out of the shadows.

Timeline: AIDS moments to remember

"We can't pretend it doesn't exist," Jarrett said. "When people share these stories, it de-stigmatizes it, it brings it out in to the light and when we do that, we improve the quality of life that all people will have."

For its part, Empowered will provide community-based grants of up to $25,000 for programs focused on women. That, Keys hopes, will help open up a meaningful dialogue in this country.

"For a woman and a black woman, you know, this is a conversation that we must have as all women. Again, as all human beings, we have to have this conversation," she said.

"I feel like this is an incredibly wonderful opportunity that we have to have a real dialogue, woman to woman, mother to mother, sister to sister, brother to sister ... father to daughter, daughter to mother, you know, friend to friend. This is what we have to start absolutely being open about."

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Targeted drugs to tackle hepatitis C

But experts debate US screening recommendations.

Beth Mole

01 May 2013

John strains to recall the gap between learning that he had hepatitis C and deciding to get treated: it was either four years or five. His thinking is clouded by the combination of three drugs that he is taking to clear the infection. After the treatments’ other side effects set in — severe flu-like symptoms, depression and exhaustion — he took leave from his job as a chef in New York. John, whose name has been changed to protect his privacy, was at high risk of catching the virus, having once been addicted to crystal methamphetamine. But as a 51-year-old, he is also a baby boomer — a member of the generation born between 1945 and 1965 — millions of whom will face the disease and its sometimes harrowing treatment.

Better drugs are on the way. But the possibility of improved treatment is intensifying a debate about whether to screen a broad swathe of the US population for hepatitis C.

Last month, the pharmaceutical company Gilead, based in Foster City, California, submitted its hepatitis-C drug sofosbuvir to the US Food and Drug Administration for approval, after phase II trials showed a 100% success rate in a few patient groups when it was used in combination with existing drugs. Last week, the first phase III results showed similarly promising results (E. Lawitz et al. N. Engl. J. Med. http://doi.org/mcc; 2013).

The drug is one of at least ten in phase III trials in the United States that promise to improve results or reduce side effects. The first of these drugs could reach the market as early as 2014, and a recommendation from the US Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, to screen an entire generation for the disease could create vast demand for them.

John is a part of a demographic time bomb. Up to 4 million Americans are infected with hepatitis C, which can irreparably damage the liver and lead to liver cancer, but because it inflicts injury slowly over decades, as many as 85% of carriers do not know that they have it. Baby boomers account for about 27% of the US population, but up to 75% of those infected with hepatitis C, possibly because injecting drugs — one infection route — was more common during their youth than in other eras. Last August, the CDC recommended screening the entire generation of people born between 1945 and 1965, as well as people in high-risk populations such as intravenous-drug users. The CDC predicts that generational screening would find an extra 800,000 cases and prevent at least 120,000 deaths. “We have an opportunity to make a real dent in the impact of the disease,” says Kimberly Page, an epidemiologist at the University of California, San Francisco.

Source: G. L. Davis et al. Gastroenterology 138, 513–521 (2010)

John’s doctor, infectious-disease specialist Kristen Marks of Weill Cornell Medical College in New York, says that screening is especially important for baby boomers because early symptoms of hepatitis C, such as fatigue and malaise, are difficult to distinguish from signs of ageing. People dismiss symptoms, says Marks, and some might not remember trying intravenous drugs in their youth. Even if they do, she adds, “they might not tell their doctor”. A peak in cases of liver scarring from untreated hepatitis C is expected in the next few years (see ‘An approaching burden’). But with the new drugs on the horizon, now is an optimistic time for treatment, says Marks. “Historically, not having good treatments was a disincentive for screening,” she says. “Now, I think there’s a renewed interest.”

But last November, the US Preventive Services Task Force (USPSTF), a panel of experts assembled by the US Department of Health and Human Services, released a draft statement giving the screening recommendation a ‘grade C’. That means that doctors should consider birth year when deciding whether to offer screening, but should take other factors into account. The mediocre grade could discourage many health-care providers — including Medicaid, the provider for people with low incomes — from pushing screenings.

As with its controversial recommendations in 2009 and 2012 to limit screening for breast and prostrate cancer, the USPSTF has tried to balance the benefits of screening against its costs and the risk of unnecessary treatment. The combination therapies used to combat hepatitis C can cost US$1,100 per week and last for up to a year, with severe side effects. Other treatments cost $4,100 per week. (Gilead declined to comment on the future price of sofosbuvir-based treatments.)

“We have an opportunity to make a real dent in the impact of the disease.”

Roger Chou, an internal-medicine specialist at Oregon Health and Science University in Portland and a scientific reviewer for the USPSTF, adds that in most patients, the disease is imperceptible: only 20% of people develop liver scarring in the first 20 years of infection, according to the CDC. Of the few baby boomers that might be caught through additional screening, says Chou, some will not need to be treated.

But new drugs, however expensive, could change the calculus for doctors and patients, says Mark Eckman, a physician at the University of Cincinnati in Ohio, who has calculated that even screening the entire US population would be cost effective given the financial and personal burdens of living with liver diseases (M. H. Eckman et al. Clin. Infect. Dis. 56, 1382–1393; 2013).

For example, sofosbuvir, which is one of a set of new antiviral drugs that specifically target hepatitis C rather than viruses in general, can achieve success rates above 90% in combination treatments of just three months. The drug inhibits the virus’s RNA polymerase, preventing viral replication. It is also being tested without the classic combination drug of pegylated interferon, which boosts the immune system but causes harsh side effects.

The USPSTF is still reviewing its draft recommendations, but it is likely to make a final decision in the next few months, well before approval of sofosbuvir or other new drugs could alter the calculations.

That is too bad, says David Thomas, a viral-hepatitis specialist at Johns Hopkins University in Baltimore, Maryland, who argues that the next generation of drugs helps to justify wide-scale screening. “It makes a pretty easy case for doing something different,” he says.

Nature 497, 18–19 (02 May 2013) doi:10.1038/497018a

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Sharecare Names Top 10 Social HealthMakers in Hepatitis C

PRESS RELEASE

May 1, 2013, 8:00 a.m. EDT

Today's 48- to 68-Year-Olds 5 Times More Likely Than Other Adults to Have Hep C

ATLANTA & SAN FRANCISCO, May 01, 2013 (BUSINESS WIRE) -- --May is Hepatitis Awareness Month--

According to the Centers for Disease Control and Prevention (CDC), people born between 1945 and 1965 are 5 times more likely than other adults to have hepatitis C--in fact, roughly 120,000 deaths could be prevented if all baby boomers were tested for hepatitis C. In light of these startling statistics, Sharecare, the health and wellness social network, has released its Top 10 Social HealthMakers in Hepatitis C. These informed individuals are leading online conversations about hepatitis C, providing invaluable insights on symptoms, treatment, support, and living with the virus.

Among them is a nurse who has treated and been treated for hepatitis C, a HepMag.com guest blogger who beat the virus with protease inhibitors, and an educator who has lived with the condition for 20 years. "Thanks to the latest treatments, four out of five HCV patients can spend the rest of their lives free of the disease," said Lucinda K. Porter, RN, #1 on the Sharecare Social HealthMakers list.

For Hepatitis Awareness Month in May, here are the Top 10 Social HealthMakers in Hepatitis C to follow:

1. Lucinda K. Porter, RN - LucindaPorterRN.com and HepMag.com

-- An RN, educator, consultant and author of Free from Hepatitis C who contracted hepatitis C in 1988, Porter served as clinical research nurse at Stanford's hepatology division and is active in hepatitis C support. Her second book Hepatitis C Treatment One Step at a Time: Inspiration and Practical Tips for Successful Treatment will be published September 2013.

2. John D. Carroll - FierceBiotech.com

-- FierceBiotech.com editor and a biotech analyst with 34 years prize-winning experience in journalism often covering hepatitis C drug releases and clinical trials, Carroll has written for Time magazine and The Dallas Morning News.

3. Margaret Dudley - Hepc-cured.com and HepMag.com

-- After contracting the virus via a tattoo needle and enduring the condition for six years before diagnosis, Dudley founded HCV Coalition for the Cure, petitioning to bring treatments to market.

4. Liz Highleyman - HIVandHepatitis.com

-- Freelance writer, editor and educator in public health, hepatitis B and C, HIV/AIDS, Highleyman is editor-in-chief of HIVandHepatitis.com and has written for HCV Advocate.

5. Adam Feuerstein - TheStreet.com

-- As senior columnist for The Street, Feuerstein reports on biotech stocks, including updates on hepatitis C drug releases and clinical trials.

6. Alan Franciscus - HCVadvocate.org

-- Franciscus is executive director of The Hepatitis C Support Project, which provides unbiased information, support and advocacy.

7. Karen Hoyt - iHelpC.com and HepMag.com

-- Founder of iHelpC.com, Hoyt beat the virus with protease inhibitors; she also guest blogs for HepMag.com.

8. Joseph S. Galati, MD - TexasLiver.com

-- A Houston-based liver disease specialist who has devoted his practice to the care of patients with acute and chronic liver disease, Dr. Galati also hosts a weekly health radio show, "Your Health First... with Dr. Galati."

9. Connie Welch - LifeBeyondHepatitisC.com

-- Blogger, sheep wrangler and educator who has lived with hepatitis C for 20 years.

10. Tom Horn - Treatment Action Group

-- Horn, a 20-year survivor of HIV, is the HIV Project Director for the Treatment Action Group (TAG) and writes for POZ.com and HepMag.com, addressing the importance of hepatitis C (HCV) testing, HIV/HCV co-infection and the staggering statistics around HCV infection.

Complete background information about all 10 Social HealthMakers in Hepatitis C can be found here: www.sharecare.com/static/top-ten-social-healthmakers.

Methodology

Sharecare Social HealthMakers (formerly SharecareNow) are among the most influential people in health and wellness on the Web, literally driving "conversations on the leading edge." They address a wide range of issues within specific topic areas while demonstrating consistent impact across multiple interactive channels--such as Twitter, Facebook, video and blogs. This impact is measured through a proprietary algorithm based on more than 100 individual metrics developed and powered by WCG, the marketing-leading digital communications agency, quantifying topic relevance, syndication, presence and reach. Prior Sharecare lists have identified Social HealthMakers in weight loss, infertility, heart disease, fitness, Alzheimer's disease and more.

About Sharecare

Sharecare is a health and wellness social network that connects people with experts, ranging from doctors and specialists to hospitals, healthcare companies and health-conscious consumers. The power behind the site's unique Q&A format is its collective wisdom, providing health-seeking consumers with answers reflecting multiple expert perspectives--greatly simplifying the search for quality information. Created by Jeff Arnold and Dr. Mehmet Oz in partnership with Harpo Productions, Sony Pictures Television and Discovery Communications, Sharecare allows people to ask, learn and act upon questions of health and wellness, creating an active community where knowledge is shared and put into practice--simply said, sharing care. Launched in 2010, Sharecare is based in Atlanta, GA.

-- Follow us on Twitter @SharecareNow

-- Like us on Facebook

-- Connect with us on LinkedIn

-- Read our Sharecare Blog

-- Watch us on YouTube

About WCG

Founded and led by chairman and CEO Jim Weiss, WCG is focused on integrated business solutions in the areas of innovation, change and growth for the world's leading companies and brands. WCG serves clients through a network of offices in San Francisco, New York, Chicago, Washington, D.C., Austin, Los Angeles and London. For more than a decade, WCG's seasoned professionals have specialized in providing analytics, content, engagement and strategy to a diverse set of clients across the consumer, technology, healthcare and pharmaceutical industries.

-- Follow us on Twitter: @wcgworld

-- Find us on Facebook

-- Read our CommonSense Blog

http://cts.businesswire.com/ct/CT?id=bwnews&sty=20130501005459r1&sid=cmtx4&distro=nx

SOURCE: Sharecare

Source

Hepatitis Outreach Network: A practical strategy for hepatitis screening with linkage to care in foreign-born communities

Journal of Hepatology
Volume 58, Issue 5 , Pages 890-897, May 2013

Ponni V. Perumalswami,  Stephanie H. Factor, Luciano Kapelusznik, Scott L. Friedman, Calvin Q. Pan, Charissa Chang, Frances Di Clemente, Douglas T. Dieterich

Division of Liver Diseases, The Mount Sinai Medical Center, Mount Sinai School of Medicine, NY, United States

Received 24 August 2012; received in revised form 26 December 2012; accepted 7 January 2013. published online 16 January 2013.

Abstract

Background & Aims

Many foreign-born persons in the US are at high risk of chronic hepatitis B (HBV) and C (HCV) infections, yet are not aware of their infection, and lack healthcare coverage or linkage to care.

Methods

A unique partnership, the Hepatitis Outreach Network, combines the expertise and resources of the Mount Sinai School of Medicine, the NYC Department of Health and Mental Hygiene, and community-based organizations, to provide education, screening and link to care in communities with high prevalence of chronic viral hepatitis. Comprehensive HBV and HCV screening identifies infected patients, who then receive further evaluation from either local or Mount Sinai physicians, combined with patient-navigators who organize follow-up visits.

Results

Of 1603 persons screened, 76 had HBV and 75 had HCV. Importantly, screening for HCV based on traditional risk factors would have missed 67% of those who tested positive. Of the 76 persons with HCV infection, 49 (64%) received a medical evaluation (26 with local providers and 23 at Mount Sinai). Of the 49 HCV-infected persons evaluated, treatment was recommended in 11 and begun in 8 (73%). Of the 76 persons with HBV infection, 43 (57%) received a medical evaluation (31 with local providers and 12 at Mount Sinai). Of the 43 HBV-infected persons evaluated, treatment was recommended and begun in 5 (100%).

Conclusions

Hepatitis Outreach Network has successfully established novel proof of concept for identifying HBV and HCV infections in foreign-born persons through use of several unique elements that effectively link them to care.

Keywords: Epidemiology, Patient navigators, Viral hepatitis, Testing, Treatment

PII: S0168-8278(13)00017-2

doi:10.1016/j.jhep.2013.01.004

© 2013 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved

Source

HIV-Infected Men at Increased Risk for Cancer

Jim Kling

Apr 30, 2013

BERLIN, Germany — HIV-infected men are at twice the risk for non-AIDS defining cancers as the general population, but highly active antiretroviral therapy has a protective benefit, according to a new study.

Little is known about how HIV infection affects the risk for non-AIDS defining cancers that don't have an infectious component. "HIV patients are living longer, and they live with chronic diseases that can compromise the immune system. People with impaired immunologic status are at increased risk for lung cancer," Laura Albini, PhD, professor of infectious diseases at the University of Brescia, Italy, told Medscape Medical News.

She presented the study results here at the 23rd European Congress of Clinical Microbiology and Infectious Diseases.

Dr. Albini and her team conducted a retrospective analysis of 5090 HIV-infected patients registered in the Local Health Authority of Brescia in Northern Italy. The researchers linked their own clinical database to the Local Health Authority general database and the Local Health Authority population-based cancer registry to diagnose nonvirus-related non-AIDS defining cancers.

They used Poisson regression to compare the risk for cancer in people infected with HIV and those in the general population living in the same geographic region.

There were 138 cancers diagnosed in 131 patients over the course of the study (42.6 per 10,000 person-years; median age at diagnosis, 49 years). The most common cancers were nonmelanoma skin (29.7%), lung (16.7%), and breast (7.3%).

More Lung Cancer

Males were at higher risk for cancer (standardized incidence ratio [SIR], 1.86; 95% confidence interval [CI], 1.55 - 2.26) than people in the general population. They also had an increased risk for lung cancer (SIR, 3.59; 95% CI, 2.36 - 5.45) and testis cancer (SIR, 3.11; 95% CI, 1.48 - 6.52).

There were no differences in prostate and breast cancers in HIV-positive men (SIR, 1.10; 95% CI, 0.53 - 2.32) and women (SIR, 0.91; 95% CI, 0.47 - 1.74).

Predictors of nonvirus-related non-AIDS defining cancers included older age (incidence rate ratio [IRR], 1.10; 95% CI, 1.08 - 1.12 for each additional year) and a shorter duration or lack of exposure to highly active antiretroviral therapy (IRR, 2.31; 95% CI, 1.38 - 3.89; P = .002). Severe immunodeficiency (CD4+ count below 50 cells/mm³) was associated with malignancies, but only in the univariate model (IRR, 1.40; 95% CI, 0.99 - 1.98; P = .057).

The increased risk for lung cancer is likely due, in part, to the fact that smoking is a common habit, but immunodeficiency also likely plays a role, according to Dr. Albini.

The results of this study are similar to those from other studies of cancer incidence in HIV-infected individuals, "although there are some differences. Other studies have shown increases in breast cancer, but this one does not," session moderator José Miró, MD, PhD, professor of medicine at the University of Barcelona in Spain, told Medscape Medical News.

The results underscore the importance of lung cancer screening in HIV patients, Dr. Miró added. "Lung cancer is really epidemic in the HIV population. Physicians should use appropriate diagnostic tools if there are any symptoms suggesting lung cancer."

Dr. Albini and Dr. Miró have disclosed no relevant financial relationships.

23rd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID): Abstract O155. Presented April 27, 2013.

Source

Embolizing Vascular Shunts Relieves Hepatic Encephalopathy

Daniel M. Keller, PhD

Apr 30, 2013

AMSTERDAM, the Netherlands ― Embolizing large spontaneous portosystemic shunts can relieve hepatic encephalopathy and can keep many patients free of it for as long as they have sufficient functional liver reserve, a new study has shown.

In the 100 days after embolization, 60% of patients were free of hepatic encephalopathy. During the overall follow-up of more than 2 years, that was reduced to still a very impressive 49%. Compared with the 2-year period before embolization, both reductions were significant (P < .001), reports Wim Laleman, MD, PhD, from the Department of Liver and Biliopancreatic Disorders at University Hospitals Leuven and the Catholic University of Leuven in Belgium.

Dr. Laleman presented the study results here at the International Liver Congress 2013.

The retrospective study involved men and women from a European multicenter cohort with cirrhosis, refractory encephalopathy, and large spontaneous portosystemic shunts that were amenable to angiographic embolization. Patients were excluded if they had a surgical shunt or transjugular intrahepatic portosystemic shunt graft, portal vein thrombosis, or hepatocellular carcinoma.

Most of the cirrhosis was caused by alcohol abuse or hepatitis C. Child–Pugh score before embolization was 7.9, and model for end-stage liver disease (MELD) score was 13.2 (range, 5 - 28).

In 37 of 38 patients, embolization was achieved with a percutaneous, transhepatic, or femoral vein approach using coils, Amplatzer plugs, or matrix. The most common spontaneous shunt was splenorenal (n = 20); the rest were mesentericocaval, periumbilical, or mesentericorenal.

In addition to the reduction in hepatic encephalopathy, embolization was associated with a reduction in the number of hospitalizations, from 3.8 in the preprocedure period to 1.3 in the follow-up period (P < .001). Hospital days were reduced from 41.0 to 17.8 (P >.001).

Quality of Life

Dr. Laleman explained that quality of life is very important in the context of hepatic encephalopathy. Before embolization, almost 73% of patients had limited quality of life and were in need of help with daily activities. After embolization, only 25% of patients had limited quality of life. Autonomy increased from 21.6% of patients to 64.9%, but there was no change in complete disability (about 10% before and after embolization), he reported.

Near-term safety was excellent. There was no mortality and 8 procedure-related complications, only 1 of which was serious (hypovolemic shock after a transhepatic approach that resolved after surgical hemostasis).

Dr. Laleman put to rest concerns about possible long-term complications of worsening liver function, thrombosis, and portal hypertensive complications. "There was no increase in the presence of gastroesophageal varices and no increase in gastropathy (2 patients developed de novo varices, but this was not considered statistically significant). With regard to ascites, we saw a similar evolution, so there was no apparent increase in portal hypertensive complications," he said.

There was no change in liver function (MELD score) from before to after the procedure (13.2 vs 15.2; P = .26). Although 4 patients had thrombotic problems, this was not statistically significant.

Patient Selection

On multivariate analysis, adjusted for time between diagnosis of hepatic encephalopathy and embolization, serum albumin, International Normalized Ratio, the presence of ascites, and preprocedure Child score, the only independent predictors of recurrence of hepatic encephalopathy were sex (odds ratio [OR], 0.06; 95% confidence interval [CI], .005 - 0.971; P = .048) and pre-embolization MELD score (OR, 1.52; 95% CI, 1.073 - 2.180; P = .019).

"Embolization of these shunts is feasible, effective, and safe, provided that sufficient functional liver reserve is guaranteed," Dr. Laleman concluded. According to the investigators, patients should have a MELD score of 11 or lower to be considered for the procedure.

This is important work because it is a large study, session chair Isabelle Colle, MD, PhD, professor of hepatology and gastroenterology and head of the gastroenterology clinic at Gent University in Belgium, told Medscape Medical News.

She explained that embolization of large spontaneous portosystemic shunts is "a good treatment for patients who have really important hepatic encephalopathy and have large shunts, because they are often Child A patients.... It's clinically important that we can offer treatment to those patients without offering transplantation."

Dr. Laleman and Dr. Colle have disclosed no relevant financial relationships.

International Liver Congress 2013: 48th Annual Meeting of the European Association for the Study of the Liver (EASL). Abstract 77. Presented April 26, 2013.

Source

Also See: Shunt Correction Eases Hepatic Encephalopathy

ViewPoints: Cost will limit uptake of off-label Gilead/Bristol-Myers Squibb Hep C combo, despite best-in-class data

(Ref: ViewPoints Desk)

April 30th, 2013

Once again, a combination of Gilead Sciences' sofosbuvir and Bristol-Myers Squibb's daclatasvir appears to offer the most efficacious way of treating patients with hepatitis C without the need for either interferon or ribavirin. However, Gilead has chosen not to pursue development of this combination – prompting speculation that off-label usage could prove a feasible alternative for physicians. Such an outcome is possible, say experts, although cost is likely to be a deciding – and ultimately limiting – factor.

Insight, Analysis & Opinion

Data unveiled last week showed that among a cohort of 41 patients treated with the sofosbuvir/daclatasvir combination, 40 patients were virus free (100 percent SVR) after 12 weeks of therapy. It is not the first time this combination has impressed; a year ago similarly robust data was released, providing a backdrop against which Gilead's decision to not pursue a combination therapy with Bristol-Myers Squibb was met with some consternation. See Spotlight On: Bristol-Myers Squibb and Gilead Sciences deliver stellar HCV results, decide to go separate ways?

Gilead claims that its decision to focus on internal developments, rather than partnering with Bristol-Myers Squibb has accelerated the development of its own efforts to bring a single tablet, interferon-sparing treatment to market. Gilead remains the leading player in this development race, albeit if its own impressive-looking combinations have yet to fully match the efficacy seen with sofosbuvir/daclastasvir, which are regarded as the best in class nucleotide NS5B inhibitor and NS5A inhibitor products, respectively.

With different assets in the HCV development space offering various mechanisms of action, mechanism diversity and potency, one suggestion is that once individual components become available, physicians will prescribe them together in an off-label capacity. In this respect, the HIV market – where combinations of best-in-class molecules are used despite different companies owning them – could prove to be a valid benchmark. Key opinion leaders (KOLs) suggest that such activity is likely to occur in the early period following the approval of new treatments, with off-label use also likely to be driven by independently-run clinical trials looking at cross-company regimens. See KOL Insight: Hepatitis C: the race for the first interferon-free regimen

Potential off-label use will have a direct impact on how companies price their own fixed-dose combinations, note KOLs, while the broader cost of treating an expanding HCV population will in turn limit the use of off-label prescribing, they add – particularly as Gilead, for example, has shown robust data for its own combination. One KOL told FirstWord that "there are just too many patients out there and the system could go bankrupt if screening and diagnosis rate of hepatitis C go up and everybody is just put on just a combination of the best drug classes. You may have people prescribing daclatasvir, simeprevir plus sofosbuvir, three drugs off label in a combination just because they feel that is really the best they can provide to their patients, but which from a healthcare perspective would be a disaster."

Source

Also See:

1. HCV Combo Impresses, but Use Unlikely (April 30, 2013)
2. Shunned Gilead/Bristol-Myers hep C combo may be too good for docs to ignore (April 28, 2013)
3. Gilead-Bristol Hepatitis C Drug Combo Cures All in Study (April 28, 2013)
4. Gilead-Bristol Hepatitis C Combo Cures 100% of Patients in Study (April 27, 2013)

FDA Rejects Two Gilead HIV Drugs as Standalone Products

Apr 29, 2013

By Toni Clarke

WASHINGTON (Reuters) Apr 29 - Gilead Sciences Inc said on Monday that U.S. health regulators rejected two of its HIV drugs as standalone therapies, citing deficiencies in documentation and validation of certain quality testing procedures.

The company is seeking approval for its integrase inhibitor elvitegravir for people with HIV who have already been treated with other products.

Gilead is also seeking approval of cobicistat, a drug that does not itself fight the virus but boosts the function of other HIV medicines.

Both drugs are already contained in Gilead's once-daily single-tablet HIV treatment Stribild, which combines four different medications and was approved in the United States last August.

Stribild contains elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil fumarate.

Gilead said it is working with the U.S. Food and Drug Administration to address the questions raised in the rejection letter in order to move the application forward.

Source

Improving Engagement in HIV Care and Treatment Adherence: An Algorithmic Approach

Benjamin Young, MD, PhD

Apr 30, 2013

Advances in antiretroviral medications have revolutionized the care and prognosis of people living with HIV around the world. Where individuals have access to trained care providers and medications, HIV-related morbidity and mortality have decreased; in many highly affected regions, new infection rates are beginning to decrease.

Yet, as impressive as these gains seem, recent studies show that only a minority of people living with HIV in the United States are successfully engaged in care and achieve viral suppression.^[1,2] Central problems in HIV care are related to delays in testing, delays in care, and early dropout from medical care, and late access to HIV testing and treatment have been associated with increased immune system damage, risk for HIV transmission, and increased hospitalizations.^[3]

Unfortunately, these seemingly obvious barriers to successful implementation of therapeutics have only recently drawn systematic attention. Improving engagement in HIV medical care is hobbled by a relative dearth of scientific literature on the vast subject. In appreciating such challenges, our group, the International Association of Providers in AIDS Care (IAPAC), convened an international expert panel to identify best practices and evidence for engagement and adherence to HIV care and treatment. These first-ever evidence-based recommendations on improving entry into and retention in HIV care and treatment adherence were published in 2012.^[4]

In the current issue of JIAPAC, we describe a clinical management algorithm based on the evidence-based recommendations that charts simple operational interventions for engagement and care and treatment adherence. We believe that such tools can assist busy care programs in improving the delivery of important health interventions.

The algorithm recommends:

• Systematic monitoring of successful entry into and retention in HIV care; multiple data sources may need to be integrated to best achieve this monitoring goal. Intensive outreach is recommended for recently diagnosed individuals who do not enter care within 6 months of diagnosis. Peers or paraprofessionals may be considered to provide the needed human resources to achieve these goals.
• The use of once-daily treatment for persons initiating therapy. Among regimens of equal efficacy and safety, fixed-dose combinations should be used to decrease pill burden.
• Monitoring of adherence to treatment by routine self-reported adherence and pharmacy refill data. Reminder devices and the use of communications technologies with an interactive component and adherence-related educations and counseling are recommended.
• Education and counseling through one-on-one and group education; multidisciplinary education and counseling are recommended.
• It is important to note that although normative guidance is a necessary step in charting a pathway for improving care, recommendations frequently are not translated into operational improvements. Indeed, it is critical that agencies that author such documents take into consideration the operational and educational needs of implementation.

As a member-oriented organization, IAPAC strives to provide practical tools to assist front-line care providers in achieving the highest possible level of care in people living with HIV. In the past, efforts have focused primarily on the use of HIV treatment guidelines from the US Department of Health and Human Services and the World Health Organization. In constructing and publishing this algorithm, we extend this effort to improving engagement in care and treatment adherence.

References

Source

Daclatasvir/asunaprevir/NS5B inhibitor effective in treatment-naive HCV patients

April 30, 2013

Treatment-naive patients with chronic hepatitis C experienced high rates of sustained virologic response from a combination of three direct-acting antivirals in a study presented at the International Liver Congress in Amsterdam.

In an open-label phase 2 study, researchers randomly assigned 32 treatment-naive patients with chronic HCV genotype 1 to 60 mg NS5A inhibitor daclatasvir (DCV) once daily, 200 mg protease inhibitor asunaprevir (ASV) twice daily and 75 mg non-nucleoside NS5B inhibitor BMS-791325 twice a day for 24 or 12 weeks (n=16 each). A second cohort was later assigned DCV, ASV and 150 mg BMS-791325 (Bristol-Myers Squibb) for 24 (n=16) or 12 weeks (n=18).

Nearly all patients had HCV RNA levels below 25 IU/mL after 4 weeks, excluding two participants from the 12-week, 150-mg group. No significant differences in virologic response were observed, with 92% of all evaluable patients experiencing SVR at 4 weeks. SVR12 and SVR24 were achieved by 94% of the first two groups, and all evaluable patients in this cohort experienced either or both SVR24 and SVR36, according to a press release.

In the second cohort, three treatment failures occurred, including virologic breakthroughs in the 12- and 24-week groups and one relapse in the 12-week group.

The most commonly reported adverse event was headache (27.3% of cases). Single cases of renal calculus and cerebral vasoconstriction unrelated to the study were considered serious adverse events, but no patients died or discontinued therapy because of treatment-related effects.

“The diversity of the hepatitis C patient population requires multiple treatment options that can enable a personalized approach,” Brian Daniels, MD, senior vice president of Global Development and Medical Affairs for Bristol-Myers Squibb, said in the release. “These data, which demonstrate comparable efficacy among the 12- and 24-week triple-DAA treatment groups, support the rapid phase 3 development of this investigational triple-DAA regimen and provide further data on daclatasvir as an important component of DAA-based therapy.”

For more information:

Everson GT. #1423: Interim Analysis of an Interferon (IFN)- and Ribavirin (RBV)-Free Regimen of Daclatasvir (DCV), Asunaprevir (ASV), and BMS-791325 in Treatment-Naive, Hepatitis C Virus Genotype 1-Infected Patients. Presented at: The International Liver Congress 2013; April 24-28, Amsterdam.

Source

Alcohol consumption, metabolic risk factors tied to cirrhosis, hepatocellular carcinoma

April 30, 2013

Heavy alcohol consumption and obesity increase the risk for liver-related morbidity and death, while metabolic risk factors also elevate the risk for hepatocellular carcinoma, according to data presented at the International Liver Congress in Amsterdam.

In a study of 107,742 women (median age 60 years) stratified according to BMI (less than 25 kg/m2 vs. 25 kg/m2 or more) and alcohol intake (15 units or fewer consumed weekly vs. more than 15), researchers observed 90 incidents of morbidity or mortality related to liver disease. Patients with high BMI and alcohol intake were at significantly increased risk (HR=7.2; 95% CI, 3.4-15.5) compared with those with low BMI and low alcohol consumption, while the association also neared statistical significance among those with low BMI and high alcohol intake (HR=2.9; 95% CI 1.0-8.4).

“These findings will have a significant impact on how we can help millions of people across the world at risk of developing liver disease,” Daniele Prati, MD, EASL Scientific Committee Member, said in a press release. “More research is required to determine the exact thresholds for each risk factor that independently and in combination increase the risk of chronic liver disease, but this is an important first step in the right direction.”

In another study presented at the congress, investigators evaluated 100 liver transplant recipients with alcoholic cirrhosis, including 24 with steatosis, 24 with metabolic risk factors such as obesity and/or diabetes (MRF), 20 with both and 32 with neither steatosis nor MRF.

Hepatocellular carcinoma (HCC) was present in 28 patients, who were significantly more likely to be overweight (54% of cases vs. 14%; P<.001) and have diabetes (43% vs. 22%; P<.04) than those without HCC. Half of participants with both steatosis and MRF had HCC, compared with 6% of those with neither. Significantly more patients in either the MRF/steatosis combined or MRF alone groups had HCC than those with neither or steatosis alone (48% vs. 13%; P=.0001). Adjustment for factors including age, sex and alcohol consumption did not eliminate the associations between HCC and obesity (P<.01) or diabetes (P<.04).

“Fatty liver and alcohol have long been known as risk factors for HCC, but this study tested their combined effect in patients with alcoholic cirrhosis,” Prati said in the release. “The results will be useful to improve the management of patients with cirrhosis, and to identify cancer at early stages.”

For more information:

Trembling PM. #115: Influence of BMI and Alcohol on Liver-Related Morbidity and Mortality in a Cohort of 108,000 Women From the General Population From UKCTOCS. Presented at: The International Liver Congress 2013; April 24-28, Amsterdam.

Pais R. #118: Metabolic Fatty-Liver Disease Increases the Risk of Hepatocellular Carcinoma in Patients With Alcoholic Cirrhosis Listed for Liver Transplantation. Presented at: The International Liver Congress 2013; April 24-28, Amsterdam.

Source

HCV Combo Impresses, but Use Unlikely

By Michael Smith, North American Correspondent, MedPage Today

Published: April 30, 2013

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania

Action Points

• Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
• This phase II trial demonstrated a nearly 100% sustained virologic response rate with the use of daclatasvir and sofosbuvir in patients with hepatitis C virus infection refractory to standard therapy.
• Unfortunately, the two drugs are made by different companies and will not be marketed together, making phase III trials difficult.

AMSTERDAM -- Researchers and clinicians got another look here at a combination of investigational oral hepatitis C virus (HCV) drugs that delivered impressive results but will likely never be marketed together.

In a small phase II cohort of very difficult-to-treat patients, the combination of sofosbuvir and daclatasvir led to viral cures in 40 of 41 patients 12 weeks after the end of therapy, according to Mark Sulkowski, MD, of Johns Hopkins University.

The 41st patient did not appear to be tested at week 12 and so was counted as a treatment failure, but was tested 24 weeks after the end of therapy and found to have unquantifiable levels of HCV RNA, Sulkowski reported at the meeting of the European Association for the Study of the Liver.

He added that of the 21 patients who have completed 24 weeks of follow-up after treatment, all have undetectable virus – the so-called 24-week sustained virologic response (SVR₂₄).

In addition, the combination was well-tolerated with few adverse events, and no patient has yet relapsed, he said.

In other words, the all-oral, once-daily combination "looks exceedingly useful," commented Geoffrey Dusheiko, MD, of Royal Free Hospital in London, who was not involved with the study but who moderated the session at which it was presented.

But the combination is running afoul of diverging corporate interests, he noted. Daclatasvir, an NS5A replication complex inhibitor, is owned by Bristol-Myers Squibb, while sofosbuvir, a nucleotide analogue NS5B polymerase inhibitor, is being developed by Gilead Sciences.

The companies have stopped collaborating on the drugs, with each firm preferring to develop its own version of the other's medication.

The result, Dusheiko said, is that "we don't have a large body of phase III data and that may restrict physicians from prescribing this particular combination."

"Unless there's a change in the thinking," he said, it's unlikely the companies will get back together, adding that for clinicians, "It's a conundrum."

Sulkowski reported on 41 patients with the hard-to-treat genotype 1 of the virus who had failed treatment with the current standard of care: a protease inhibitor -- either telaprevir (Incivek) or boceprevir (Victrelis) -- combined with pegylated interferon and ribavirin.

Such patients have no treatment options, Sulkowski said. He and colleagues randomly assigned the 41 volunteers to take sofosbuvir and daclatasvir alone or with ribavirin for 24 weeks. The primary endpoint of the analysis was unquantifiable HCV RNA 12 weeks after the end of therapy – the so-called SVR₁₂.

All patients but one had unfavorable variants of the IL28B gene, which predicts response to interferon treatment, and 33 of 41 had HCV genotype 1a, which is regarded as more difficult to treat than 1b.

Nevertheless, Sulkowski reported, high response rates were seen early in treatment and by the end of therapy all 41 patients had unquantifiable virus, a state that persisted (with the one technical exception) through 12 weeks post-treatment.

There were no serious adverse events in patients taking the combination alone, no discontinuations owing to adverse events, and no grade 3 or 4 adverse events.

In the other arm, the combination plus ribavirin was nearly as well-tolerated with one serious adverse event – a single patient with hypokalemia.

Adverse events reported by at least 10% of patients included fatigue, headache, hair loss, muscle aches, constipation, and diarrhea, Sulkowski said, but all were mild or moderate.

The study had support from Gilead and Bristol-Myers Squibb. Sulkowski reported financial links with the company, as well as with Novartis, BMS, Gilead, Janssen, Vertex, BIPI, Abbott, Merck, Roche/Genentech, BIPI, and Pfizer.

Dusheiko reported financial links with Gilead, GSK, BMS, and Boehringer Ingelheim.

Primary source: European Association for the Study of the Liver
Source reference:
Sulkowski MS, et al "Sustained virologic response with daclatasvir plus sofosbuvir ± ribavirin (RBV) in chronic HCV genotype (GT) 1-infected patients who previously failed telaprevir (TVR) or boceprevir (BOC)" EASL 2013; Abstract 1417.

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Also See:

1. Shunned Gilead/Bristol-Myers hep C combo may be too good for docs to ignore (April 28, 2013)
2. Gilead-Bristol Hepatitis C Drug Combo Cures All in Study (April 28, 2013)
3. Gilead-Bristol Hepatitis C Combo Cures 100% of Patients in Study (April 27, 2013)

GENFIT : GFT505 AT THE HEART OF POTENTIAL THERAPIES DURING THE ANNUAL EASL CONGRESS

PRESS RELEASE

* Reuters is not responsible for the content in this press release.

Tue Apr 30, 2013 11:45am EDT

GENFIT: GFT505 AT THE HEART OF POTENTIAL THERAPIES DURING THE ANNUAL EASL CONGRESS

Lille (France), Boston (Massachusetts, United States), April 30, 2013 - GENFIT (Alternext: ALGFT; ISIN: FR0004163111), a biopharmaceutical company at the forefront of drug discovery and development, focusing on the early diagnosis and preventive treatment of cardiometabolic and associated disorders, today announces that NASH was a prominent theme at the international liver congress of EASL held in Amsterdam, and that GFT505 is indisputably recognized as one of the most promising drug candidates in this indication.

NAFLD and NASH is a major preoccupation of experts in hepatology. As such, these liver disorders associated with conditions such as obesity and type 2 diabetes mellitus, were the subject of over 50 scientific communications during the EASL congress, underlining in particular the morbidities and increasing prevalence, not only in industrialized but also emerging countries. During a state-of-the-art session entitled "NAFLD 2013: a clinical update", Pr. Christopher Day clearly provided the latest results on epidemiology, pathophysiological processes, and natural history of the disease, which pointedly put forward the urgent need for new therapies. In this context, Pr. Day considered the mechanism of action of GFT505 as a promising approach presently in clinical evaluation for NASH.

In addition to the conference of Pr. Day, other communications were presented on GFT505 as an excellent drug candidate for the treatment of NASH. Notedly, in his presentation entitled « An overview of lipotoxicity by nuclear receptors », Pr. Bart Staels detailed the roles of nuclear receptors PPARa and PPARd, targets of GFT505, in the mechanisms associated with NASH. Based on these known mechanisms, Pr. Staels presented the latest preclinical and clinical results demonstrating the efficacy of GFT505, and indicated that these new findings have been accepted for publication in major international peer reviewed scientific journals (Hepatology and Diabetes Care). Their official publications will be announced in the coming weeks.

The important satellite meeting organized by GENFIT, which gathered together over 90 clinical investigators and key opinion leaders from different countries implicated in the GFT505-212-7 study, provided confirmation of the acute interest which the scientific community has on GFT505 as a treatment of NASH. The investigators noted in particular the exceptional efficiency of patient recruitment in the study, which demonstrates the hope and anticipation incited by GFT505 in NASH patients who today are without any therapeutic solution.

*About NAFLD/NASH:
NAFLD (non-alcoholic fatty liver disease) and in particular NASH (non-alcoholic steatohepatitis) are serious liver diseases that can lead to cirrhosis and liver cancer. The development of NAFLD/NASH is associated with the pathophysiological process of insulin resistance in patients that are overweight and/or diabetic. NAFLD is believed to affect 70-80% of diabetic patients, and progresses to chronic liver disease (NASH) in 20-50% of cases. Mortality due to liver disease is thus 2-3-fold higher in the diabetic population than in the overall population. The NASH market was estimated at 615 $M in 2010 and should reach 2,008 $M in 2018.

About GENFIT:

GENFIT is a biopharmaceutical company focused on the Discovery and Development of drug candidates in therapeutic fields linked to cardiometabolic disorders (prediabetes/diabetes, atherosclerosis, dyslipidemia, inflammatory diseases.). GENFIT uses a multi-pronged approach based on early diagnosis, preventive solutions, and therapeutic treatments and advances therapeutic research programs, either independently or in partnership with leading pharmaceutical companies, including Sanofi, to address these major public health concerns and their unmet medical needs.
GENFIT's research programs have resulted in the creation of a rich and diversified pipeline of drug candidates at different stages of development, including GENFIT's lead proprietary compound, GFT505, that is currently in Phase IIb.
With facilities in Lille, France, and Cambridge, MA (USA), the Company has approximately 80 employees. GENFIT is a public company listed on the Alternext trading market by Euronext(TM) Paris (Alternext: ALGFT; ISIN: FR0004163111). www.genfit.com

Contacts:

GENFIT
Jean-François Mouney - CEO & Chairman of the Management Board
Ph. +333 2016 4000

Milestones - Press Relations
Bruno Arabian
Ph. +331 7544 8740 / +336 8788 4726 - barabian@milestones.fr

2013.04.30 PR GENFIT EASL

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Intercept Pharmaceuticals Announces Additional Results of Global Primary Biliary Cirrhosis Study Group Analysis Presented at EASL

PRESS RELEASE

April 30, 2013, 8:02 a.m. EDT

 

Data Support Unmet Therapeutic Need in Primary Biliary Cirrhosis and Strong Statistical Correlation of POISE Phase 3 Primary Endpoint With Clinical Outcomes

NEW YORK, April 30, Apr 30, 2013 (GLOBE NEWSWIRE via COMTEX) -- Intercept Pharmaceuticals, Inc. /quotes/zigman/12230574/quotes/nls/icpt ICPT -0.09% , a clinical stage biopharmaceutical company focused on the development and commercialization of novel therapeutics to treat chronic liver diseases, today announced additional details relating to the analysis presented by the Global Primary Biliary Cirrhosis Study Group (Study Group) at the annual meeting of the European Association for the Study of the Liver (EASL) held in Amsterdam on April 24-28, 2013. The Study Group presented an analysis of data from over 2,100 primary biliary cirrhosis (PBC) patients, among whom 981 patients met Intercept's ongoing Phase 3 POISE trial entry criteria at the time they initiated ursodiol therapy of having an alkaline phosphatase (ALP) level exceeding 1.67 times upper limit normal (ULN) and/or an abnormal bilirubin level. The analysis of this cohort of patients from the Study Group further substantiates the primary endpoint used in POISE as being strongly predictive of adverse clinical outcomes such as liver transplant and death in PBC patients.

"This independent analysis from the Study Group further validates the use of a surrogate endpoint in PBC trials to predict long-term outcomes," said Mark Pruzanski, M.D., Chief Executive Officer and President of Intercept. "Our selection of the POISE trial endpoint was based on a recent emerging consensus of leading PBC opinion leaders and we are glad to see that the Study Group data analyzed to date support its clinical utility."

The data show that after one year of ursodiol therapy 58.7% of the patient cohort (n=576/981) had an inadequate therapeutic response as determined by failure to meet the POISE trial primary endpoint, which is defined as the achievement of both an ALP level of less than 1.67 times ULN (with a minimum 15% reduction from baseline) together with a normal bilirubin level. In the non-responder group, 30.0% of patients went on to require a liver transplant or die (n=173/576) as compared to 12.6% of patients in the responder group (n=51/405), reflecting a 2.4-fold higher event rate for the non-responders (p=4.5x10E-10).

In order to censor out deaths due to causes other than PBC-associated liver failure, the Study Group, among other things, analyzed a younger subgroup of patients who were under 60 years old (n=666) at the time they initiated ursodiol therapy. In this subgroup, 61.3% of patients (n=408/666) failed to meet the POISE endpoint after one year of ursodiol therapy and 26.2% of these patients went on to require a liver transplant or die (n=107/408), as compared to 7.4% of patients in the responder group (n=19/258), reflecting a 3.6-fold higher event rate for the non-responders (p=1x10E-7).

The event rate among the responders in this subgroup was 41.3% lower than the event rate of the responder group in the overall patient cohort that included older patients. We believe that this difference is likely due to the greater exclusion of mortality unrelated to PBC in the younger patient subgroups, resulting in even greater differentiation of the responder and non-responder groups.

About The Global Primary Biliary Cirrhosis Study Group

The Global Primary Biliary Cirrhosis Study Group is currently comprised of a group of 15 academic medical centers from eight countries that are pooling their data to investigate the relationship between biochemical assessments of liver function and adverse clinical outcomes in primary biliary cirrhosis. Intercept is sponsoring this independent academic research program but is not involved in the data collection and analysis, which are being conducted by Dr. Henk van Buuren and Dr. Bettina Hansen of Erasmus University Medical Centre in Rotterdam, The Netherlands. The data demonstrate that the primary endpoint being used in Intercept's Phase 3 POISE trial is highly statistically predictive of liver transplant-free survival in primary biliary cirrhosis patients. Intercept anticipates final data from at least 4,000 patients will be collected and analyzed as part of the study.

About Obeticholic Acid (OCA) and the POISE Trial

Intercept's lead product candidate, obeticholic acid, is a bile acid analog and first-in-class agonist of the farnesoid X receptor (FXR). OCA is initially being developed for the second line treatment of primary biliary cirrhosis in patients with an inadequate response to, or who are unable to tolerate, ursodiol (ursodeoxycholic acid), the only approved therapy for this indication. Primary biliary cirrhosis is a chronic autoimmune liver disease that may progress to cirrhosis and liver failure, and it is currently the fifth leading indication for liver transplant in the United States. Intercept is currently conducting a Phase 3 clinical trial of OCA in primary biliary cirrhosis, called the POISE trial, which is anticipated to serve as the basis for seeking regulatory approval in the United States and Europe. Intercept completed enrollment of 217 patients in the POISE trial in December 2012 and expects results to be available in the second quarter of 2014. OCA has orphan drug designation in both the United States and Europe for the treatment of PBC. Intercept owns worldwide rights to OCA outside of Japan and China, where it has out-licensed the product candidate to Dainippon Sumitomo Pharma.

About Intercept

Intercept is a biopharmaceutical company focused on the development and commercialization of novel therapeutics to treat orphan and more prevalent liver diseases utilizing its expertise in bile acid chemistry. For more information about Intercept, please visit the Company's website at www.interceptpharma.com.

Safe Harbor Statement

This press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding the relationship between ALP and bilirubin and adverse clinical outcomes, the clinical utility of the POISE trial selected endpoints and any potential consensus relating thereto, the acceptance by regulatory authorities of the POISE trial endpoint or results, clinical, preclinical and regulatory developments for our product candidates, the anticipated results of our clinical and preclinical trials and other development activities, and our strategic directives under the caption "About Intercept." These "forward-looking statements" are based on management's current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to: the initiation, cost, timing, progress and results of Intercept's development activities, preclinical studies and clinical trials; the timing of and Intercept's ability to obtain and maintain regulatory approval of OCA and any other product candidates it may develop, and any related restrictions, limitations, and/or warnings in the label of any approved product candidates; Intercept's plans to research, develop and commercialize future product candidates; the election by Intercept's collaborators to pursue research, development and commercialization activities; Intercept's ability to attract collaborators with development, regulatory and commercialization expertise; Intercept's ability to obtain and maintain intellectual property protection for its product candidates; Intercept's ability to successfully commercialize its product candidates; the size and growth of the markets for Intercept's product candidates and its ability to serve those markets; the rate and degree of market acceptance of any future products; the success of competing drugs that are or become available; regulatory developments in the United States and other countries; the performance of third-party suppliers and manufacturers; Intercept's ability to obtain additional financing; Intercept's use of the proceeds from its recently completed initial public offering; the accuracy of Intercept's estimates regarding expenses, future revenues, capital requirements and the need for additional financing; the loss of key scientific or management personnel; and other factors discussed under the heading "Risk Factors" contained in Intercept's annual report on Form 10-K for the year ended 2012 filed with the Securities and Exchange Commission on April 1, 2013, as well as any updates to these risk factors filed from time to time in Intercept's other filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and Intercept undertakes no duty to update this information unless required by law.

For more information about Intercept, please contact Mark Pruzanski, M.D., or Barbara Duncan, both of Intercept Pharmaceuticals, at 1-646-747-1000.

http://www.globenewswire.com/newsroom/ti?nf=MTMjMTAwMzA1NjcjMjMwMjQ=

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