HCV Update Selected Highlights: key new HCV drugs, timelines & recent news developments

Provided by NATAP

written for NATAP by Jules Levin: Currently approved are 2 protease inhibitors telaprevir & boceprevir. In phase 3 now are 4 drugs: 2 proteases TMC435 & BI1335; nucleotide GS7977; and NS5A BMS052. Also in phase 3 is Peg Lambda, a peginterferon that has showed in trials similar efficacy to current Peginterferons with little of the side effect. Phase 3 for these drugs should be finished in about one year with varying finish timelines between these drugs. Abbott is about to start phase 3 studies, they have 4 drugs in 3 classes: protease, NS5A, HCV polymerase nonnucleoside inhibitors (NNIs). Gilead has drugs in 4 classes: nucleotide, protease, HCV polymerase nonnucleoside inhibitors (NNIs), NS5A. BMS has drugs in 4 clases: NS5A, HCV polymerase nonnucleoside inhibitors (NNIs), nucleotide (trial just suspended, evaluating), protease; Roche/Genentech has drugs in 3 classes: protease, nuke, HCV polymerase nonnucleoside inhibitors (NNIs). Vertex has drugs in 3 classes: protease, nucleotide, HCV polymerase nonnucleoside inhibitors (NNIs). Merck has drugs in 2 classes: protease in development in addition to boceprevir, NS5A. Tibotec has protease TMC435 in phase 3 now with other drugs further back in development.

So in about 1 year we will have 2 brand new classes of drugs BMS052 the potent NS5A, GS7977 the potent nucleotide, plus the 2 new proteases currently in phase 3 BI1335 & TMC435. At this time we don't know if patients & clinicians will be able to combine the NS5A+GS7977 or a 3-drug combination of a protease TMC435 or BI1335 + the NS5A BMS052+GS7977. A small phase 2 study at EASl in April of about 40 patients showed SVR rates of 100% using GS7977+BMS5435, but there is not a followup study ongoing with these 2 drugs. There is an ongoing study now in null responders lookimg at TMC435+GS7977, we await these data, expecting good results. For null responders we have some data below in small studies finding that 2 BMS orals, the protease+NS5A + peg/RBV could cure 100% of patients.

Is there any doubt that we should be able to achieve 100% cure rates for all treatable patients?

Following this chart are links to the key studies recently reported that capture the data for these drugs.

Phase III Hallmark QUAD: ASV+DCV+Peg+Rib (Nulls/Partials) asunaprevir+BMS NS5A
Phase III Hallmark QUAD: ASV+DCV+Peg+Rib (Nulls/Partials)
This study is currently recruiting participants.
Verified July 2012 by Bristol-Myers Squibb
First Received on April 5, 2012. Last Updated on July 26, 2012

Phase III Hallmark DUAL: ASV+DCV (Nulls/Partials, Intolerants/Ineligibles. Naives)
Phase III Hallmark DUAL: ASV+DCV (Nulls/Partials, Intolerants/Ineligibles. Naives)
This study is currently recruiting participants.
Verified July 2012 by Bristol-Myers Squibb
First Received on April 18, 2012. Last Updated on July 23, 2012 EASL /AASLD Key Studies: interferon-free + studies for key new oral HCV drugs:

ASL: Potent Viral Suppression With the All-Oral Combination of Daclatasvir (NS5A Inhibitor) and GS-7977 (Nucleotide NS5B Inhibitor), +/- Ribavirin, in Treatment-Naive Patients With Chronic HCV GT1, 2, or 3 (100% SVR gt1, 91% gt2) - (04/19/12)

EASL: TMC435 with peginterferon and ribavirin in treatment-experienced HCV genotype 1 patients: the ASPIRE study, a randomised Phase IIb trial - (04/19/12)

EASL: TMC435 in patients infected with HCV genotype 1 who have failed previous pegylated interferon / ribavirin treatment: Virologic analyses of the ASPIRE trial - (04/19/12)

EASL: Once Daily GS-7977 Plus Ribavirin in HCV Genotypes 1-3: The ELECTRON Trial - (04/21/12)

EASL: GS-7977 + PEG/RBV in HCV Genotype 1: The ATOMIC Trial An End To Response-Guided Therapy - (04/20/12)

EASL: GS-7977 400 mg QD Safety and Tolerability in the Over 500 Patients Treated for at Least 12 Weeks - (04/25/12)

AASLD: Treatment with the 2nd generation HCV protease inhibitor BI 201335 results in high and consistent SVR rates - results from SILEN-C1 in treatment-naïve patients across different baseline factors - (11/08/11)

AASLD: SILEN-C3: treatment for 12 or 24 weeks with BI 201335 combined with peginterferon alfa-2a and ribavirin in treatment-naïve patients with chronic genotype-1 HCV infection - (11/07/11)

EASL: Peginterferon Lambda-1A (Lambda) Compared With Peginterferon Alfa-2A (Alfa) in Treatment- Naive Patients With HCV Genotypes 2 or 3: First SVR24 Results From EMERGE Phase IIb - (04/20/1

Once-daily NS5A Inhibitor (BMS-790052) Plus Peginterferon-alpha-2a ... Apr 17, 2010 ... Once-daily NS5A Inhibitor (BMS-790052) Plus Peginterferon-alpha-2a And Ribavirin Produces High Rates Of Extended Rapid Virologic Response In ... www.natap.org/2010/EASL/EASL_32.htm

BMS-790052 is a First-in-class Potent Hepatitis C Virus (HCV) NS5A .

BMS-790052 is a First-in-class Potent Hepatitis C Virus (HCV) NS5A Inhibitor for Patients with Chronic HCV Infection: Results from a Proof-of-concept Study -

EASL: A 12-Week Interferon-Free Regimen of ABT-450/r + ABT-333 + Ribavirin Achieved SVR12 in More Than 90% of Treatment-Naïve HCV Genotype-1-Infected Subjects and 47% of Previous Non-Responders - (04/23/12)

EASL: A 12-Week Interferon-Free Regimen of ABT-450/r, ABT-072, and Ribavirin was Well Tolerated and Achieved Sustained Virologic Response in 91% Treatment-Naïve HCV IL28B-CC Genotype-1-Infected Subjects - (04/19/12)

EASL: Dual Oral Therapy with NS5A Inhibitor Daclatasvir (BMS-790052) and NS3 Protease Inhibitor Asunaprevir (BMS-650032) in HCV Genotype 1b-Infected Null Responders or Patients Ineligible/Intolerant to Peginterferon/Ribavirin - (04/19/12)

EASL: SVR4 and SVR12 with an interferon-free regimen of BI 201335 AND BI 207127, +/- ribavirin, in treatment-naïve patients with chronic genotype-1 HCV infection: Interim results of SOUND-C2 - (04/22/12)

EASL: The efficacy and safety of the interferon-free combination of BI 201335 and BI 207127 in genotype 1 HCV patients with cirrhosis: Interim analysis from SOUND-C2 - (04/20/1

Quadruple Therapy With BMS-790052, BMS-650032 and Peg-IFN/RBV for 24 Weeks Results in 100% SVR12 in HCV Genotype 1 Null Responders: original slide presentation at EASL April 2011 Proof of Concept that SVR is Achievable Without Peg/RBV - 4/11 null responder patients achieved SVR w/o Peg/Rbv, with only BMS-790052 (NS5A inhibitor) + BMS-650032 (protease inh) - (02/03/12)

EASL: Gilead: Interim Sustained Virologic Response Rates in Treatment-Naïve HCV Genotype 1a and 1b Patients Treated for 12 or 24 Weeks with an Interferon-Free All-Oral Quad Regimen - (04/21/12)

EASL: RAPID AND SUSTAINED ACHIEVEMENT OF UNDETECTABLE HCV RNA DURING TREATMENT WITH RITONAVIR-BOOSTED DANOPREVIR/PEG-IFNα-2A/RBV IN HCV GENOTYPE 1 OR 4 PATIENTS: DAUPHINE WEEK 36 INTERIM ANALYSIS - (04/22/12)

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Key Recent Developments and other EASL Studies of note:

EASL: In Vitro Resistance Analysis of Merck's HCV NS5a Inhibitor MK-8742 Demonstrates Increased Potency AgainstClinical Resistance Variants and Improved Resistance Profile - (04/23/12)

EASL: Safety and Antiviral Activity of ABT-267, a Novel NS5A Inhibitor, During 3-Day Monotherapy: First Study in HCV Genotype-1 (GT1)-Infected Treatment-Naïve Subjects - (04/25/12)

EASL: Antiviral Activity and Resistance Profile of the Novel HCV NS5A Inhibitor GS-5885 - (04/25/12)

EASL: A Phase 2a Study of BMS-791325, an NS5B Polymerase Inhibitor, With Peginterferon Alfa-2a and Ribavirin in Treatment-Naive Patients With Genotype 1 Chronic Hepatitis C Virus Infection - (04/25/1

SVR24 AMONG G1/4 TREATMENT-NAIVE PATIENTS RECEIVING MERICITABINE IN COMBINATION WITH PEG-IFNα-2A/RBV: FINAL ANALYSIS FROM THE JUMP-C STUDY - (04/24/1

INTERFERON-FREE TREATMENT WITH A COMBINATION OF MERICITABINE AND DANOPREVIR/R WITH OR WITHOUT RIBAVIRIN IN TREATMENT-NAIVE HCV GENOTYPE 1-INFECTED PATIENTS - (04/24/1

GS-9669, A Novel NS5B Non-Nucleoside Thumb Site II Inhibitor, Demonstrates Potent Antiviral Activity, Favorable Safety Profile and Potential for Once-Daily - (04/24/1

A Phase 2a Study of BMS-791325, an NS5B Polymerase Inhibitor ...
www.natap.org/2012/EASL/EASL_60.htm
A Phase 2a Study of BMS-791325, an NS5B Polymerase Inhibitor, With Peginterferon Alfa-2a and Ribavirin in Treatment-Naive Patients With Genotype

Patients of all IL28B Genotypes have High SVR Rates when Treated with VX-222 in Combination with Telaprevir/Peginterferon/Ribavirin in the ZENITH Study - (04/24/1

VX-222 Vertex HCV polymerase nonnucleoside inhibitors (NNIs)Polymerase Inhibitor 3 Days Monotherapy
www.natap.org/2010/EASL/EASL_02.htm
VX-222 Vertex HCV polymerase nonnucleoside inhibitors (NNIs)Polymerase Inhibitor 3 Days Monotherapy. Reported by Jules Levin EASL Apr 14-18 2010. Vienna Austri

Vertex QUAD Therapy Yielded 83-93% SVR with 12 weeks duration ...
www.natap.org/2012/APASL/APASL_11.htm
VX-222 is a selective, noncompetitive inhibitor of the hepatitis C virus (HCV) NS5B polymerase.1 Telaprevir (TV

Achillion Announces Positive SVR4 Results From Phase 2 Study of Sovaprevir (Formerly ACH-1625) and Advancement of ACH-3102 - (08/09/1

BMS Suspends Study of Nucleotide BMS094 Formerly INX189 - (08/02/12)
Vertex Nucleotide Analysis - (08/01/1

Vertex Announces Positive Results from Viral Kinetic Study of the Nucleotide Analogue ALS-2200 in People with Hepatitis C - (07/30/1

Gilead Begins Single Pill Hepatitis C Study for 2014 Approval - (07/27/1

Open-Labeled Study of PSI-7977 and RBV With and Without PEG-IFN in Treatment-Naïve Patients With HCV GT2 or GT3, and GT1 - (07/13/1

A phase 1, randomized, placebo-controlled, 3-day, dose-ranging study of GS-5885, an NS5A inhibitor, in patients with genotype 1 hepatitis C - (06/20/12

Medivir announces an interferon-free phase II combination trial with TMC435 and daclatasvir to commence shortly - (07/10/12)

Open-Label Study of GS-7977 + Ribavirin Pre-Transplant - (06/22/1

Presidio Pharmaceuticals Successfully Completes Phase 1 Proof-of-Concept for PPI-668, its Potent HCV NS5A Inhibitor, in Hepatitis C Patients with Genotype-1 Infection - press release - (06/26/1

Idenix Announces Positive Clinical Data for HCV Drug Candidates IDX184 and IDX719(NS5A) - (06/20/12

Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2-6: TMC435-C202, a phase IIa, open-label study - (05/23/12)

EASL: Use of Telaprevir Plus Peg Interferon/Ribavirin for Null Responders Post OLT With Advanced Fibrosis/Cholestatic Hepatitis C - (05/04/12)

EASL: Ribavirin Dose Modification in Treatment-naïve and Previously Treated Patients Who Received Telaprevir Combination Treatment: No Impact on Sustained Virologic Response in Phase 3 Studies - (05/04/12)

EASL: NOVEL NS5A INHIBITOR ACH-2928 PHASE 1 RESULTS IN HEALTHY VOLUNTEERS AND HCV GT-1 PATIENTS - (05/02/12)

EASL: CUPIC: French Early Access Program - Compassionate Use of Protease Inhibitors in Viral C Cirrhosis - (04/26/12)

EASL/2011: Genotypic and Phenotypic Characterization of NS3 Variants Selected in HCV-Infected Patients Treated with ABT-450 - (04/05/11)

EASL: Alisporivir plus ribavirin is highly effective as interferon-free or interferon-add-on regimen in previously untreated HCV-G2 or G3 patients: SVR12 results from VITAL-1 Phase 2b study - (04/22/12)

EASL: Alisporivir (ALV) plus Peg-interferon/Ribavirin (PR) in HCV G1 Treatment-experienced Patients Achieves Primary Endpoint with Superior Efficacy at Treatment Week 12 Compared to Retreatment with PR - (04/22/1

GSK2336805 HCV NS5A Inhibitor Demonstrates Potent Antiviral Activity in Chronic Hepatitis C (CHC) Genotype 1 Infection: Results from a First Time in Human (FTIH) Single and Repeat Dose Study - (11/09/11)

EASL: Presidio Pharmaceuticals Announces Phase 1a-1b Clinical Results with PPI-668, a Potent Pan-genotypic HCV NS5A Inhibitor - (04/25/12

Safety and Efficacy of Vaniprevir (MK-7009) in Combination with Peg-interferon a-2a (Peg-IFN)/Ribavirin (RBV) in Genotype 1 Treatment-Experienced HCV-Infected Japanese Patients - (11/16/1

MK-5172, a Second Generation HCV NS3/4A Protease Inhibitor is Active Against Common Resistance Associated Variants (RAVs) and Exhibits Cross-Genotype Activity - (11/07/1

Safety and Antiviral Activity of MK-5172, a Next Generation HCV NS3/4a Protease Inhibitor with a Broad HCV Genotypic Activity Spectrum and Potent Activity Against Known Resistance Mutants, in Genotype 1 and 3 HCV-Infected Patients - (11/07/1

ANA-598 HCV Non-Nuke Phase 2b Study Preliminary Data Results Background to Phase IIb Study - (10/14/11)

New Data Reported on INX-189, HCV Nucleotide
www.natap.org/2011/HCV/112911_01.htm
Nov 29, 2011 - top-line safety and antiviral data from its ongoing clinical trial designed to evaluate additional doses of INX-189, an oral nucleotide polymerase

BI 207127 is a potent HCV RNA polymerase inhibitor during 5 days monotherapy in patients with chronic hepatitis C - (11/04/0

Safety, pharmacokinetics and antiviral effect of BI 207127, a novel HCV RNA polymerase inhibitor, after 5 days' oral treatment in patients with chronic hepatitis C - (04/27/0

Pharmacokinetics of a Polymerase Inhibitor, ABT-333, in Treatment-naïve HCV Genotype 1-Infected Subjects Following Treatment with 2 days of ABT-333 Followed by 26 Days of ABT-333 Plus Pegylated Interferon and Ribavirin (12/08/0

Safety, Tolerability, Pharmacokinetics and Antiviral Activity of the HCV Polymerase Inhibitor ABT-072 Following Single and Multiple Dosing in Healthy Adult Volunteers and Two Days of Dosing in Treatment-Naïve HCV Genotype 1-Infected Subjects (12/08/09)

Source

The Auckland Statement on Viral Hepatitis

The Auckland Statement Monday 10 September 2012, 8:43AM

Media release from The Auckland Statement

Viral hepatitis is an urgent health concern needing immediate action to prevent new infections and to prevent the rising burden of cirrhosis and liver cancer - and avoidable deaths.
In Australia and New Zealand alone, there are half a million stories of people living with hepatitis B and hepatitis C. Every single day 50 more New Zealanders and Australians are diagnosed with chronic viral hepatitis and more and more people are dying from cirrhosis and liver cancer each year. We have the capacity, knowledge and tools to tackle viral hepatitis head-on. We know what needs to be done. It is time for action and that is why we are calling on parliamentarians, responsible Ministers, health departments, and others to act now to prevent new infections and prevent avoidable deaths.

Our targets by 2016, are to:

• Halve the incidence of new hepatitis C infections by doubling the amount of new injecting equipment distributed in the general community and implementing NSPs in prisons apply consistent approaches to funding hepatitis B vaccinations for all those at greatest risk ensure at least 80% of all people living with hepatitis B or hepatitis C are diagnosed guarantee that 5% of people living with hepatitis C receive antiviral treatment each year guarantee that 10% of people living with hepatitis B receive antiviral treatment.
• A substantial scaling up of resources and efforts is needed to stop these epidemics in their tracks - otherwise liver cancer will continue to be one of the fastest increasing causes of cancer death in Australia and New Zealand. Achieving our targets will require resolute leadership,respect for human rights, a focus on those at greatest risk and in greatest need, supportive legal frameworks and a society which tolerates diversity and does not discriminate against those at risk of, or living with viral hepatitis. Those most affected by viral hepatitis often experience significant barriers to accessing health care, these include: people who inject or have injected drugs, people born overseas in countries with widespread viral hepatitis infection, Maori, Pacific Islander, Aboriginal and Torres Strait Islander peoples. While these are groups most at risk of, or most affected by viral hepatitis, achieving the prevention and treatment targets in this Statement is a human rights obligation for all Australians and New Zealanders.

SEPTEMBER 2012

THE 8TH AUSTRALASIAN VIRAL HEPATITIS CONFERENCE CALLS FOR URGENT
ACTION TO PREVENT NEW INFECTIONS AND STOP THE RISING DEATH TOLL.

• Ensure full and free access to evidence-based and effectiveviral hepatitis prevention by maximising the effectiveness ofNSPs/NEPs, removing barriers to peer distribution of injectingequipment, providing access to new injecting equipment in prisons and adequately funding peer education among peoplewho inject drugs. Access to funded hepatitis B vaccination forthose at greatest risk of infection must be improved throughinclusion in nationally consistent immunisation schemes.Improve early diagnosis and timely access to qualitytreatment, care and support for all in need by reducing thenumber of people with viral hepatitis who remain undiagnosedor unaware of how treatment can improve and extend their lives.
• To create an effective, ethical and humane response to viralhepatitis we must enhance access to diagnosis, treatmentand care delivered in the most appropriate settings.Speed up action to improve community understanding ofviral hepatitis by ensuring information on how to avoid infectionis freely available, facilitating open discussion, engendering moresupportive community attitudes, reducing stigma and discriminationand increasing support for evidence-based public health policies.
• Drive progress towards our targets as action and change inmany areas is required and a failure to act in any one area willhold back overall progress.

To achieve our targets we must:

• Ensure a policy and legal environment that is focused onending the stigma and discrimination routinely experienced bythose at greatest risk of, and living with, viral hepatitis. Laws andpractices that criminalise or treat people without basic dignity orhuman rights, have no place in an effective response to viral hepatitis.
• Acknowledge the size of the epidemics and commit to thelevel of strategic and long-term investment required to curbnew infections, increase timely access to quality treatment andcare for all in need and end the rising death toll.
• Foster strong vision, commitment and leadership on viralhepatitis at all levels that is maintained over the long-term andstrategically focused on the areas of highest need.
• Commit fundamentally to the principles of genuinepartnership which first and foremost requires meaningfulengagement with the people at greatest risk of, and living with, viral hepatitis to ensure an effective response. A commitment topartnership between the affected communities, governments,health and social services and researchers must underpin theagenda for action and change on viral hepatitis.

THE TIME TO ACT IS NOW! Sign on now at www.aucklandstatement.com

There are many challenges ahead, but the time to act is now. A failure to act now would see a steadily increasing number of people infected and a rising number of deaths from liver failure and cancer.

The 8th Australasian Viral Hepatitis Conferencecalls on parliamentarians,governments, health professionals and all members of the community to accept the challenge to create an effective and humane response to viral hepatitis in full partnership with the affected communities. Sign on now and be part of our agenda to change the face of viral hepatitis. Stop new infections. Stop the rising death toll.

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Hepatitis C drugs offer hope for cure

Dr. Brad Hare of S.F. General Hospital says it's more important than ever to identify hepatitis C carriers. Photo: Beck Diefenbach, Special To The Chronicle

Erin Allday

Published 5:16 p.m., Tuesday, September 11, 2012

Scientific breakthroughs, one piled on top of another at breakneck speed over the past few years, have put medical researchers on the cusp of curing almost everyone who suffers from hepatitis C, if not wiping out the disease entirely.

With 180 million people in the world thought to be infected with the virus - 12,000 of them in San Francisco alone - that's potentially a huge public health coup, doctors and scientists say.

In a little more than a decade, a virus that was once almost untreatable could be made nearly extinct.

"It is just a remarkable moment in the history of hepatitis C," said Dr. Warner Greene, director of the virology and immunology division at the Gladstone Institute in San Francisco. "I think hepatitis C and its sequela - liver cancer, cirrhosis, liver transplants - can largely be gone in the future. We just won't have to worry about it."

In the past year, new treatments have come out that already have doubled the number of people who can be cured of hepatitis C. Now the race is on among drug developers to market the first medical cocktails that would cure almost everyone on the planet, and do it safer and faster than the best treatments currently available.

New treatments - both those already available and those expected to be approved in the next five or so years - were a large part of the reason the U.S. Centers for Disease Control and Prevention recommended this summer that all Baby Boomers get screened for hepatitis C.

That generation is thought to have the largest number of undiagnosed cases of the disease, with so many of them potentially exposed to the virus in the wild, drug-friendly hippie years of the '60s and '70s. Until recently it wasn't practical to screen millions of people for possible cases of hepatitis C because few good treatments were available.

Hepatitis C's spread

Hepatitis C is a virus transmitted through the blood, similar to HIV. It's often spread through shared needles used by intravenous drug abusers. Decades ago, and even still in some developing parts of the world, people were exposed to hepatitis C through unsterilized equipment used for tattoos or surgical procedures. Also, the U.S. blood supply wasn't screened for hepatitis C until the early 1990s, so people sometimes became infected from a blood transfusion or organ transplant.

In roughly 20 percent of hepatitis C cases, the body's immune system fights off the virus without any medical intervention and probably without the individual ever being aware of having it. The remaining cases develop into chronic hepatitis C.

In some of those cases, the virus may lie dormant for decades, or even a lifetime, but in about 1 in 5 chronic cases, the virus will attack the liver, scarring it and causing cirrhosis, and potentially leading to liver cancer and liver failure. The infection causes about 10,000 deaths a year in the United States, and it's the leading reason for liver transplants. Hepatitis C is especially prevalent in people who also have HIV infections; in fact, HIV-positive patients are more likely to die of hepatitis-caused liver disease than of AIDS or HIV.

Antiviral drugs

It's only in the past seven years or so that doctors and scientists discovered the first antiviral drugs that can stop the virus, giving the body's natural immune system a chance to fight it off. The cure rate with those drugs is 75 to 80 percent, but they require that patients also take interferon, a toxic medication that can cause disabling side effects for a year.

In the next five years, researchers expect to develop even more potent antiviral medications - drugs that will cure more than 90 percent of patients, and do it in half the time and without the interferon.

"There's no question that with these new treatments, cure is going to be the rule and not the exception," said Dr. Brad Hare, medical director of the HIV/AIDS ward at San Francisco General Hospital, who studies HIV and hepatitis C co-infections. "It's more important than ever to identify people with hepatitis C, because we have something even better to offer them."

That said, Hare added, it's unlikely that the virus will ever be eradicated. There will always remain a pocket of people who don't respond to drug therapy or aren't able to take it for some reason. Those who have been cured can be reinfected.

And getting new medications to the tens of millions of people affected by hepatitis C won't be easy, especially because the drugs will almost definitely be expensive.

Strains on the system

Just screening the millions of Baby Boomers in the United States, and getting those who test positive for hepatitis C into treatment, could be an overwhelming strain on the health care system, public health experts say. Drugs in development could ease some of that burden if they're easier to take and more effective than the current treatments.

Hepatitis C was discovered in the late 1980s, although scientists had known for years that a virus existed that was causing inflammation in the liver and that wasn't the hepatitis A or B viruses.

The U.S. Food and Drug Administration approved the first treatment for hepatitis C - the chemotherapy drug interferon - in 1991, and added a second drug, ribavirin, in 1998. Those two medications were considered a breakthrough therapy for a virus that had previously been untreatable, but the treatment itself was rough and not all that effective.

The ribavirin comes in pill form, but the interferon has to be given intravenously three times a week for 48 weeks. Both drugs, especially the interferon, often come with awful side effects - major depression and, sometimes, suicidal thoughts, plus fatigue, nausea and flu-like symptoms.

And the worst of it is that the treatments lead to a cure only roughly half the time - less than half for patients with the most common strain of hepatitis C.

"A lot of us didn't have bad symptoms before we went on treatment," said Daniel Berrner, a San Francisco resident who was diagnosed with both HIV and hepatitis C in 2005, and underwent successful treatment for the latter in 2009. "People maybe feel some fatigue, but that's it. So to convince them to feel awful for a year when they're not feeling that bad to begin with is a really hard thing to do."

Because treatment was, for many people, tougher to endure than the virus itself, many doctors over the years have "triaged" patients by performing liver biopsies or blood tests to determine if hepatitis C was causing severe enough damage to treat even at the risk of failure. If patients weren't experiencing acute symptoms and their livers seemed relatively healthy, they'd often postpone treatment.

More seek treatment

Whether to get treatment for hepatitis C is still a personal decision and best made after a thoughtful conversation with a primary care doctor or a liver expert, doctors said. But increasingly patients are being encouraged to get treatment, even if their infection isn't particularly virulent.

"I still try to triage based on the risk of end-stage liver disease. But now more patients are willing to be treated," said Dr. Natalie Bzowej, a liver disease specialist at California Pacific Medical Center.

Bzowej helped lead national research into one of the first antiviral treatments that targeted hepatitis C, a protease inhibitor called telaprevir made by Vertex Pharmaceuticals, which was approved by the FDA in June 2011. A similar drug, boceprevir from Merck, also won FDA approval last year.

Remarkable success

In clinical trials, about 80 percent of patients with the most common strain of hepatitis C who took one of those drugs, plus the usual interferon and ribavirin combination, were cured. That was a remarkable improvement over the previous 40 to 50 percent cure rate.

Also encouraging: Most of the patients who were cured were able to stop taking the medications after just 24 weeks, cutting the treatment time in half.

The reason for the difference is that the new drugs single out the hepatitis C virus specifically, whereas the interferon and the ribavirin essentially just give a boost to the body's natural immune system. For many people, the immune system is not strong or fast enough on its own to fight off the virus.

Protease inhibitors are best known as a class of drugs used to treat HIV infection. They work by attacking specific enzymes, or proteases, in a virus that are a key part of the replication process. By inhibiting those enzymes, the virus is unable to reproduce and eventually dies off.

Now, scientists are looking for the next line of drugs to attack other points of the hepatitis life cycle. The pharmaceutical industry is racing toward clinical trials - companies battling to be the first to get new drugs, especially those that would make interferon obsolete, to the market.

Multidrug attack

Doctors and scientists alike expect the first of the new wave of drugs to be available in four or five years. Part of the reason not everyone can be cured of hepatitis C is that, like many viruses, it mutates so quickly and becomes immune to drugs. So ideally, doctors will have at their disposal several drugs - maybe dozens - that will attack the virus on several fronts at once.

If those drugs are strong and fast enough, they could cure patients without the need for interferon. Protease inhibitors and other antiviral drugs aren't without side effects, but the symptoms are much less severe than those from interferon, and the newest classes of drugs may work in as little as 12 weeks, or about half the time it takes telaprevir, the protease inhibitor, to do the job.

"I feel like we are glimpsing the beginning of the end for hepatitis C," said Dr. Cami Graham, vice president of global medical affairs at Vertex. "We really are beginning to see what that path to eradication is going to look like."

Long incubation period

Both drug developers and doctors alike said they are advising patients not to raise their hopes too high. Almost all of the clinical trials are in their earliest stages, and for the Baby Boomers especially, patients with decades-old infections may not have even a few years to wait for new treatments.

"What we have now is better than anything we've had in a long time," said Dr. Joanna Ready, chief of gastroenterology at Kaiser Santa Clara. "What will be even better is interferon-free therapies, and the early studies have been very, very, very promising. But the disease has such a long incubation period and damages the liver over decades, so we really need to be following people over time.

Still, Ready said, she's hopeful.

"If we don't wipe out hepatitis C entirely, we can probably make it go away like polio, where you haven't gotten rid of it but you've really beaten it down," she said. "The science behind these treatments is improving every day. And the more we know, the better we are at treating it."

Erin Allday is a San Francisco Chronicle staff writer. E-mail: eallday@sfchronicle.com

Source

Combo Pills Fail to Get More HIV Patients on Meds

This report is part of a 12-month Clinical Context series.

By Ed Susman, Contributing Writer, MedPage Today

Published: September 11, 2012

Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, BSN, RN, Nurse Planner

SAN FRANCISCO – Single-pill regimens that simplify HIV treatment were of no help in getting people who don't take medication to start, researchers said here.

About 10% of patients prescribed a single-pill regimen did not fill those prescriptions, Cal Cohen, MD, of the Community Research Initiative of New England, in Boston, reported at the Interscience Conference on Antimicrobial Agents and Chemotherapy.

"What I found striking about these results," Cohen told MedPage Today, "was when patients were prescribed single-pill regimens there was no difference in the percentage of patients who were completely non-adherent."

About 8% of patients prescribed a non-nucleoside reverse transcriptase inhibitor-based regimen didn't fill those prescriptions; 12% of patients with boosted protease inhibitor-based regimens and 10% of those with an integrase inhibitor-based regimens didn't fill those prescriptions, according to Cohen.

The differences were not statistically significant, he said.

Doctors have believed that as HIV regimens become easier to use – such as a once-daily, single-pill regimens – the adherence levels would improve, said Cohen, who is also with Harvard Medical School/ Brigham and Women's Hospital in Boston. But in this study that compared non-adherent and partially adherent patients, there was no progress in the completely non-adherent group.

Cohen and colleagues retrospectively examined the LifeLink database of pharmacy and medical claims, identifying patients with an HIV diagnosis between January 2009 and the end of 2011 who received complete antiretroviral prescriptions. Adherence was reported as the percent of time with a complete regimen, a partial regimen and no antiretroviral medication. Refill data were used to analyze compliance.

The researchers found that 1,751 patients were assigned single tablet regimens; 522 were on regimens that included raltegravir; 1,601 patients were prescribed regimens containing a boosted protease inhibitor; and 675 were on a non-nucleoside reverse transcriptase inhibitor-based regimen.

The group also found that patients who were partially adherent – they took some drugs as prescribed and others randomly or not at all for periods that lasted as long as a month – ended up being hospitalized more frequently when compared with people who were prescribed single-tablet regimens. The partially adherent patients also ended up hospitalized 43% to 54% more often than the completely non-adherent patients.

For example, completely non-adherent single-tablet-regimen patients were hospitalized about 10.2% of the time, compared with 14.6% of those on the raltegravir-based therapy who took part of their regimen some of the time (P<0.0001). However, Cohen said that one of the limitations of the study is that patients were not randomized to one treatment or the other, allowing for unmeasured confounding to exist.

Cohen said the database didn't specify if the patients were hospitalized for HIV/AIDS-related illness. But he said his study suggests that single-pill regimens would eliminate hospitalizations among patients who were partially adherent, so he recommended using the simplified regimens.

In commenting on the study, Dan Bowers, MD, adult HIV and primary care provider at the Callen-Lourde Community Health Center Clinic, New York City, told MedPage Today, "I am not surprised at these results. There [is] a certain percentage of patients who just will not take their medications. It is not just limited to HIV patients. Some patients with any form of chronic disease will not take medication. There is a certain level that is beyond breakthrough."

The study was supported by Gilead Sciences.

Cohen has disclosed commercial interests with Bristol-Myers Squibb, Janssen Pharmaceuticals, Merck & Co.; and ViiV Healthcare. Bowers had no disclosures.

Primary source: Interscience Conference on Antimicrobial Agents and Chemotherapy
Source reference:
Cohen C et al, "H-211 - Association between selective adherence to antiretroviral therapy and hospitalization risk in an HIV population" ICAAC 2012.

Source

Presidential Proclamation -- National Alcohol and Drug Addiction Recovery Month, 2012

The White House

Office of the Press Secretary

For Immediate Release August 31, 2012

NATIONAL ALCOHOL AND DRUG ADDICTION RECOVERY MONTH, 2012

BY THE PRESIDENT OF THE UNITED STATES OF AMERICA

A PROCLAMATION

Every day, millions of Americans with substance use disorders commit to managing their health by maintaining their recovery from drug or alcohol addiction. People in recovery are not strangers: they are our family members, friends, colleagues, and neighbors. During National Alcohol and Drug Addiction Recovery Month, we recognize their strength and resilience. In partnership with Americans in recovery, let us rededicate ourselves to combatting prejudice surrounding addiction, removing barriers to recovery, and standing with all those seeking lives free from substance use.

My Administration is committed to advancing evidence based recovery solutions. Over the past 3 years, we have worked to strengthen substance abuse prevention and treatment programs, and to support Americans in recovery. We have taken steps to identify and remove laws, policies, and practices that impede recovery. And as part of our 2012 National Drug Control Strategy, we are promoting early intervention and taking action to break the cycle of drug abuse and incarceration.

Drug and alcohol abuse continue to take a tragic toll on millions of lives across our country. Yet, while more remains to be done, men and women across our country are making great strides. This month, let us encourage their progress, celebrate the transformative power of recovery, and thank the many Americans who, often strengthened by their own experiences, are working to improve the health and safety of our communities.

NOW, THEREFORE, I, BARACK OBAMA, President of the United States of America, by virtue of the authority vested in me by the Constitution and the laws of the United States, do hereby proclaim September 2012 as National Alcohol and Drug Addiction Recovery Month. I call upon the people of the United States to observe this month with appropriate programs, ceremonies, and activities.

IN WITNESS WHEREOF, I have hereunto set my hand this thirty first day of August, in the year of our Lord two thousand twelve, and of the Independence of the United States of America the two hundred and thirty-seventh.

BARACK OBAMA

Source

Vaccine Trial Reveals Weak Spots in HIV's Armor

An AIDS vaccine has been a major goal of researchers for two decades. Image: Karen Kasmauski/Science Faction/Corbis

A new analysis identifies targets for an immune response that could improve AIDS vaccines

By Ewen Callaway and Nature magazine

From Nature magazine

HIV is finally revealing its weak spots to researchers, bringing an effective vaccine against AIDS closer to reality.

A paper published in Nature today¹ sheds light on how a vaccine can turn the immune system against the invading virus and so offer protection from infection. The results are also being presented at the AIDS Vaccine 2012 conference in Boston, Massachusetts, this week.

The findings help to explain the results from a clinical trial of an AIDS vaccine that have puzzled researchers since they were published three years ago². The trial, called RV144, was the first to score a success and see a reduction in HIV infections. But the vaccine’s relatively low response rate of 31% left researchers scratching their heads.

A clue emerged last year with the revelation that those who responded to the vaccine and fended off HIV tended to produce antibodies against a specific part of the virus's protein shell called the V1/V2 loop³. The study published today goes a stage further, showing that the people who were vaccinated yet still contracted HIV had been infected by viruses that had mutations in the the V2 portion.

“This is a really good paper,” says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland. “It adds to the growing body of information indicating that an immune response against components of the V1/V2 loop is important in vaccine-induced protection against infection.”

The team behind the study was led by Morgane Rolland and Jerome Kim at the US Military HIV Research Program in Silver Spring, Maryland. They examined 936 HIV sequences collected from 44 trial participants who received the vaccine and became infected, and 66 people who got the placebo. The trial was randomized, so any systematic differences in the viral DNA sequences between the two groups will be due to selective pressure by the vaccine in favour of viruses that do not match the vaccine, Rolland says.

The team identified two mutations that seemed to be linked to vaccination success. Both were located in the V2 region of the V1/V2 loop. Rolland and Kim's team compared the rates of infection with viruses whose sequence varied at these two sites between people who received the vaccine and those who got a placebo. People who received the vaccine were 80% less likely to be infected by viruses with these mutations, compared to people who got a placebo. The implication is that the vaccine triggered an immune response that prevented certain viruses from infecting them, and only viruses with different sequences at those two sites had a good chance of creating an infection.

Another study, led by researchers at NIAID, to be presented at the vaccine conference this week analysed the molecular structure of antibodies from the blood of vaccinated people and found that some of their antibodies recognized the same amino acids in the V2 region.

The question facing vaccine developers now is how to improve the response against V2. A vaccine similar to that used in RV144 is set to be tested in South Africa and among men who have sex with men in Thailand in two trials that will begin around 2014. Scientists hope that giving a booster within a year of the first jab and a new adjuvant will lead to a stronger and longer-lasting response against HIV and its V2 region, says Kim who is helping to design the trials.

Mounting a response against V2 “isn’t the whole answer to vaccine protection”, says Fauci, but “you can be darn sure people are going to figure out how to rev it up”.

Source

British researchers uncover genetic clues to common autoimmune liver disease

[Date: 2012-09-11]

A team of scientists has used a new technology to uncover three genetic regions associated with primary biliary cirrhosis (PBC), a chronic and progressive disease of the liver.

The aim of the study was to survey more thoroughly regions of the genome known to underlie other autoimmune diseases, to discover if they also play a role in PBC susceptibility.

Scientists used a DNA microchip called Immunochip in their tests: the advantage of Immunochip over genome-wide technologies is that it focuses only on regions of the genome known to be associated with an autoimmune disease, and thus captures more of the genetic variation within these regions. Immunochip can therefore be used to more thoroughly test these key candidate genes for association to a whole-host of immune-related traits, and to identify low-frequency and rare genetic variants associated with disease that would likely be missed by a microarray covering a broader range of genetic regions.

Writing in the journal Nature Genetics, the researchers outline how they identified three genetic regions associated with PBC, increasing the number of known regions associated with the disorder to 25.

By combining the results from this survey with details of gene activity from a database called ENCODE, they were able to identify which cell types are most likely to play a role in PBC.

PBC affects approximately one in a thousand women over the age of 40. The condition is characterised by inflammation in the bile ducts that blocks the flow of bile, damaging the liver cells and causing further inflammation and scarring. In severe cases, this results in the need for a liver transplant.

As there is currently no cure for PBC, treatment is focused on slowing down the progression of the disease and treating any symptoms or complications that may occur. The biological pathways underlying primary biliary cirrhosis are poorly understood, although autoimmunity, where the body attacks its own cells, is known to play a significant role.

Co-senior author of the study Dr Carl Anderson from the Wellcome Trust Sanger Institute comments: 'Previous genetic screens have identified 22 regions of the genome underlying PBC risk, and many of these are known to play a role in other autoimmune diseases, such as multiple sclerosis and type I diabetes. Using the Immunochip we were able to perform a much more thorough screen of the genomic regions previously associated with other autoimmune diseases. This resulted in us identifying a further three regions involved in PBC risk and identifying additional independent signals within some of those we already knew about.'

The hope is that these results could lead to the development of a new therapeutic approach for the treatment of PBC.

For more information, please visit:
Wellcome Trust Sanger Institute:
http://www.sanger.ac.uk/

Category: Miscellaneous
Data Source Provider: Wellcome Trust Sanger Institute
Document Reference: Liu, J. Z. et al., Dense fine-mapping study identifies novel disease loci and implicates coding and non-coding variation in primary biliary cirrhosis risk, Nature Genetics, 2012. doi:10.1038/ng.2395
Subject Index: Medicine, Health; Life Sciences; Scientific Research

RCN: 35009

Source

Bristol-Myers Squibb Discontinues Development of BMS-986094, an Investigational NS5B Nucleotide for the Treatment of Hepatitis C

Company will share BMS-986094 data with other companies developing similar hepatitis C drugs to inform patient safety measures

Thursday, August 23, 2012 6:20 pm EDT

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE: BMY) announced today that the Company has discontinued development of BMS-986094 (formerly known as INX-189), a nucleotide polymerase (NS5B) inhibitor that was in Phase II development for the treatment of hepatitis C. This decision was made in the interest of patient safety, based on a rapid, thorough and ongoing assessment of patients in a Phase II study that the Company voluntarily suspended on August 1, 2012. The U.S. Food and Drug Administration (FDA) subsequently placed the compound on clinical hold.

The initial case of heart failure, which was the basis for halting the study, subsequently resulted in death. The Company is working in close collaboration with the FDA and clinical study investigators to conduct ongoing, comprehensive assessments and close follow-up of all BMS-986094 study patients. To date, nine patients have been hospitalized, including the initial patient; two patients remain hospitalized. While the cause of these unexpected events, which involve heart and kidney toxicity, has not been definitively established, the Company has determined that it is in the best interest of patients to halt development of BMS-986094.

“The decision to halt development of BMS-986094 has been guided by our overriding interest in protecting patients,” said Elliott Sigal, M.D., Ph.D., Executive Vice President and Chief Scientific Officer, Bristol-Myers Squibb. “In the interest of all patients participating in hepatitis C clinical studies, and in cooperation with the FDA, we will make relevant information on BMS-986094 available to inform the development of other investigational compounds to treat hepatitis C. We will also work expeditiously to share the results of our further investigations more broadly in the medical and scientific community.”

Bristol-Myers Squibb is committed to investigating this safety issue further, including studies to evaluate the potential mechanism of this toxicity. The Company will continue close monitoring and follow-up of patients who have received BMS-986094 across all studies.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol-Myers Squibb, visit www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.

 

Contact:

Bristol-Myers Squibb Company
Media:
Sonia Choi, 609-252-5132
sonia.choi@bms.com
or
Cristi Barnett, 609-252-6028
cristi.barnett@bms.com
or
Investors:
John Elicker, 609-252-4611
john.elicker@bms.com
or
Timothy Power, 609-252-7509
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Discriminatory Donor Policies Substitute Stereotypes for Science

People rest on tables as they give blood for the Red Cross in Princeton, New Jersey. The lifetime deferral policy for MSM blood donors has been called into question for years because of its lack of a scientific basis and its failure to reflect the current technologies used by blood donation centers across the country. SOURCE: AP/Mel Evans

By Andrew Cray | September 11, 2012

Every day in the United States, 43,200 people—one every two seconds—need life-saving blood transfusions. In that same 24 hours, 18 people will die while waiting for a donor organ, with the gap between donated organs and those on the waitlist growing every year. Our country is in the midst of what could only be described as a critical shortage of the blood, tissue, and organ donations that sustain and improve the lives of patients across our country.

Yet the Department of Health and Human Services’ policies on donor eligibility prevent donation by gay men because of outdated assumptions that are decades out of step with medical science. These policies harm patients who would benefit from the department modernizing these standards, which amount to little more than discriminatory relics of the past. As noted by Rep. Mike Quigley (D-IL), “Equality for the LGBT community is closer than ever, but outdated and discriminatory policies … must evolve to match advancements in science and technology.”

Thirty years ago The New York Times ran an article describing “a matter of urgent public health and scientific importance.” The urgent matter was the appearance of a new disease, then known as gay-related immunodeficiency, or GRID, and now known as the human immunodeficiency virus, or HIV. That same year, several blood transfusion recipients who did not match the pattern for transmitting GRID were diagnosed with the disease, and researchers later began to understand the role that blood transfusion and other transfer of human tissues played in the spread of the disease.

These events culminated in the Department of Health and Human Services developing the first of several policies that would restrict gay men from donating life-saving blood, tissue, and organs. This initial policy on blood donor eligibility—requesting voluntary deferral by “sexually active homosexual and bisexual men with multiple partners”—was the most plain of the donation policies that would evolve over the next several decades in targeting donors for exclusion on the basis of their sexual orientation.

But these deferral policies reveal more than just a problematic reaction to the early stages of the HIV epidemic in the United States. They also offer a glimpse into the persistent discriminatory motivations that underlie current limitations on blood, tissue, and organ donation by men who have sex with men, or MSM. These policies, which have endured despite significant advances in testing, screening, and transmission prevention, are vestiges of antiquated bias and misinformation, and no longer align with the progress made in medical technology and public health policy.

Blood donation

The ban on MSM blood donation is the most well-known of the U.S. donation policies that discriminate against men who have sex with men. This policy, modified from the original voluntary deferral established in the 1980s, has grown to require permanent deferral by any man who has had sex with another male, even once, since 1977. By contrast, non-MSM donors who are also considered to be high risk are often permitted to donate with little or no deferral period at all. A person who has heterosexual sexual contact with a person who has used injection drugs, for example, is only prohibited from donating blood for 12 months.

The lifetime deferral policy for MSM blood donors has been called into question for years because of its lack of a scientific basis and its failure to reflect the current technologies used by blood donation centers across the country. The technological developments of the past decade have made blood testing so effective that the probability of HIV transmission through blood transfusion is only one in 1.5 million—less than half the risk posed in the mid-1990s.

The use of a more precise blood donor questionnaire could further reduce this risk by asking questions about sexual practices, including the use of barrier contraceptives and the sexual contact a potential donor has participated in. This would reflect the actual variation in transmission risk based on the type of sexual contact a potential donor has had, as well as the reduction in that risk through the use of condoms.

While the Department of Health and Human Services recently proposed a pilot study designed to explore alternative donation deferral policies for men who have sex with men—a move toward evidence-based donor screening practices—the blood donation ban remains in effect. This in turn aggravates an ongoing blood shortage, which could be drastically reduced or even eliminated by lifting the MSM donation ban, potentially saving an additional 650,000 lives each year.

Tissue and tissue product donation

The same arm of the Food and Drug Administration that regulates blood donation—the Center for Biologics Evaluation and Research—also sets eligibility standards for donors of tissue and tissue products. Examples of the types of tissue that the center regulates include bone, skin, heart valves, tendons, and sperm.

The conversation about tissue donation policies—specifically sperm donation—has been reignited over the last month with a slew of bloggers, doctors, and even television shows criticizing the FDA’s policy. But even though the last month has seen increased talk about tissue donor standards, industry guidance put in place by the Center for Biologics Evaluation and Research on tissue donation by gay men and other men who have sex with men has been in place for five years.

The restrictions on tissue donor eligibility for men who have sex with men, however, are less restrictive than those on blood donor eligibility. Rather than a lifetime prohibition on donation, men who have had sex with another man in the preceding five years are ineligible to donate, effectively imposing a five-year abstinence requirement for potential gay donors.

Though less restrictive, tissue donor standards still discriminate against men who have sex with men by limiting their eligibility more tightly than other prospective donors who are considered to be high risk. As with blood donation, for example, a person who has heterosexual sexual contact with an injection drug user is only prohibited from donating blood for 12 months.

Tissue donor eligibility standards propagate the same outdated stigmatizing message about gay men as the blood donation ban, and still without scientifically valid rationale. Furthermore, tissue donation standards applying to sperm donors adversely affect lesbian, gay, bisexual, and transgender families. Some gay women prefer to receive sperm from gay donors, and prohibiting donation for a significant number of these men puts additional barriers in place to creating families, at the cost of the autonomy and the preferences of parents.

Organ donation

The last and probably least well-known discriminatory MSM donation policy relates to organ donor eligibility. Organ donation standards are set by a different branch of the Department of Health and Human Services than blood and tissue policies—the Health Resources Services Administration, which sets criteria for donors of vascularized human organ transplants, including the kidney, liver, heart, lungs, and pancreas.

Organ donor eligibility standards represent the current best balance, though not ideal, between maintaining a safe supply of donor organs while treating men who have sex with men fairly when compared with other potential donors. Currently, organ procurement organizations are required to obtain a medical history for potential donors to identify factors associated with increased risk for disease transmission, including HIV transmission. If a potential donor meets criteria set forth in the current Public Health Service guidance, the organ procurement organization must communicate that information to transplant programs receiving organs from the donor. The guidance classifies men who have had sex with another man in the preceding five years as high risk.

A second policy requires that transplant programs obtain informed consent prior to transplantation of an organ when, in that transplant program’s medical judgment, the donor has a recognized increased risk for disease transmission. As a result of these two policies, sexually active MSM organ donors are not subject to any deferral requirement or donation ban, but the transplant programs receiving the organs, and possibly the organ transplant recipient, must be informed of the purported increased risk factors of the donor.

Of course, policies based on the presumption that men who have sex with men pose increased risk miss the mark by failing to recognize the variation in risk between kinds of sexual contact, both for MSM and non-MSM potential donors. And similar to practices in blood donor screening, MSM organ donors are not asked about use of condoms, once again failing to acknowledge the drastically reduced risk of disease transmission associated with safer sex practices.

Unique to the context of organ donation is the treatment of HIV-positive donors and transplant recipients. Individuals at high risk for HIV, as well as individuals who are HIV positive, can receive organ transplants. But a recent study suggests that approximately 500 HIV-positive people in need of replacement livers and kidneys could receive them each year if organ donations by HIV-positive donors were also permitted. This change could potentially provide transplanted organs to every HIV-positive transplant candidate on the waiting list.

For HIV-positive potential donors, however, legislative roadblocks prevent the donation of potentially life-saving organs. Regulations implementing the National Organ Transplant Act of 1984, passed at the height of antigay rhetoric surrounding HIV/AIDS, require the adoption of standards for preventing the acquisition of organs from individuals known to be infected with HIV. The act thus prohibits the acquisition of organs from HIV-positive donors, while hundreds of HIV-positive people in need of donated organs languish on long transplant waitlists.

The discriminatory roots of this ban are underscored by the fact that HIV transmission policies are significantly more restrictive than policies addressing other infections that can also be transmitted during the transplantation process. Individuals who test positive for Hepatitis C, for example, are permitted to donate organs to patients who also have Hepatitis C.

Donation policies need to be based in science, not in discriminatory bias

Balancing the safety and adequacy of the nation’s donated blood, tissue, and organs is undoubtedly a pressing health policy challenge. But the use of policies that discriminate against gay men, resting on presumptions that are decades behind science, do not reflect the best solution. Instead, the donation limitations for men who have sex with men promote homophobic attitudes and inaccurate assumptions about gay men that drive the HIV epidemic and prevent progress in the development of evidence-based policies and standards.

Ensuring improved public health and safety will require full use of advances in medical technology, the development of donor screening standards that accurately measure risk equally among all potential donors, and dedication to public policy that progresses beyond outdated biases.

Andrew Cray is a Research Associate for LGBT Progress at the Center for American Progress.

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Injection drug use, blood transfusions biggest risk factors for hepatitis C

Allison RD. J Infect Dis. 2012;206:654-661.

September 6, 2012

The study, which began enrollment in August 1990, included 738 volunteer blood donors who tested positive for hepatitis C antibodies. Confirmation testing was done using third-generation recombinant immunoblot assays (RIBA). The donors were interviewed by a physician about their histories, including illicit drug use. Liver biopsy specimens were taken from 185 patients with RIBA-confirmed hepatitis C.

Among the 738 volunteers, 469 had hepatitis C confirmed using RIBA. On multivariate analysis, the most significant risk factor was injection drug use, with an OR of 35 (95% CI, 10.4-218), followed by receiving a blood transfusion before 1991, with an OR of 9.9 (95% CI, 5.6-18.3). Intranasal cocaine use was also a significant risk factor, with an OR of 6.4 (95% CI, 3.8-11.2). In a subset of intranasal cocaine users who denied injection drug use and blood transfusion, the OR was 8.5 (95% CI, 4.9-15.1).

Among those who were confirmed with RIBA, 384 had hepatitis C virus RNA. From these patients, 33% of liver biopsy specimens showed no fibrosis, 52% had mild fibrosis, 12% had bridging fibrosis and 2% had cirrhosis.

“Identification of silent HCV carriers and access to treatment remain major public health hurdles, but among treated subjects, the number who will not achieve a sustained virologic response has been reduced dramatically with the recent licensure of protease inhibitors,” the researchers wrote. “Since the majority of HCV-infected individuals will not be treated in the near term, continued long-term follow-up is critically needed to provide better estimates of clinical and histologic outcomes after 3 or more decades of HCV infection."

Disclosure: The researchers report no relevant financial disclosures.

Source

Challenges remain in reaching 100% cure rate in HCV

September 10, 2012

SAN FRANCISCO — More than 20 years after hepatitis C was first discovered, its incidence has increased significantly, but there have also been significant advances in its treatment, according to a keynote lecture by Charles M. Rice, PhD, at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy.

Rice, the Maurice R. and Corinne P. Greenberg Professor in Virology at The Rockefeller University, discussed how far we’ve come in identifying and treating hepatitis C, but also emphasized that challenges remain to reach the 100% cure rate goal.

“The treatment for hepatitis C is going to get more complicated before it gets simple,” Rice said. “The good news is that the field is changing on a daily basis.”

Burden of HCV

Hepatitis C is a global problem, affecting more than 130 million people worldwide. Although its incidence in the United States has declined since 2007, the mortality associated with hepatitis C has surpassed that of HIV and it is expected to continue to rise. In fact, it is not expected to peak until about 2020, Rice said.

According to Rice, one of the reasons that hepatitis C has taken a back seat to other infectious diseases is that it is initially asymptomatic. There is a slow progression to symptomatic disease, so most people do not know that they are infected.

“We are unable to predict which patients are going to go on to develop liver cancer or cirrhosis, or which people are going to live 50+ years and ultimately succumb to another illness,” Rice said. “This is a frustrating aspect of hepatitis C, for both patients and clinicians.”

Since its discovery in 1989, there have been several goals related to hepatitis C. One, cleaning up the blood supply, has been successfully reached in the United States. An ongoing goal is educating high-risk people and another goal, treatment success, is dependent on identifying people who are infected.

“Many people don’t know of their infection until they already have severe liver damage,” Rice said. “Less than 50% of people with hepatitis C know that they have it.”

As for research of hepatitis C, there are challenges. The first is that the virus is difficult to replicate in cell cultures. The ideal model for research is the chimpanzee model, which is the most important model for all hepatitis viruses. The problem is that it is very difficult and expensive to work with. There is not yet a small animal model that is ideal for researching the virus.

Despite these challenges, the good news is that successful treatment does represent a cure in most cases, Rice said. Sustained virologic response is defined as having undetectable virus at 6 months after treatment. In 95% of the cases that achieve that, the response is durable.

Treatment response

Treatment for hepatitis C has also improved since interferon alfa was approved by the FDA for treatment. The addition of ribavirin to interferon significantly improved the rate sustained virologic response, though alone, ribavirin had no effect. Later, the introduction of pegylated interferon also demonstrated a benefit.

Within the past year, the most significant addition to the treatment armamentarium has been protease inhibitors, boceprevir (Victrelis, Merck) and telaprevir (Incivek, Vertex).

However, although we are approaching a 75% cure rate with the protease inhibitors, they are associated with adverse effects. Patients who are receiving these therapies, along with pegylated interferon and ribavirin, are often hospitalized, Rice said. The drugs are also expensive.

“We’re at a stage where we have good proof of concept that these antivirals can improve therapy, but we still have a long way to go,” Rice said.

Eventually, the goal is to find treatment regimens that do not include pegylated interferon, and if possible, regimens that include neither pegylated interferon or ribavirin, Rice said. One promising option is the combination of daclatasvir (Bristol-Myers Squibb) and GS-7977 (Gilead), which resulted in a cure rate of 100% just 4 weeks after going off treatment, according to a study presented at the European Association for the Study of Liver Disease this year.

“This is very exciting,” Rice said. “We’ve gone from the mystery virus discovered in the mid-80s, to having diagnostics in place in the early 90s, and now approaching a 75% cure. The question is how do we get to a 100% cure? This is the ultimate goal.”

For more information:

Rice C. Emerging New Issues in the Management of Hepatitis C Infection. Presented at: 52nd ICAAC; Sept. 9-12, 2012; San Francisco.

Disclosure: Dr. Rice reports financial relationships with Apath, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, iTherX, Merck, Novartis and Vertex Pharmaceuticals.

Source

Warning over sirolimus in HCV-positive liver transplantation

By Kirsty Oswald, medwireNews Reporter

10 September 2012

Liver Transpl 2012; 18: 1029–1036

medwireNews: Sirolimus, whether given at the time of liver transplantation (LT) or after, is associated with poorer outcomes in patients with hepatitis C virus (HCV) infection compared with those who do not take the immunosuppressant, shows a US study.

The findings help provide important information on the controversial use of mammalian target of rapamycin (mTOR) inhibitors as primary immunosuppressants after LT.

"The results of this analysis suggest that mTOR inhibitors should be used with great caution in LT recipients with HCV infections," write Michael Charlton (Mayo Clinic and Foundation, Rochester, Minnesota, USA) and colleagues in Liver Transplantation.

The study included 26,414 transplant patients, included in the Scientific Registry of Transplant Recipients. Overall, 12,589 had an underlying HCV infection and sirolimus was prescribed at discharge in 1685 patients. Patients were followed up at 6 months and annually thereafter.

Multivariate analysis showed that patients with HCV were 26% more likely to die within 3 years if they were given sirolimus at discharge compared with those who were not. However, in HCV-negative patients, there was no significant association between sirolimus and risk for mortality.

In comparison, the calcineurin inhibitor, tacrolimus was associated with a 26% reduction in the risk of 3-year mortality in HCV-positive patients and a 44% reduction in HCV-negative patients.

To minimize the likelihood that their findings were due to sirolimus being prescribed in the most high-risk patients, the authors conducted a propensity analysis, controlling for factors known to affect posttransplant survival. However, the influence of sirolimus on 3-year mortality persisted.

The authors also found that patients taking sirolimus for longer than a year and those that began treatment more than a year after surgery had reduced survival compared with those who took the immunosuppressant immediately after surgery but for less than a year.

In an accompanying editorial, Parul Agarwal and Michael Lucey (University of Wisconsin, Madison, USA) say that the study "sounds an important note of warning regarding the use of mTOR inhibitors in HCV-infected LT recipients."

However, they caution that the study has significant limitations and say that further research is needed.

"A greater understanding of the relative impact of available immunosuppressive agents on key posttransplant outcomes is one of the most pressing needs of the LT community," the authors concur.

medwireNews (www.medwire-news.md) is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2012

Free abstract

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Acupuncture Does Help for Chronic Pain

By Nancy Walsh, Staff Writer, MedPage Today

Published: September 10, 2012

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

Acupuncture provides more relief from various types of chronic pain than does usual care and should be considered a valid therapeutic option, the authors of a meta-analysis concluded.

For back and neck pain, osteoarthritis, and chronic headache, pain scores among patients treated with acupuncture were 0.23 (95% CI 0.13 to 0.33), 0.16 (95% CI 0.07 to 0.25) and 0.15 (95% CI 0.07 to 0.24) standard deviations below the scores for patients receiving sham acupuncture (P<0.001 for all), according to Andrew J. Vickers, DPhil, of Memorial Sloan-Kettering Cancer Center in New York City, and colleagues.

But effect sizes were even larger when acupuncture was compared with no acupuncture, with scores of 0.55 (95% CI 0.51 to 0.58), 0.57 (95% CI 0.50 to 0.64), and 0.42 (95% CI 0.37 to 0.46) standard deviations lower (P<0.001 for all), the researchers reported online in Archives of Internal Medicine.

Acupuncture is recognized as having certain physiologic effects that can contribute to pain relief, but no plausible mechanism has been identified that could lead to long-term benefits for chronic pain, with the result that the treatment remains "highly controversial," according to the researchers.

Many controlled studies of acupuncture for pain have been published, but quality has been inconsistent and reliability has been questioned.

To provide more clarity about the effects of acupuncture on pain, Vickers and colleagues conducted an individual patient data meta-analysis based exclusively on high quality randomized trials.

Included trials required pain of at least a month's duration, with the primary endpoint being assessed at least a month after acupuncture treatment began.

The researchers were able to acquire the original raw data for 29 studies that included 17,922 patients.

To explain the clinical significance of the effect sizes found in the meta-analyses, they noted that a typical pain score in a clinical trial might be 60 on a 100-point scale.

If the standard deviation was assumed to be 25, scores after treatment could be 30 for true acupuncture, 35 for sham acupuncture, and 43 for no acupuncture, they estimated.

Another way of looking at this would be that if response was categorized as a decrease in pain of 50%, response rates would be 50% for true acupuncture compared with 42.5% and 30% for sham acupuncture and no acupuncture, respectively.

"The average effect, as expressed in the meta-analytic estimate of approximately 0.5 [standard deviations], is of clear clinical relevance whether considered either as a standardized difference or when converted back to a pain scale," Vickers and colleagues stated.

They noted that there was significant heterogeneity in a number of the analyses, particularly in the control groups of the various studies.

In some trials, for example, patients in the usual-care control groups were permitted to have rescue analgesics only, while in other studies there were exercise and physical therapy programs.

Moreover, in the sham acupuncture trials, different approaches were permitted, such as using nonpenetrating needles and using non-needle methods such as inactive electrical stimulation.

Other limitations of the meta-analysis included the possibility of bias when acupuncture was compared with no acupuncture and the use of different endpoints in some trials.

Nonetheless, the authors stated that their findings should be considered "both clinically and scientifically important."

They noted that many clinicians would be unwilling to refer a patient for acupuncture if the effects derived only from the nonspecific belief on the part of the patient that the treatment would help.

But the finding that true acupuncture had significantly greater effects than the sham procedure indicates that the effects of the procedure do extend beyond placebo, they observed.

This is "of major importance for clinical practice," meaning that acupuncture should be considered "a reasonable referral option for patients with chronic pain," they stated.

In an invited commentary accompanying the meta-analysis, Andrew L. Avins, MD, of Kaiser-Permanente in Oakland, Calif., argued that the benefits indeed were primarily those associated with the placebo effect, because the pain relief was so much greater when acupuncture was compared with usual care than when compared with the sham procedure.

But whether that should mean acupuncture has no value for patients, largely because of uncertainty as to its mechanisms of action, is a crucial concern, he pointed out.

"The ultimate question is: does this intervention work (or, more completely, do its benefits outweigh its risks and justify its cost)?" Avins wrote.

For acupuncture, the current meta-analysis offers "some robust evidence" that acupuncture does provide greater chronic pain relief than usual care, mechanisms of effect aside.

"Perhaps a more productive strategy at this point would be to provide whatever benefits we can for our patients, while we continue to explore more carefully all mechanisms of healing," Avins concluded.

Funding for this work was provided by the National Center for Complementary and Alternative Medicine, the Samueli Institute, and the U.K. National Institute for Health Research.

Authors and editorialist all reported no financial disclosures.

Primary source: Archives of Internal Medicine
Source reference:
Vickers A, et al "Acupuncture for chronic pain: individual patient data meta-analysis" Arch Intern Med 2012; DOI: 10.1001/archinternmed.2012.3654.

Additional source: Archives of Internal Medicine
Source reference:
Avins A "Needling the status quo" Arch Intern Med 2012; DOI: 10.1001/archinternmed.2012.4198.

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Hepatitis C: What You Need To Know About This Silent Killer

Created on Friday, 31 August 2012 16:21

Written by NAPSI

San Diego, California (NAPSI) - Nearly 5 million Americans are infected with hepatitis C, but 75 percent of people with the disease don’t even know they have it because it is often symptomless for decades.

Hepatitis C is a serious liver disease spread through infected blood. It is the leading cause of liver failure, liver cancer and liver transplants and contributes to up to 15,000 deaths a year in the U.S.

But—there is good news. For many people, hepatitis C can be cured.

Boomers Most at Risk

Eighty-two percent of people with hepatitis C are baby boomers (those born between 1945 and 1965) but, alarmingly, almost three-quarters (74 percent) of boomers have never been tested or are unsure if they’ve been tested for the disease, according to a new survey. Even more alarming, 80 percent do not consider themselves at any risk for the disease.

The findings of the survey, which was conducted by Harris Interactive as part of I.D. Hep C, a national American Gastroenterological Association (AGA) campaign intended to educate the public about hepatitis C, raise concern because they show a widespread lack of knowledge about the disease.

Those at risk for hepatitis C include:

• People who had blood transfusions or organ transplants before 1992;

• People with tattoos or body piercings;

• People who used intravenous drugs, even once;

• People who work in a health care setting;

• People with HIV.

African Americans and Hispanics are also affected at a significantly higher rate than the general population.

Screening Is Key

Hepatitis C is diagnosed with a simple blood test, but screening is not currently part of routine testing. This means you may think you have been tested, but chances are you haven’t.

As part of the I.D. Hep C campaign, the AGA is urging baby boomers and others at risk to talk to their health care providers about being tested. By visiting www.IDHepC.org, people can learn more about hepatitis C and how to get tested. The AGA is also encouraging people to visit the website and take a virtual pledge to get tested and spread the word. I.D. Hep C is sponsored by Vertex.

Source

Lactulose and Probiotics Are Effective in Preventing Recurrent Hepatic Encephalopathy

Both treatments were significantly more effective than placebo.

Hepatic encephalopathy (HE) is a common complication of hepatic cirrhosis. Lactulose has been effective in treating patients with acute or recurrent HE, but data supporting its use are lacking. Probiotics might also be beneficial for these patients, by altering gut flora to reduce ammonia production, although few studies have evaluated probiotics in this setting.

Now, investigators have conducted an open-label, randomized, controlled trial to evaluate the efficacy of lactulose and probiotics in 235 consecutive cirrhotic patients at a single hospital in India who had recovered from HE and had not received any HE medication. Patients were randomized to lactulose (30 mL 3 times daily), probiotics (1 capsule containing 112.5 billion viable lyophilized bacteria 3 times daily), or placebo. The primary endpoint was development of overt HE, according to West Haven criteria.

During 12-month follow-up, recurrent HE developed in more patients receiving placebo (37) than lactulose (18; P=0.001) or probiotics (22; P=0.02). Rates of hospitalization and death from causes other than HE were similar among the three groups.

Comment: Although unblinded, this study was large and well executed. It demonstrated that lactulose and probiotics are similarly effective in secondary prophylaxis of HE. Whether all probiotics would be as effective is unclear, but we now potentially have other therapeutic options for preventing recurrent HE in addition to rifaximin plus lactulose (JW Gastroenterol Mar 24 2010).

— Atif Zaman, MD, MPH

Published in Journal Watch Gastroenterology August 10, 2012

Citation(s):

Agrawal A et al. Secondary prophylaxis of hepatic encephalopathy in cirrhosis: An open-label, randomized controlled trial of lactulose, probiotics, and no therapy. Am J Gastroenterol 2012 Jul; 107:1043.

• Medline abstract (Free)

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