September 12, 2012

To care or not to care? That is the question.

by Chrissy Welsh

''You have hepatitis C....You have hepatitis C....You have hepatitis C''

Those words reverberated in my head as if they had been shouted at the bottom of a deep gorge in the Grand Canyon itself. Nothing I did would make those words go away. Why had this happened to us?

Hi...my name is Louise, I care for my partner, best friend & soulmate who's name is Thelma. It was December 2003, just a week before Christmas, when the Doctor called with the news which would turn our lives upside down and inside out....things would never be the same again. Hepatitis C had invaded our home and our dreams. In fact, this was a nightmare just beginning and we were in for the fight of our lives. We were ready for the battle, ready to fight back and determined to evict this uninvited squatter. Bring it on, we said...bring it on. How naive we were!

The dragon had quietly gorged on Thelma's liver for around 25 years, but now it had risen from its slumber. She had been sick for two years and, looking back, the signs were all there. The typical symptoms of Hep C. Terrible crippling fatigue, nausea, itchy and blotchy skin, severe flu like symptoms and aching, loss of appetite, infections and mood swings. I still, to this day, have no idea how she continued to work full time, commuting to London every day, clocking up more than 500 miles a week. The work was challenging enough for a healthy individual, how she coped, day in, day out, goodness only knows. But things were catching up with her and eventually overtook the drive and determination not to be beaten....it was time for Thelma to stop and time for me to step up to the plate. Almost overnight, I became a full-time carer and self appointed advocate for all her medical needs.

Hospital appointments were happening thick and fast...blood tests, ultrasound scans, colonoscopy, endoscopy, biopsy and an overall assessment by a gastroenterologist with a dubious bedside manner. Thelma was prodded and poked to within an inch of her life and the obvious indifference of the specialist Hep C nurse was beginning to test me to the point that I just wanted to punch him in the face. He dared to suggest that Thelma was psychosomatic and doubted the severity of her symptoms! He really doesn't know how close he came to losing both his upper limbs. I was ready to tear them off with my bare hands. Thelma, surprisingly, convinced me it was not a good idea.

Time passed by, medical tests continued and Thelma's condition worsened. I knew the difficulties of caring for a loved one, we had cared for Thelma's parents right up to the end for each of them. It is exhausting on the body and the mind and can be a severe test on relationships. I had no idea, however, how challenging it would be to care for a partner of more than 20 years. Our relationship was about to be tested to the absolute limit. It was now December 2006, almost exactly 3 years since diagnosis of the virus was made and we were about to embark on one of the darkest winters of our lives. A 24 week course of combination therapy treatment with Pegylated Interferon and Ribavirin was about to begin. The nurse administered the first injection of Interferon and Thelma swallowed the first dose of Ribavirin. It was a Friday, a cold day, but the sun shone brightly. From here on in, Friday would always be shot day and Thelma would be injecting herself. I quietly gave thanks for that. I felt bad about it for days, but still thankful that it was not going to be a part of my duties. We returned home and quietly saw out the rest of the day peacefully together. Day 1, week 1 of 24 came to a close with nothing out of the 'ordinary' to report.

By week 8, Thelma was ready to quit. I was ready to quit. The side effects of this treatment were more horrendous than either of us could have imagined. I asked questions of myself over and over. Was I caring for her in the right and proper way? Surely, it couldn't be like this throughout the whole 24 weeks, how is a person to endure such an onslaught?

Thelma cried. She wanted out and just the very thought of continuing on made her cry some more. I made the call to the 'dragon's office' and broke the news. I was met with silence....but not for long. The next 60 seconds or so felt like I was standing outside the headmaster's office, head bowed, waiting for the inevitable swish of the cane. I felt like a naughty schoolgirl who's parents would be VERY disappointed. Then it stopped because I stopped listening and suddenly the anti-authority, rebellious schoolgirl came back to say ‘hello’ and I fired at him with all guns blazing.

How DARE he speak to me in that way? How DARE he make Thelma or myself feel like an utter failure? How dare he continue to breathe?

Thelma listened on. The look on her face was that of someone who had been beaten into submission, unrecognizable to the person she was just 2 short months before. That made my blood boil further and my tirade continued.....then I was done.

Once again I was met with silence. I did begin to wonder if my splendid retort has been for nothing, maybe he had hung up on hearing my onslaught? But no, he was still there, but a lot less sure of himself than a minute or so previously. I told him Thelma was quitting and no amount of emotional, medical blackmail was going to change that. He had threatened, yes, threatened that Thelma would NEVER be offered re-treatment again, from anywhere in the UK, that she was ungrateful and a failure. Is it any wonder I almost seared his ears permanently shut with the fire in my words? I had become the fire breathing dragon and my treasure was not going to be plundered or abused. Thelma was and always will be my treasure. This 'heated' exchange ended with the intervention of some common sense. Even though it wasn't and still isn't standard practice for the 24 week treatment regime, he decided to back down and agreed that if Thelma carried on with treatment to week 12, a viral load check would be carried out to see if she was responding. If she wasn't, he agreed that treatment should stop, but if she WAS responding, he asked, rather than demanded, that Thelma might consider seeing the treatment throughout the full 24 weeks. My response was that we would consider his offer and get back to him the following day.

The 12 week test did indeed show that Thelma was responding to treatment and that the required minimal response rate had been attained. We were, naturally, delighted to hear this but several weeks later it occurred to me that we didn't actually have any proof that the 12 week test had REALLY been carried out! A kind of placebo, perhaps? Hmmm! Our mistrust and suspicions loomed again but by now Thelma was 3/4 of the way through, the side effects had continued and my heart ached for her more and more with each passing day. We were alone with this nightmare. Not one source of support did we have. No family, no friends, no one who either understood our situation or cared to understand. It wasn't the first time we were alone with our woes but never had we felt so utterly isolated from life and the world in general. Apart from each other, I felt no love being directed toward us.....not one human being cared! This only served to make me stronger, I would be our support network, I would be Thelma's source of love and compassion. We didn't need anyone else!

Finally, week 24 was at an end. Hoorah! The end of treatment blood test told us the virus was undetected. What joy to the ears! Our expectations were high. We began to laugh & joke together, making plans once more for the future. It felt fantastic to be happy again!

Devastation doesn't even begin to describe the feeling when the call came. Thelma had relapsed at the 6 month post treatment test. We cried. We held each other, Thelma gently rocking in my arms. The hurt and the feeling of loss was soon replaced by utter contempt and hatred....yes, hatred....of the virus, the treatment, which had failed us, and the complete lack of after care from the hospital. We had been dropped like a hot cake. To be honest with you, the level of 'care' had been questionable throughout, but now there was nothing, nada, a big fat zero. I stopped calling the hospital. What was the point? They didn't give a flying toss about us. That's if they ever did. Once again, we were completely alone with our woes. Nobody cared, we didn't matter to anyone. I actually only wanted people to care about Thelma, not me. I didn't matter in all this and besides, the attitude of MY family had always been one of ''Oh, that Louise, she can take care of herself!'' Oh! Really?! Well stuff the lot of you then! We started this alone and we shall finish this alone. We didn't need anyone else.

Four long years passed us by. Life went on, of a fashion, but everything had changed. Thelma was sick, very sick. My mind was always racing, trying to think of alternative ways to help make her better. We spent a small fortune on all manner of mixtures and potions. The local Health Store staff even knew my name and I was greeted with a wide smile on each visit, but had a considerably lighter purse on leaving the store! Nothing was helping. Dare I bring the subject up? Dare I mention THAT word? I hesitated, but time was marching on. I decided to bite the bullet, hope for the best and waited for the backlash!

2010 and we were back in the same department, the same corridor of the same hospital. Everything was the same here, but nothing was the same. We sat on those uncomfortable seats, the clinical walls bearing down on us with the familiar smells and sounds permeating our very souls. I felt like screaming! Poor Thelma had a look of terror on her face. I was sure she was going to do a runner from there at any moment. Perhaps she would have had it not been for an unfamiliar, deep Irish accent calling her name,

''Hello! You must be Thelma & Louise. My name's Mary, I'm very pleased to meet you both.''

The words 'Once more, unto the breach dear friends' swirled around my head. Were we crazy? Had we lost our minds? After a fair battle, the hospital had agreed to re-treat Thelma, but it was made very very clear to us that in the event of this treatment not being a success there would be no third treatment. Almost like a threat. I remember thinking that nothing much had changed then. The consultant was just as much of an arse as he had been all those years previously. I did notice that he’d shed a lot of weight and pondered on this for a while as he 'talked us through the process.' I remember wondering if he’d been on some sort of strict dietary regime or perhaps he’d been ill.

I came to the conclusion that either way, regardless of what his exterior now looked like, he was still an arse on the inside. I'm certain he picked up on my thoughts as his words started to drift back to my ears. It was the look on his face, the look of someone who’d just realised that the patient and carer had sussed him out a long time ago. Our relationship was never going to be good.

The great news was that Thelma now had what appeared to be a much nicer specialist nurse. The bad news was that the treatment duration would be 48 weeks this time! 48 WEEKS! Were they kidding us? It was explained that, in view of the fact that Thelma had relapsed on attempt no. 1 (AN1 is our code for it), the rate of 'success' had been lowered to 30%. So, it was thought that the sensible thing to do was to double the regular treatment time, but still on the standard therapy as there had been no progress with new treatments for geno type 2 & 3. But 48 weeks of that crap? Thelma was already shaking inside but she was determined to give it her best shot. We were much better prepared this time, much more informed and much less likely to put up with any bullshit from anyone - especially the hospital. And, on top of that, thanks to inheriting a trusty old laptop from a dear friend who had recently passed (R.I.P. Kay) I had found my Hepper family online via the book of face. I cannot even begin to put into words how grateful I was and how very fortunate I was to be welcomed and accepted into some wonderful support groups, with so many people I had never met, and probably would never meet. Yet here I was! One of them and I didn't even HAVE Hepatitis C. I was just a carer, but in their eyes I was as important as anyone else. I embraced the support, the encouragement, the wisdom and the love of my Facebook friends....they had become my family.

So, here were are....August 2012, 48 weeks of torment and tears are behind us now. Thelma did it! She made it to the end of treatment! I won't pretend it was easy by any stretch of the imagination. Once again we were tested to the extreme. Some days were so bad I thought Thelma would HAVE to quit, that there was just no way she could continue to batter herself with those chemicals any longer. There were many tantrums and tears, many sleepless nights and we questioned our decision to go ahead with all the grief again. We had our ups and downs with the hospital. It was never going to be any other way and we still have zero support from our families. In fact, not once has any of our blood family even called to our home to see how Thelma's doing. Not one member of our blood family has ever picked up the phone to call us. Not one member of our blood family has mailed a card with caring, loving words of encouragement. Not even a Christmas card dropped onto our doormat. But I have my Hepper family. The most caring and compassionate group of people who understand and empathise with all we have endured over the years. People who are always there to offer a kind word or advise on any concerns I may have. Without these most wonderful people, this particular journey would have been so much harder for Thelma and myself. I cannot thank my Hepper family and Facebook friends enough. There are no words, just love.

And we have each other. That is always a constant and has been for 26 years. Not bad, huh? Of course we argue from time to time. Of course we say things we wish hadn't been said. Of course we have regrets, but we have each other. The good news is that, since week 4 of the 48 weeks of treatment, Thelma's blood results have returned showing the virus as undetectable. We are so very happy at this news, but we remain calm and level headed until the final results come in at the beginning of February 2013. Will the results favour us this time? Who knows? Maybe we'll get lucky. Maybe we'll get a break. That would be nice. If the worst were to happen we will face it together. I doubt there's much chance that Thelma and I will drive off the edge of a cliff in the Grand Canyon any day soon, or in our case, off the edge of Beachy Head here on the South East coast of the UK. We are strong! We are good together! We are soul mates and we shall prevail!

The question is: To care or not to care?

Answer: To care, always!

Overcoming Barriers to Care for Hepatitis C - Perspective

Download the PDF here

N Engl J Med June 28 2012

Paul J. Clark, M.B., B.S., M.P.H.-T.M., and Andrew J. Muir, M.D., M.H.S.

"can we afford not to improve the accessibility of treatment for hepatitis C?......better patient awareness......The challenge of improved diagnosis and treatment------greatest barrier to treatment is lack of diagnosis........disproportionate distribution of the burden of hepatitis C among vulnerable groups. The risk of HCV infection is highest among blacks and Hispanics.......many people with hepatitis C may be at a disadvantage in terms of health literacy, which limits their capacity to successfully engage with health care services to obtain a diagnosis and treatment. Engagement in the health system is a necessary though not sufficient condition for availing oneself of the benefits from recent developments in therapy for hepatitis C."

Thanks to steady scientific and therapeutic advances related to hepatitis C virus (HCV), now is a time of much optimism regarding the care of HCV-infected patients.1 Many seminal developments have been documented, and the number of new agents and regimens being studied in clinical trials suggests that gains will continue to be made in the tolerability and efficacy of treatments for HCV infection.1 These advances raise the hope that we may overcome the barriers created by the relatively poor efficacy and tolerability of peginterferon alfa plus ribavirin, the historical backbone of treatment in hepatitis C. Although optimism is justified, so is some degree of caution, for as treatment improves, the true rate-limiting factor in achieving better outcomes may turn out to be access to diagnosis and treatment.

To better understand progress in the care of patients with hepatitis C, one must consider the populations we treat and the health system context in which we treat them. According to a 2010 strategic report from the Institute of Medicine (IOM),2 lack of knowledge and awareness on the part of health care providers, persons at risk for infection, health policymakers, and the public contributes to the risk of ongoing transmission and lost opportunities for diagnosis, treatment, and prevention. Although therapy that has limited efficacy and harsh side effects provides minimal incentive for patients and clinicians to pursue diagnosis and treatment, the greatest barrier to treatment is lack of diagnosis: estimates suggest that about half of the approximately 3.2 million Americans infected with HCV are unaware of their infection, and only a tiny fraction are treated (see table).3,4 At the population level, this low rate of disease detection limits the possibility that new therapies can deliver potential downstream economic and public health benefits of the interruption of increases in HCV-related mortality and in liver transplantation for such complications of HCV infection as end-stage liver disease and hepatocellular carcinoma.

trends

The challenge of improved diagnosis and treatment is made more acute by the disproportionate distribution of the burden of hepatitis C among vulnerable groups.

The risk of HCV infection is highest among blacks and Hispanics, people with lower levels of education, and the poor.4 Analysis of data from the National Health and Nutrition Examination Survey (NHANES) indicates that as compared with non-Hispanic whites, non-Hispanic blacks have nearly twice the odds, and Mexican Americans have more than two and a half times the odds, of having HCV antibodies. In addition, people with a family income below the poverty line had nine times the odds of testing positive for HCV antibodies, as compared with people who had a household income two times the poverty threshold or higher.4 The IOM's strategy report cites numerous studies indicating that whites are more likely than blacks to be evaluated for HCV infection and to undergo and complete treatment for it, and there are similar disparities with regard to treatment of, and mortality associated with, hepatocellular carcinoma, a major complication of hepatitis C.2

According to another analysis of NHANES data, only marginally more than one third of patients with hepatitis C who were medically eligible for treatment had private medical insurance.5 In fact, infection with HCV was independently associated with the likelihood of being uninsured, even after adjustment for socioeconomic and demographic factors. Uninsured patients with hepatitis C may also be more likely to seek care in emergency rooms than in clinics or health centers - a finding that has important implications for programs aimed at improving diagnosis and treatment in vulnerable groups.5

Taken together, these data suggest that many people with hepatitis C may be at a disadvantage in terms of health literacy, which limits their capacity to successfully engage with health care services to obtain a diagnosis and treatment. Engagement in the health system is a necessary though not sufficient condition for availing oneself of the benefits from recent developments in therapy for hepatitis C.

In response to the IOM's national strategy, the Department of Health and Human Services (DHHS) has developed a road map for education and care, focusing on disparities in health literacy and access to care, to better target programs for prevention, diagnosis, and treatment of viral hepatitis (www.hhs.gov/ash/initiatives/hepatitis). If the Affordable Care Act assists patients in overcoming constraints on access to treatment for hepatitis C, the public health effect may be far more profound than that achievable with improved therapy alone.

What concrete measures might public health agencies take to improve awareness, diagnosis, and treatment of hepatitis C? Efforts to increase community awareness are enhanced by targeting high-priority populations with culturally sensitive and linguistically appropriate educational messages. Understanding community-specific epidemiologic factors facilitates the creation of programs tailored to settings with a high prevalence of HCV infection (e.g., correctional facilities) or groups with increased risk of transmission (e.g., injection drug users) or high prevalence (e.g., migrants from Egypt and some Southeast Asian countries). A successful example of this approach is Stanford University's Jade Ribbon Campaign to increase the detection of chronic hepatitis B and subsequent vaccination and treatment among Asian and Pacific Islander Americans. Of 1206 adults screened for chronic hepatitis B in its "3 For Life" pilot program, half showed no serologic evidence of immunity, and 85% of these persons were then able to be vaccinated against hepatitis B.

On a population scale, the Centers for Disease Control and Prevention has recently proposed a birth-cohort approach to screening for HCV - testing everyone born between 1945 and 1965 (an age group with increased risk of HCV exposure from the 1960s through the 1980s), rather than following the current risk-based screening recommendations (www.cdc.gov/Hepatitis/HCV/BirthCohortTesting.htm). Improved rates of referral to specialists for treatment depend not only on better patient awareness, but also on improved knowledge among primary care providers, which requires a greater focus on HCV in undergraduate and postgraduate continuing medical education.

Finally, if such measures successfully increase the rates of HCV detection, clinical questions remain. Do all HCV-infected persons require treatment? Many will not have progressive liver injury leading to cirrhosis, and only a minority will have hepatocellular carcinoma. Should the decision to treat be based on the risk of progressive liver disease or cancer, or simply on the presence of the infection? Historically, histopathological evidence of inflammation or fibrosis from liver biopsy was used to identify candidates for treatment, to improve the risk-benefit ratio associated with poorly efficacious, toxic, and expensive peginterferon alfa plus ribavirin therapy. Future regimens may be more efficacious and eventually less toxic but will surely be even more expensive. What clinical variables or biomarkers are sufficiently sensitive to identify patients at low risk for complications who may not need treatment? Does a more nuanced treatment approach dilute the simple message of "detect and treat," which resonates with many patients, clinicians, and the pharmaceutical industry?

The fragmentation and underfunding of public health services reflect a health system that's poorly positioned to improve the awareness, prevention, diagnosis, and treatment of hepatitis C - the necessary steps to interrupting the progress of this silent epidemic.2 We are at a critical juncture, determining whether, supported by health care reform, initiatives such as those suggested by the DHHS can translate the rhetoric of health disparities into better programs and outcomes for patients with hepatitis C. If the evolution in service delivery is successful, this may be a watershed moment not only for HCV therapeutics, but also for access to hepatitis treatment, improving care for all Americans infected with HCV.

Hepatitis C offers a window into contentious issues in health care reform. How can therapy be made more accessible, and if it is more accessible, how will we as a community pay for it? At a population level, improving the diagnosis and treatment of HCV infection will be expensive but will avert much illness and death from decompensated liver cirrhosis and hepatocellular carcinoma, the prevalence of which is projected to substantially increase over the next decade, at major cost to the community.2,3 The possibility of achieving future cost savings, particularly for disadvantaged groups, raises the question: can we afford not to improve the accessibility of treatment for hepatitis C?

Source

HCV Research: new HCV drugs coming; interferon-free therapy

Provided by NATAP

from Jules of NATAP. There are 4 new oral HCV drugs in the middle now of phase 3 studies, the last step before FDA approval & being in pharmacy - protease inhibitor TMC435, protease BI-335, NS5A BMS-052, and nucleotide GS-7977. Will we be able to combine 3 drugs in 1 regimen (protease+052+7977), we don't know? Small interferon-free studies reported at liver meeting EASL in April 2012 found 90-100% cure rates in treatment-naive patients: A phase 2 40-patient study at EASL in treatment-naives showed 100% SVR(cure) rate with 052+7977 with 24 weeks of therapy; 2 small phase 2 studies with protease ABT450/r+ a NNRTI+rbv found 90-95% SVR(cure) rates with only 12 weeks of therapy. Phase 3 for ABT450 is expected to begin soon.

Ongoing studies include a phase 2 of 435+7977 in treatment-experienced, and you can see new planned studies immediately below. Vertex is expected to reveal any day now results from ongoing early clinical studies of the 2 Alios nucleotides. BMS is developing nucleotide INX189 (now called BMS-986094); protease 435 + this nucleotide will be studied.

A study is planned to examine interferon-free regimens including: protease ABT-450/r + NS5A ABT-267 and/or NNRTI ABT-333, with & without ribavirin.

Large HCV Drug Pipeline

In addition to the new HCV drugs in later stages of development which I discuss above there is much more going on in new HCV drug development. Boerhinger Ingelheim has a NNRTI in development along with their protease. Roche is studying in patients a potent HCV protease danoprevir/r and 2 additional drugs nucleoside mericitabine and a NNRTI, phase 3 with danoprevir is being planned. Merck is developing a potent protease MK5172 in early patient studies and a potent 2nd generation NS5A. Biotech Achillion has 2 proteases and a potent 2nd generation NS5A in early patient studies. GSK has a potent NS5A in patient studies. Biotech Presidio has potent NS5A in early patient studies. Biotech Idenix has a NS5A and a lesser potent nuke in earlier development. Gilead has along with nucleotide 7977 & NS5A 5885, also a protease and a NNRTI. BMS also has a protease and as mentioned in earlier report their nucleotide BMS-986094 (formerly INX-189), and additional new HCV drugs. And again Abbott has a protease, 2 NNRTIs, and a NS5A. In addition to Tibotec's protease TMC435 and additional drugs in early development.

All these drugs are expected to follow after the ongoing phase 3 studies of 4 new drugs described in my earlier report. Interferon-free therapy is expected to cure a lot of patients, but for some of the hardest to treat prior null responders potent 3/4-oral drug regimens will have to be explored and also just in case a potent multi-oral regimen with 2 orals +pegIFN and ribavirin looks to be very successful in early studies and will be further studied. BMS has a potent new interferon called lambda interferon which appears to have few side effects, which could be used for patients who might need an extra boost from interferon, as well as for HBV. The duration of therapy with interferon-free therapy, which used to be 48 weeks for genotype 1 patients, is expected to be shortened to 24 weeks and 12 weeks for some patients. Many of these drugs are effective for all genotypes 1-6, particularly, 2-4.

Besides good treatment we need HCV testing programs because 80% of HCV-infected in USA are undiagnosed, don't know they have HCV; there aren't enough well-trained clinicians to take care of & treat patients; we need patient-support service to keep patients in care. NYC's Dept of Health has launched just last month the first large-scale urban comprehensive $2 million HCV testing project providing new rapid HCV testing, linkage-to-care, care in community-clinics, and web-based training/case studies for clinicians by expert clinicians implemented by this project.

Medivir announces TMC435 in an expanded clinical collaboration: TMC435+BMS NS5A, TMC435+INX189
18-Apr-12

· Expanded clinical study program evaluating a combination of TMC435 and daclatasvir (BMS-790052)

· TMC435 and BMS-986094 (formerly INX-189), two direct-acting antivirals in combination, will be evaluated in clinical trial

Stockholm, Sweden - Medivir AB (OMX:MVIR), the research-based speciality pharmaceutical company focused on the development of high-value treatments for infectious diseases, announces that its development partner, Janssen R&D Ireland has broadened its clinical collaboration agreement with Bristol-Myers Squibb Company (NYSE:BMY).

· This announcement concerns an expansion of the clinical collaboration agreement between Tibotec Pharmaceuticals (now Janssen R&D Ireland) and Bristol-Myers Squibb (NYSE:BMY) announced by Bristol-Myers Squibb on 2nd December 2011

· Bristol-Myers Squibb and Janssen have agreed, pending the outcome of the upcoming phase II study, to further study daclatasvir (BMS-790052) and TMC435 in a phase III trial.

· Bristol-Myers Squibb and Janssen have agreed to conduct a drug-drug interaction study with TMC435 and BMS-986094. Results from the DDI study will guide the further evaluation of the use of TMC435 and BMS-986094 in HCV patients.

TMC435 and daclatasvir (BMS-790052)

In the agreement announced on 2ndDecember 2011, TMC435, a once daily potent NS3/4A protease inhibitor (PI) in phase III development for the treatment of genotype-1 chronic hepatitis C virus (HCV) infection will be investigated in a combination in a phase II trial with Bristol-Myers Squibb's investigational NS5A replication complex inhibitor, daclatasvir (BMS-790052), also in phase III development.

In the upcoming phase II study the companies will evaluate the potential to achieve sustained viral response 12 and 24 weeks post treatment in null responder and interferon intolerant patients with HCV genotype 1. This study is planned to start later in 2012.
TMC435 and BMS-986094 (INX-189)

The expanded clinical agreement also includes clinical evaluation of a combination of TMC435 and the nucleotide polymerase NS5B inhibitor BMS-986094, formerly known as INX-189. A drug-drug interaction (DDI) study with TMC435 and BMS-986094 will be conducted. Results from the DDI study will guide the further evaluation of the use of TMC435 and BMS-986094 in HCV patients.

Charlotte Edenius, Executive VP Research & Development, of Medivir commented: "We are very excited to see this expanded collaboration between Janssen and Bristol-Myers Squibb and to be investigating TMC435 with the nucleotide BMS-986094 and to expand the clinical collaboration evaluating TMC435 with daclatasvir. This represents one of several strategies to explore TMC435 in interferon free regimens; a development we believe will be an important advancement in the HCV field for patients."

About TMC435

TMC435 is a highly potent once-daily (q.d.) investigational drug that is being jointly developed by Janssen R&D Ireland and Medivir to treat chronic hepatitis C virus infections in genotype 1 patients.
TMC435 - On-going global phase III program in brief:

· TMC435-C208 or QUEST-1 in 375 treatment-naïve genotype-1 patients

· TMC435-C216 or QUEST-2 in 375 treatment-naïve genotype-1 patients

· TMC435-C3007 or PROMISE in 375 genotype-1 patients who have relapsed after prior interferon-based treatment

· Phase III program in Japan, includes 417 genotype-1 treatment naïve and treatment experienced patients

· TMC435-C3001 is a phase III efficacy, safety and tolerability study comparing TMC435 versus telaprevir, each in combination with Pegylated Interferon α-2a (PegINF) and ribavirin (RBV), in hepatitis C genotype-1 infected patients who were null or partial responders to prior PegINF/RBV therapy

· TMC435-C3011 is an open label, single arm phase III trial to explore the efficacy, safety and tolerability of TMC435 150 mg once daily, in combination with PegIFN/RBV in 100 treatment naïve or treatment experienced, hepatitis C genotype-4 infected patients

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

Medivir announces TMC435 in an expanded clinical collaboration: TMC435+BMS NS5A, TMC435+INX189 - (05/30/12)

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

Open-Label Study of GS-7977 + Ribavirin Pre-Transplant - (06/22/12)

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)

Rapid and strong antiviral activity of the non-nucleosidic NS5B polymerase inhibitor BI 207127 in combination with peginterferon alfa 2a and ribavirin - (06/20/12)
Interferon-Free Regimens at EASL - (04/24/12)

There are about 8 interferon-free regimens below and/or presented at EASL, in one study in 40 easier-to-treat treatment-naive patients we saw 100% cure rate with interferon-free regimen consisting of 2 HCV oral drugs Gilead's 7977+BMS' 052; and 90-05% cure rates were seen with interferon-free regimen with Abbott's 450+072+rbv.

Recent Successes and Noteworthy Future Prospects in the Treatment of Chronic Hepatitis C: TOWARD AN INTERFERON-FREE FUTURE? - (06/20/12) Ira Jcobson

"proof of the concept that HCV infection can be cured without interferon" ......"undetectable HCV RNA 4 weeks after end of treatment in 44 of 44 genotype 1 treatment-naive patients with 24 weeks of total therapy.......SVR 12 exceeding 90% over 40 genotype 1 treatment-naive patients"..."SVR 12 exceeding 90% over 40 genotype 1 treatment-naive patients" with 12 weeks therapy

HIV Coinfection With Hepatitis C Virus: Evolving Epidemiology and Treatment Paradigms - (06/20/12) "Rates of health care use and disability are 70% greater in coinfection than in HCV monoinfection"....."Studies of DAAs for coinfected patients are lagging behind those for patients with HCV monoinfection

HCV Viral Load Reduction Improved Inflammation, Fibrosis, Clinical Outcomes with PegIFn Lead-In Maintenance therapy in HALT-C - (07/10/12)

Overcoming Barriers to Care for Hepatitis C - Perspective - (07/10/12)

Hepatitis C Treatment Highlights From the 2011 American Association for the Study of Liver Disease Meeting - (07/12/12)

Global Burden of Hepatitis C: Considerations for Healthcare Providers in the United States - (06/20/12)

lack of access to screening, care, and treatment limit the use of these therapies for most persons living with HCV infection globally, and deaths from preventable cirrhosis and liver cancer continue to increase. Governments need to address viral hepatitis comprehensively by improving surveillance, prevention, care, and treatment. In the United States, healthcare providers must be cognizant of the global burden and epidemiology of HCV infection and follow current screening care and treatment recommendations

Source

Download the PDF here

An investigator initiated emergency IND (#109,999) was obtained from the United States Food and Drug Administration to provide antiviral treatment for this single patient with severe recurrent cholestatic HCV infection following LT.

Liver Transplantation July 2012

Robert J. Fontana 1, Eric A. Hughes2, Henry Appelman 3 , Robert Hindes 4, Dessislava Dimitrova 2, Marc Bifano

Abstract

Recurrent hepatitis C virus infection following liver transplantation can lead to accelerated allograft injury and fibrosis. The aim of this study is to report the first ever use of daclatasvir (BMS-790052), a potent orally administered NS5A replication complex inhibitor, in combination with peginterferonα and ribavirin in a liver transplant recipient. A 49 year old female developed severe recurrent HCV genotype 1b infection 4 months after transplant with severe cholestasis on biopsy and an HCV RNA of 10,000,000 IU/ml, alk phos of 1525 IU/ml, and total bilirubin of 8.4 mg/dl. Despite partial virological suppression with peginterferonα and ribavirin, progressive allograft failure ensued culminating in retransplantation at 9 months. At 3 months after the second transplant, daclatasvir 20 mg per day, peginterferona2a 180 ug/ week and ribavirin 800 mg/ day were prescribed for early recurrent cholestatic HCV. Serum HCV RNA became undetectable at week 3 of treatment and remained undetectable during 24 weeks of triple therapy as well as during post-treatment follow-up. Daclatasvir was well-tolerated and the trough drug levels were within the targeted range throughout treatment. The cyclosporine trough levels were also stable during and after therapy. Conclusion: The lack of anticipated drug-drug interactions between daclatasvir and the calcineurin inhibitors coupled with its potent antiviral efficacy make this agent in combination with peginterferon and ribavirin an attractive antiviral regimen worthy of further study in liver transplant recipients with recurrent HCV.

Introduction

Liver failure and hepatocellular carcinoma (HCC) due to chronic hepatitis C virus (HCV) infection are the leading indications for liver transplantation (LT) in the United States (1). However, recurrence of HCV infection following LT is nearly universal and characterized by high serum HCV RNA levels and variable severity of allograft hepatitis (2, 3). The rate of fibrosis progression is greatly accelerated compared to non-transplant HCV patients with 10-30% developing cirrhosis within 5 years of transplant (4,5). The accelerated course of recurrent HCV infection is attributed, in part, to the use of potent immunosuppressants, treatment of acute rejection, and other donor and recipient factors. Not surprisingly, LT recipients with chronic HCV have a significantly lower 5-year survival compared to other recipients due to a higher rate of graft failure from recurrent disease (6,7).

Peginterferon (pegIFN) and ribavirin combination therapy are frequently used for selected LT recipients with recurrent HCV infection (8-10). In addition, several studies have shown that LT recipients who achieve a sustained virological response (SVR) have significantly improved survival compared to partial responders as well as untreated patients (11-13). However, many LT recipients are incapable of initiating interferon therapy due to pancytopenia, renal insufficiency, and/or other medical and psychiatric co-morbidities. In addition, antiviral response rates are lower in LT recipients compared to non-transplant patients (30% vs 45% SVR in genotype 1) due, in part, to the use of immunosuppressive agents and the need for more frequent antiviral medication dose reductions and/or early discontinuation (8-10). Therefore, better tolerated and more effective treatments for LT recipients with recurrent HCV are urgently needed. The direct acting antiviral agents, telaprevir and boceprevir, in combination with pegIFN and ribavirin were recently shown to significantly improve SVR rates in both treatment na•ve and previously treated genotype 1 patients (14-17). However, both of these agents are contraindicated in LT recipients due to potentially severe and life-threatening drug-drug interactions with cyclosporine and tacrolimus as well as the lack of efficacy and safety data in this patient population (18, 19). Daclatasvir (BMS-790052; DCV, Bristol-Myers Squibb, Princeton, NJ) is an investigational oral NS5A replication complex inhibitor in development with demonstrated antiviral efficacy when combined with pegIFN and ribavirin in treatment na•ve and previously treated patients with HCV genotypes 1 and 4 (20-25). In phase 2 clinical trials, DCV has been generally well tolerated in combination therapy with no unique adverse events identified to date. Furthermore, In vitro and in vivo testing suggests that DCV should not lead to any clinically significant drug-drug interactions when co-administered with other drugs that are metabolized by CYP3A4 such as cyclosporine, tacrolimus, and sirolimus (24). The aim of the current study is to report on the first successful use of a DAA, DCV, in combination with pegIFN and ribavirin in a LT recipient with severe, interferon-refractory cholestatic HCV infection.

Results

Initial pre- and post-transplant course- A 49 year-old female healthcare provider acquired HCV genotype 1b infection after an inadvertent needle stick in 1990. She was initially treated with interferon monotherapy without clearance and retreated with full dose pegIFN and ribavirin for 48 weeks in 2002 with suppression of HCV RNA to undetectable levels followed by post-treatment relapse. The patient also had a history of diabetes mellitus, hypertension, and a body mass index of 35 kg/m2. Her Interleukin 28-B (IL28B) genotype at rs12979860 was CT. The patient progressed to decompensated cirrhosis with ascites, gastrointestinal bleeding, and encephalopathy and was listed for transplant with a model for end stage liver disease (MELD) score of 11. Following the diagnosis of a 2 cm HCC, she received a MELD upgrade to 22 points. While hospitalized with a MELD score of 32 on hemodialysis, she received a cadaveric liver transplant from a donor that was < 40 years old with a cold ischemia time of 9 hours. Induction immunosuppression consisted of basiliximab (Simulect, Novartis, East Hanover, NJ) on post-op days (POD) #1 and #4 as well as intra-operative steroids. She was discharged home on POD # 22 on cyclosporine, mycophenolate mofetil and prednisone with stable liver biochemistries.

At month 4 following her first LT, serum alkaline phosphatase (Alk P) was 1,525 IU/ml, bilirubin was 8.4 mg/dl and an HCV RNA level was 10.8 x 106 IU/ml. Evaluation for biliary strictures was negative and a liver biopsy showed intense pericentral cholestatic reaction with lymphocytic inflammation indicative of recurrent HCV (Figure 1A). As a result, pegIFNα2a 180 ug/week and ribavirin 1200 mg/day were initiated. At week 4 of antiviral therapy her bilirubin had increased to 17.9 mg/dl and a repeat liver biopsy demonstrated severe cholestatic HCV with perisinusoidal fibrosis. Although HCV RNA had declined to 3.2 x 10 3 IU/ml at treatment week 12, her cholestasis worsened with an Alk P of 1959 IU/ml and bilirubin of 36.8 mg/dl and antiviral therapy was discontinued due to her worsening clinical status (Figure 2).

The patient was subsequently hospitalized with severe encephalopathy requiring intubation and coagulopathy with an INR of 1.9. She underwent retransplantation with a MELD score of 36 while in the ICU. In this instance, a 19 year old cadaveric donor was utilized with a cold-ischemia time of only 7 hours. Initial immunosuppression consisted of cyclosporine, mycophenolate mofetil, and steroids. She was discharged home 4 weeks later on cyclosporine and prednisone and fully recovered. At week 12 following the second liver transplant, her Alk P had risen to 673 IU/ml with an ALT of 88 IU/ml and a total bilirubin of 1.4 mg/dl. A cholangiogram revealed no evidence of obstruction and the serum HCV RNA level was 4.0 x 106 IU/ml. Due to the diagnostic uncertainty, a liver biopsy was obtained that showed mild periportal and lobular hepatitis with a lymphocytic infiltrate (Figure 1B).

Daclatasvir in combination with pegIFN and ribavirin treatment- The patient was started on DCV 20 mg/day, pegIFNα2a 180 ug/ week and ribavirin 800 mg/day at week 12 after the second liver transplant due to the suspicion of early recurrent HCV infection with cholestatic features. Concomitant medications included cyclosporine 75 mg bid, prednisone 4 mg day, pantoprazole 40 mg/day, nifedipine 60 mg/ day, lasix 20 mg per day, ursodeoxycholic acid 600 mg per day, erythropoietin 20,000 units/week and atenolol 25 mg/day along with insulin and calcium with vitamin D. Serum HCV RNA became undetectable at week 3 of antiviral therapy with associated improvements in serum ALT and alk phos levels (Figure 2). At week 16 of antiviral therapy, the patient experienced an episode of herpes zoster reactivation that was successfully treated with valacyclovir over 4 weeks.

At treatment week 19, her serum ALT and Alk P levels increased to 99 and 517, respectively. A liver biopsy showed immune mediated allograft hepatitis with extensive plasma cell infiltration and hepatic necrosis. At that time, her ANA and anti-smooth muscle antibody were negative, quantitative immunoglobulin levels were normal, and her cyclosporine trough level was in the therapeutic range at 100 ng/ml. Since this was felt to be immune mediated allograft dysfunction due to interferon, the pegIFN dose was reduced to 135 ug/week and the prednisone dose was increased from 2 to 20 mg per day for the remainder of her treatment course.

After 24 weeks of triple antiviral therapy, an additional 4 weeks of pegIFN and ribavirin consolidation therapy were given. Following cessation of the antiviral medications at week 28, her serum ALT was 82 and Alk P was 294 with a normal total bilirubin. At post-treatment weeks 12 and 24, her HCV RNA remained undetectable with a serum ALT of 50, Alk P of 220 IU/ml and total bilirubin of 0.6 mg/dl. At week 32 following treatment, the patient is feeling well with normal liver biochemistries while receiving cyclosporine 75 mg bid, prednisone 5 mg daily, and azathioprine 100 mg per day and HCV RNA remains undetectable.

Pharmacokinetic assessment: Plasma concentrations of DCV at treatment week 2 were 137, 102, 112, 218, 451 and 376 ng/mL at predose, 0.5, 1.0, 2.0, 4.0 and 6.0 hr post dose, respectively. Trough values at weeks 4, 6, 8, 12 and 24 were 129, 160, 270, 161, and 87 ng/mL, respectively.

Discussion

Recurrent HCV infection following LT can lead to accelerated allograft injury and fibrosis due to the high levels of HCV replication and ongoing suppression of the host immune response to viral antigens (4,5).

Patients who receive monoclonal antibody induction therapy or who require treatment for acute rejection with pulse steroids are at particular risk for severe recurrent HCV infection as well as recipients of older donor allografts (7,27,28). Our patient developed severe recurrent cholestatic HCV infection within 4 months of her initial transplant in the absence of monoclonal antibody induction therapy and despite receiving a younger donor liver with a short cold-ischemia time. Despite minimizing her immunosuppression and early introduction of pegIFN and ribavirin combination therapy, the patient developed progressive and life-threatening cholestatic graft failure. The liver biopsies at months 4 and 5 showed classic features of severe cholestatic HCV infection (Figure 1A) (28, 29). This particular variant of recurrent HCV infection tends to occur within the first year of LT and is characterized by the development of inflammatory infiltrates, cholestasis, and hepatocyte ballooning that can frequently lead to early graft failure and premature death. Although there have been case reports of salvage antiviral therapy, most patients die of infection or progressive allograft failure (27).

Although prior data have shown poor outcomes with retransplanation in patients with severe recurrent HCV infection, a second transplant was offered to this patient due to her young age, excellent functional status and good general health (31,32). Fortunately, she had adequate physiological reserve to recover and was discharged home within 4 weeks of retransplantation. However, when the patient began to manifest early recurrent cholestasis with associated histological changes at 3 months following her 2nd transplant (Figure 1B), initiation of a potent DAA-based (DCV) antiviral therapy in combination with pegIFN and ribavirin was undertaken.

In comparison to her initial postLT treatment course, a rapid suppression of HCV RNA at week 3 was observed with associated improvements in serum ALT and Alk P levels while receiving DCV in combination with pegIFN and ribavirin (Figure 2). In addition, the HCV RNA remained undetectable throughout the 24 week course of triple antiviral treatment even though she had been previously treated 3 times without success. Furthermore, viral replication remained suppressed even despite an intensification in her immunosuppressive regimen due to allograft dysfunction at week 19 and an intentional reduction in the dose of pegIFN. We considered discontinuing all 3 antiviral agents at this point but wanted to complete a full 24 weeks of treatment in light of her prior lack of clearance with pegIFN and ribavirin. A reduced dose of 20 mg DCV was used throughout treatment in this patient due to the potential for cyclosporine to increase the plasma levels of daclatasvir. The plasma trough levels of DCV at weeks 2, 4, 8, 12, and 24 ranged from 87 to 270 ng/mL which is similar to what has been reported in non-immunosuppressed HCV patients receiving daclatasvir 60 mg per day (21). In addition, the observed Cmax of DCV of 451 ng/ml is similar to the values observed in non-transplant patients receiving a 30 mg once daily dose (21). The Tmax for the patient was 4 hours which is longer than the mean Tmax previously reported for non-transplant patients under fasting conditions but within the range observed when patients received DCV under fed conditions. Overall, the exposure observed for this subject is within the therapeutic range for DCV where safety and efficacy have been observed suggesting that cyclosporine did not have a clinically significant effect on DCV exposure.

Antiviral therapy was well tolerated in this LT recipient who was receiving concomitant cyclosporine, prednisone, and several other medications. The episode of herpes zoster at antiviral treatment week 19 was not felt to be related to the DCV study medication nor the pegIFN and ribavirin treatment since solid organ transplant recipients are known to be at increased risk for zoster reactivation (33-35). In addition, the zoster improved despite continued antiviral therapy. The other adverse event experienced by this patient of immune-mediated allograft hepatitis is being increasingly reported in LT recipients receiving interferon (8, 36, 37). Many HCV patients with immune-mediated hepatitis have detectable serum autoantibodies and develop a plasma cell rich infiltrate in the allograft which responds to increased immunosuppression. Some investigators speculate that immune-mediated hepatitis may be due to rapid suppression of HCV RNA and reflect an ÒImmune-reconstitutionÓ syndrome as reported in HIV patients treated with anti-retroviral therapy (37). In support of this, Interferon therapy can promote HCV-specific CD4 and CD8 responses in the liver but additional prospective studies of viral kinetics and intrahepatic immune responses are needed (38). Hepatitis C patients with cholestasis and plasma cell hepatitis on their baseline biopsy or elevated alkaline phosphatase levels prior to antiviral therapy may be at particular risk for this complication (36,37). Other studies have suggested that virological responders to interferon therapy who experience improved liver function and metabolism of calcineurin inhibitors may be at increased risk of developing rejection during antiviral therapy (39,40).

Although our understanding of this clinic-pathological entity is evolving, many patients improve with either a reduction or discontinuation of Interferon therapy or with an increase in their immunosuppression but cases of progressive hepatitis with graft failure and death have been reported (36). In the current patient, we were reluctant to stop the antiviral therapy in light of her progressive liver failure with her first transplant and rapid response to the 3-drug antiviral treatment. Therefore, the dose of pegIFN was reduced and the corticosteroid dose was increased to treat the immunemediated allograft hepatitis. Fortunately, this patient was successfully supported through a full 24 week course of triple antiviral therapy and her liver biochemistries further improved during follow-up. In addition to being highly effective, DCV was not associated with any clinically significant drug-drug interactions in our patient. In particular, the trough levels of cylcosporine remained in the target range of 75 to 125 ng/ml during and after treatment.

In summary, we report the first successful use of a direct acting antiviral agent in combination with pegIFN and ribavirin in a LT recipient with severe, interferon refractory cholestatic HCV. Despite 3 prior attempts at antiviral therapy including a course of pegIFN and ribavirin after the first LT, the patient developed early cholestatic HCV after her second transplant. The rapid suppression of HCV RNA to undetectable levels within 3 weeks of initiating treatment with DCV and pegIFN and ribavirin along with the improved liver biochemistries suggest that effective antiviral therapy can lead to improved outcomes in these patients. In addition, the ability of this patient to remain suppressed despite the need to reduce the pegIFN dose and increase the dose of steroids is encouraging with regard to the potency and efficacy of DCV based combination antiviral therapy. Furthermore, the fact that only 24 weeks of triple antiviral therapy was required to achieve an SVR in this patient is also promising for other genotype 1 LT recipients who frequently have difficulty tolerating 48 weeks of treatment. However, the optimal duration of triple antiviral therapy in HCV genotype 1a versus genotype 1b LT recipients requires further investigation. The favorable safety profile of DCV in combination with pegIFN and ribavirin observed in this patient and other studies including potentially minimal drug-drug interactions with the calcineurin inhibitors also make it an attractive agent to explore in future studies of LT recipients. Finally, it is hoped that if combination regimens of potent oral antiviral agents such as daclatasvir with other DAA classes such as NS3 protease inhibitors (asunaprevir or TMC435) or NS5B nucleoside polymerase inhibitors (INX-189 or GSI-7977) with or without ribavirin can be safely administered to non-transplant patients, many additional LT recipients with recurrent HCV will be able to be treated. However, additional prospective studies will be needed (41, 42).

Source

Incivek (telaprevir) product labeling revised

The Incivek (telaprevir) product labeling was recently revised to include the following changes:

1. Update the clinical comment for neuroleptic drug pimozide in Section 4 Contraindications to state: "Potential for serious and/or life-threatening adverse reactions such as cardiac arrhythmias"

2. Update Section 5 Warnings and Precautions subsection 5.4 Anemia to state: "Hemoglobin should be monitored prior to and at least at weeks 2, 4, 8 and 12 during INCIVEK combination treatment and as clinically appropriate."

3. Update Section 5 Warnings and Precautions subsection 5.6 Laboratory Tests to state the following: Use of a sensitive real-time RT-PCR assay for monitoring HCV-RNA levels during treatment is recommended. The assay should have a lower limit of HCV-RNA quantification equal to or less than 25 IU per mL and a limit of HCV-RNA detection of approximately 10-15 IU per mL.

4. Update Section 7 Drug Interactions to remove desipramine from Table 5: Established and Other Potentially Significant Interactions. Also added to Section 7 was a statement that no dose adjustment is needed for Incivek when given with either raltegravir or buprenorphine. The corresponding results from the drug-drug interaction trial with raltegravir and buprenorphine are included in Section 12 Pharmacokinetics.

5. Update Section 14 Clinical Studies to include revisions to the definition of sustained virologic response (SVR) and to correct the SVR rates for African American and Cirrhotic subpopulations as follows:

SVR was defined as HCV RNA less than 25 IU per mL at last observation within the SVR visit window (i.e., weeks 32-78 for patients assigned to 24 weeks of treatment and weeks 56-78 for patients assigned to 48 weeks of treatment).

Trial 108 (ADVANCE)

  • Twenty-six subjects were Black/African Americans. The overall SVR among Black/African American subjects was 62% (16/26). Among these subjects, 35% (9/26) were assigned to 24 weeks of treatment and of those 89% (8/9)achieved SVR.
  • Twenty-one subjects had cirrhosis at baseline and the overall SVR in these subjects was 71% (15/21). Among subjects with cirrhosis, 43% (9/21)were assigned to 24 weeks of treatment and of those 78% (7/9)achieved SVR.

Trial 111 (ILLUMINATE)

  • Sixty-one (11%) of subjects had cirrhosis at baseline. Among subjects with cirrhosis, 30 (49%) achieved an eRVR: 18 were randomized to T12/PR24 and 12 to T12/PR48. The SVR rates were 61% (11/18) for the T12/PR24 group and 92% (11/12) for the T12/PR48 group.
  • Blacks/African Americans comprised 14% (73/540) of trial subjects. Thirty-four (47%) Black/African American subjects achieved an eRVR and were randomized to T12/PR24 or T12/PR48. The respective SVR rates were 88% (15/17) and 88% (15/17), compared to 92% (244/266) for Caucasians among randomized subjects.

Trial C216

  • Twenty-six percent (139/530) of INCIVEK-treated subjects had cirrhosis at baseline. SVR rates among cirrhotic subjects who received INCIVEK combination treatment compared to Pbo/PR48 were: 84% (48/57) compared to 7% (1/15) for prior relapsers, 34% (11/32) compared to 20% (1/5) for prior partial responders, and 14% (7/50) compared to 10% (1/10) for prior null responders.
  • Four percent (19/530) of treatment experienced subjects who received INCIVEK combination treatment were Black/African Americans; the SVR rate for these subjects was 63% (12/19) compared to 66% (328/498) for Caucasians.

The complete revised label1 can be viewed on the FDA web site at Drugs@FDA2.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

Source

Early treatment could clear Hepatitis C

Published online 31 August 2012

Nature

Using mathematical models to understand the behavior of the deadly hepatitis C virus, Indian scientists have shown that the microbe's sensitivity towards drugs varies in various phases of the disease1. They say early treatment could actually clear the virus entirely from the system for a sustained period.

"There are multiple phases when the sensitivity of the infection to drug treatment varies. We found that early treatment of the infection is likely to result in sustained virological response," says Raghvendra Singh, an assistant professor in the Department of Chemical Engineering at the Indian Institute of Technology Kanpur.

Singh got interested in the area partially from the concern that many victims may neither know of their infection nor when or how they got the virus, and partially while working with retroviruses as a gene delivery vehicle during his doctorate.

A large number of people around the world are infected with hepatitis C, the virus that primarily affects liver cells or hepatocytes. Majority of the newly infected patients become chronic carriers of the virus. Chronic infection progressively causes liver damage, resulting in cirrhosis and liver failure. Some patients also develop liver cancer due to the harmful proteins produced from the HCV genetic material in the infected cells. After the initial infection, the virus enters the blood stream and reaches the target tissues.

Then, the HCV particles attach themselves to the wall of the hepatocytes through receptors and co-receptors and the virus enters the cell. Inside the cell, it uses the host machinery to produce its proteins and replicate its genetic material, needed for the assembly and release of the new viral particles from the cells.

Significant progress has been made towards understanding the pathogenesis of the disease, structure of the virus, finding drug targets and development of drugs as well as understanding their effects on the disease. Yet, in nearly half of the treated patients, the virus persists or rebounds after the therapy.

Singh and his team's mathematical model also showed that the drug, which blocks new infections of the target cells, is more potent in clearing the infection than the drug, which blocks the production of the virus from the infected cells.

Currently, most patients are treated during the late phase of the infection, partly due to the late detection of the disease. "Our finding, on the other hand, recommends treatment during the acute phase and development of more sensitive screening methods to detect the infection early," he says.

Since vaccines for HCV and HIV are not available yet, drugs are the only hope for millions infected with these viruses. "It is encouraging to see that besides the interferon- and ribavirin, many newer drugs are undergoing clinical trial for HCV and there is a sense of optimism that the cure may be in sight," Singh says.

· References

1. Gupta, S. et al. Analysis of the virus dynamics model reveals that early treatment of HCV infection may lead to the sustained virological response. PLoS ONE. doi: 10.1371/journal.pone.0041209 (2012)

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Analysis of the Virus Dynamics Model Reveals That Early Treatment of HCV Infection May Lead to the Sustained Virological Response

Saurabh Gupta, Raghvendra Singh*

Department of Chemical Engineering, Indian Institute of Technology Kanpur, Kanpur, India

Abstract

Considerable progress has been made towards understanding hepatitis C virus, its pathogenesis and the effect of the drug therapy on the viral load, yet around 50% of patients do not achieve the sustained virological response (SVR) by the standard treatment. Although several personalized factors such as patients' age and weight may be important, by mathematical modeling we show that the time of the start of the therapy is a significant factor in determining the outcome. Toward this end, we first performed sensitivity analysis on the standard virus dynamics model. The analysis revealed four phases when the sensitivity of the infection to drug treatment differs. Further, we added a perturbation term in the model to simulate the drug treatment period and predict the outcome when the therapy is carried out during each of the four phases. The study shows that while the infection may be difficult to treat in the late phases, the therapy is likely to result in SVR if it is carried out in the first or second phase. Thus, development of newer and more sensitive screening methods is needed for the early detection of the infection. Moreover, the analysis predicts that the drug that blocks new infections is more effective than the drug that blocks the virus production.

Introduction

Hepatitis C, a single stranded RNA virus belonging to flaviviridae family, has a high prevalence rate with an estimated 170 million likely carrier worldwide [1]. Around 4.1 million individuals may be carrying the virus in the U.S. alone, majority developing the chronic infection [2]. Chronic infection may progressively cause liver fibrosis, resulting in cirrhosis in around 20% of the patients [1], [3]. It has also been linked to development of hepatocellular carcinoma [4], with likely role of HCV core protein [5]. The antiviral cytokine, interferon-α, had been the corner stone of the chronic HCV treatment for many years. However, treatment with IFN-α was effective in achieving the sustained virological response (SVR) in less than 20% of the patients [6]. The combination therapy, which includes ribavirin along with IFN-a, and replacement of IFN-α by pegylated interferon have further improved the treatment, increasing the SVR rate to more than 50% [6], [7], [8]. More recently, a HCV protease inhibitor, telaprevir, has shown potential to improve the SVR rate further [9], [10], an inhibitor of HCV NS5A, a protein critical in viral life cycle and a likely drug target, has been identified [11], and many more drugs are undergoing clinical trials. Thus, considerable progress has been made in treating the infection and identifying newer targets for the drug therapy. Yet, in a significant percentage of the patients, the infection persists or resurges after the completion of the treatment, many developing liver cirrhosis and cancer. Therefore, better understanding of the role of the drugs in achieving SVR as well as the progression of disease is needed.

A model of virus dynamics has been previously described [12]-[16]. It has helped in explaining multiple aspects of HIV [17], [18], [19], HBV [14], and HCV [20], [21] infections. The in-vivo study on the effect of the IFN-α showed a biphasic response and it was found that IFN-α likely decreases the initial viral load mainly by blocking the virus production from the infected cells [20]. In some patients, besides the two phases of decline of the viral load, an intermediate shoulder phase, in which the viral load remains nearly constant [22]-[25], has been observed. This triphasic viral load decay has been explained by taking into account the proliferation of hepatocytes [25], [26], [27] in the original model. Besides explaining many observed viral decay profiles, the model also revealed that for the efficacies of the drug higher than a critical value, the infection will be cleared during the treatment and for efficacies lower than the critical value, a new steady state of infection may be reached [26], [27]. Thus, the likelihood of achieving SVR as well as development of drug resistance may depend on the efficacy of the drug treatment [18].

Although a lot is known about IFN-α, its role in modulating immune response, and its antiviral activity, it is not clear why the therapy fails to achieve SVR in around 50% of cases. The response of the therapy may depend on factors such as: the HCV genotype [28]-[31], level of hepatic fibrosis [32], [33], the viral load [29], body weight and age of the patient [34], [35]. Besides these variables, it is known that replacing IFN-α with pegylated interferon increases the chances of achieving SVR significantly, likely due to better half life and bioavailability of the drug, and a higher dose of pegylated interferon is more effective in achieving SVR than a lower dose [8]. Moreover, a significant percentage of the patients, who were previously treated with IFN-α and ribavirin combination therapy, achieved SVR when retreated with pegylated interferon and ribavirin [36]. Furthermore, retreating the patients with higher dose of IFN-α for 6 months caused 29% of the patients to achieve SVR [37] and it has been found that interferon alfa-2b decreases viral load in a dose dependent manner [38]. Thus, the dose of the drug and its bioavailability may be an important factor in determining the outcome of the therapy [38] and regression analysis based on clinical data has been used to predict the dose of IFN plus ribavirin that may be required to maximize the number of patients who clear the virus during the therapy [39].

These studies prompted us to look mechanistically into the role of effective dosing of the drug in achieving SVR. We performed the sensitivity analysis on the standard virus dynamics model. The analysis revealed that there are four time periods, in which the sensitivity of the infection to drug treatment varies. Based on this finding, we added a perturbation term in the model to simulate the drug treatment during a specific phase of the infection. The perturbation analysis showed that the first and second phases are the most effective for the antiviral therapy. Further, the study shows that the drug that blocks new infections is more potent in achieving SVR than the drug that blocks the virus production.

Discussion

Interestingly, the sensitivity analysis of the virus dynamics model with respect to the two efficacy parameters showed multiple phases, suggesting that the time of the start of the therapy may be an important factor in determining the response. The magnitude of the sensitivity coefficient describes how the uninfected, infected cells and the viral load will change at a given time if the efficacy of the drug is varied at that time. On the other hand, the slope of the sensitivity coefficient vs time plot describes how the uninfected, infected cells and the viral load will vary with time if a drug of a fixed efficacy is applied during a time period (equation 11 and 15).

If a 6 month therapy is carried out in the first or the second phase of the infection, the increase in the dose of the drug steadily delays the point of inflection in the dynamics, delaying the approach to the steady state. As the dose is further increased to a certain value, the uninfected, infected cells and the viral load do not reach the same steady state as they did for the lower doses but the infected cells and the viral load decrease to zero while the uninfected cells increase to the same number as the total number of the cells. Thus, the steady state of the infection has been altered from a 31.25% infected cells and 9.4x106 viral load to an uninfected state. It also suggests that a critical efficacy of the drug is needed to achieve the SVR as described by others [26], [27]. For the same mode of the drug, in the first and second phases, the doses required to achieve the SVR are nearly the same. In addition, in these phases, the alteration of the steady state is very sensitive to the dose and a small increase in the perturbation could change the steady state from the "infected state" to an "uninfected state". These effects are likely due to the early phase of the infection. As the viral load and infected cells decline, the number of uninfected cells increases. When the viral load reaches zero during the therapy, there are no virus particles left to propagate the infection and the cells remain uninfected even after the therapy has been withdrawn. A lower dose of the drug may be needed to achieve SVR if the mode of action of the drug is to block the de novo infections than to block virus production since the former affects the new infections directly while the later affects it indirectly by reducing the plasma virus concentration.

In contrast, in the third phase, due to the positive slope of the sensitivity curve for the viral load and infected cells, the drug serves as an activator of the infection (equation 11 and 15). It causes the viral load and the infected cells to increase. The slopes of the sensitivity curves in this phase gradually changes to zero (Fig. 1 B, C) so is the effect of the drug. When the perturbation is withdrawn, the system returns to the infected state.

In the final phase, the infection has reached the steady state in which the uninfected, infected cells and the viral load have attained equilibrium. Thus, all the sensitivity coefficients have attained constant values (Fig. 1 A, B, C). Since, the slope of the sensitivity coefficient vs time plot is zero in this phase, a drug may not perturb the system either as an activator or a repressor.

Time of start of the therapy is an important factor in determining the outcome. For both modes of action of drugs, there is an optimum time to start the treatment. Since the magnitude of the slope of the sensitivity curve for the infected cells and the viral load progressively increases in the first and second phases, reaching a point of inflection in the second phase (Fig. S2 B, C), a therapy close to this time will be the most effective, giving the lowest dose that could alter the steady state of the infection.

Our analysis shows that blocking new infections is more effective than blocking virus production. Although significant changes in the model will be needed for it to be applicable to direct acting antivirals [41], its implications to DAAs are interesting. It can be inferred that blocking wild type virus at an early phase of HCV lifecycle is better yet the direct acting antivirals produce drug resistant viral quasispecies, depending on the phase they block. Genetic barrier to resistance of NS3/4A protease inhibitors, which block an early phase of HCV lifecycle, has been shown to be low [42], [43]. On the other hand, genetic barrier to resistance of nucleoside analog polymerase inhibitors, which block a later phase of the viral lifecycle, have been shown to be high while that of the nonnucleoside polymerase inhibitor is low [42], [43]. Therefore, there may be optimum phases at which a drug may be highly effective in terms of both blocking the wild type infection and limiting the number of drug resistant viral quasispecies.

From the present study, we conclude that the treatment during the first and second phases of the infection will likely result in SVR, explaining the recent clinical studies [44]-[48]. Therefore, development of better HCV screening tools is needed so that the infection is detected early on. Furthermore, we found that the drug that blocks de novo infections is more effective in achieving the SVR.

Source

Food insecurity adds to health problems in HIV

By Genevra Pittman

NEW YORK | Wed Sep 12, 2012 4:20pm EDT

NEW YORK (Reuters Health) - People with human immunodeficiency virus (HIV) who don't have reliable access to nutritious food are more likely to end up in the hospital than those who regularly get enough to eat, a new study from San Francisco suggests.

Researchers said that could be because taking HIV medication or accessing early treatment may not be a priority for people who don't know where their next meal is coming from.

So-called food insecurity may also point to other underlying problems in people with HIV, such as poverty, mental illness and addiction.

"Food insecurity is a significant problem, but when you have a chronic disease, it only exacerbates things," said Seth Kalichman, a psychologist who has studied adherence to HIV treatment and food access at the University of Connecticut in Storrs.

Kalichman, who wasn't involved in the new report, said the combination of hunger and HIV - which hampers the immune system - makes people especially susceptible to other diseases.

The Centers for Disease Control and Prevention estimate that at the end of 2008, close to 1.2 million teens and adults were living with an HIV infection in the United States.

For the new research, Dr. Sheri Weiser of the University of California, San Francisco and her colleagues regularly interviewed 347 people with HIV who were homeless or living in shelters or low-income, temporary housing.

At the study's start, about one-quarter of them had visited an emergency room in the past three months and 11 percent had recently been admitted to a hospital. One-third of the participants reported severe food insecurity and more than half had at least some trouble consistently getting food.

Over the next two years, the researchers found people who were very anxious or uncertain about their food supply or without access to nutritious options were twice as likely to be hospitalized as those who didn't report any food insecurity.

They were also 70 percent more likely to visit an ER, Weiser's team reported in the Journal of General Internal Medicine.

Part of that could be the result of poorer disease control and more HIV-related symptoms, researchers said.

"They're trying to find food on a daily basis - it really can significantly impact their medication adherence," Kalichman told Reuters Health.

"The struggle to find food supersedes remembering to take your medications."

There's also a strong link between mental illness and food insecurity, Weiser said, in addition to the general health problems that come with not getting adequate nutrition.

"No matter what, it's clear that there needs to be better integration of food services and health services," she told Reuters Health.

For example, clinics that treat low-income people need to have social workers available to connect patients to food and housing resources, she added.

Kalichman said more research needs to be done on other strategies to link hungry, food-insecure people, with or without HIV, to reliable food sources such as nutrition assistance programs.

And the researchers emphasized the need to continue to put funding into such food programs for the sick and poor.

"Access to food, hunger and nutrition are central to our efforts to improve the health of people living with HIV-AIDS," Dr. David Bangsberg from Harvard Medical School in Boston, who also worked on the new study, told Reuters Health.

"Cutting food sources is penny-wise kind of foolish when the cost of treating somebody with advanced AIDS is orders of magnitude more expensive than the cost or providing adequate nutrition," he said.

SOURCE: bit.ly/OgtukT Journal of General Internal Medicine, online August 18, 2012.

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Hepatitis C fight - 'watershed moment'

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

Earlier this year, an editorial in the New England Journal of Medicine declared that the world was in a "watershed moment" in the history of treatment for hepatitis C, a virus that is believed to infect roughly 180 million people globally. Dr. Warner Greene, director of the Gladstone Institute of Virology and Immunology in San Francisco, agrees wholeheartedly - and believes that with recent advances in treatments and a cure, the world could be on the cusp of nearly wiping out the virus.

Q: What does the hepatitis C virus do to the body?

A: This is an RNA virus that infects hepatocytes, cells in the liver. That's why you ultimately get hepatitis, or inflammation in the liver, and that can progress on to cirrhosis. About 20 percent of people spontaneously clear the hepatitis C virus, and of the rest, about 20 to 25 percent will progress to cirrhosis, and eventually end-stage liver disease. Hepatitis C is the leading reason behind liver transplants in the United States.

Q: For many years, hepatitis C has been treated with interferon. What is interferon?

A: Interferon is a type of protein called cytokine. It normally triggers an antiviral response in the body. It inhibits key steps in the (hepatitis C) virus life cycle that allow it to replicate. But it's doing it at a cost. Cytokine is pretty toxic. It makes patients very sick.

Q: Last year the Food and Drug Administration approved new drugs to treat hepatitis C. How do they work?

A: It's just like with HIV - you're attacking multiple, key proteins needed for the hepatitis C virus lifecycle. Now you have these small molecules that are attacking the virus itself, as opposed to trying to induce an antiviral response, like with interferon.

These drugs are proving to be just dynamite. We're very close to being able to cure everybody of hepatitis C. The natural history of hepatitis C virus infection has been fundamentally changed.

Q: Why has hepatitis C been so hard to treat historically?

A: One thing that limited progress was the lack of an infectious molecular clone to use in the laboratory to test drugs. It was only in the last few years that an infectious molecular clone came out of Japan. Before that, none of them fully replicated (in the lab). When the molecular clones came along progress just took off at light speed.

Then the blueprint for working on HIV became very informative - protease inhibitors, polymerase inhibitors, they were all targeted very quickly, by multiple pharmaceuticals. Many of the pharmaceuticals just moved their HIV discovery teams into HCV. Progress has been made so rapidly here because the trail had been blazed by all of the HIV drugs.

Q: Will we be able to wipe out hepatitis C entirely?

A: In contrast to HIV, we do have the capability of doing that - essentially curing everyone who got infected. While we have made tremendous progress against HIV, we still don't have a cure, we still don't have a vaccine. The situation for HCV is dramatically different. A cure is achievable. Someday soon, the cure using an interferon-free cocktail is going to be routine.

Then it becomes more of an implementation issue - how you distribute these drugs, what you charge for them. There are 180 million people infected worldwide, five to six times the size of the HIV epidemic, and many are living in resource-poor settings. We're going to have to figure out how to deal with the developing world.

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New HCV Drugs: non nucleoside polymerase inhibitors

Provided by NATAP

by Jules Levin

Many observers have written off the class of HCV drugs non nucleoside polymerase inhibitors because resistance can develop quickly but does it really matter if this drug is used in combination with 2 other potent HCV drugs??? HCV protease is a potent class (3-4.5 or even 5 logs for a few proteases), as well HCV nucleotide is also a potent class (4.5 logs) and of course a big reason it's liked is because resistance is very hard to develop or won't at all. And of course NS5A is a potent class of drug (4-5 logs). The non nucleoside polymerase inhibitors in development have shown a wide range of potency from 1.3 logs to 3.5 logs on average). Here is a review of this 'can't get no respect' class. What is interesting about this class is several of these drugs are fairly well along in development and are not far at all away from becoming avaliable. In phase 3 right now however are GS7977, a potent 4.5 log nucleotide, BMS052, a potent 5 log NS5A, and 2 once daily proteases BI1335 & TMC435. Combining GS-7977 with BMS052 provides on average 9 to 9.5 logs potency & 100% cure rate was reported in naive gt1 patients in small study of about 40 patients at EASL, and a null responder study is ongoing combining TMC435 + GS7977 which on average has a 8.5 log potency. If you combined a protease + BMS052+GS7977 you are talking about a 13-14 log potency. And Vertex just announced their nucleotide ALS2200 showed 4.5 logs in the initial study, while we wait for the initial results from their 2nd nucleotide ALS2158, what about the possibility of combining 2 nucleotides, we dont know exactly what that would produce. Pharmasset combined their 2 nucleotides before Gilead bought them and although they had some additive benefits it wasn't double the potency. So that's why the non nucleosides 'can't get no respect'. Still, 80% of HCV-infected remain undiagnosed, efforts to identify by screening this large pool of patients is almost totally absent at this time, so there remains a very large patient pool not yet even knowing they have HCV. In addition, there is the global pool of patients outside the US. In Western & in moreso in Eastern Europe where access even now to telaprevir & boceprevir is very limited due to the costs of the drugs & the failing economies, but this is true in other parts of the globe as well. In places like India, Asia, So & Central America etc access will be a challenge. So there is a lot of time before many patients can be identified & access treatment. It is estimated well over 120 million have HCV globally, with as much as only 8 million in the US. How will the rest of the world get access & what classes of drugs will be in the regimens they might have access to??? What role will pricing play & distribution systems? Another factor is GS-7977+Rbv is a simple 2 drug combination being studied now with phase 3 data in gt1 and gt2/3 in coinfected & monoinfected. This combination is potent but obviously not as potent as some other combinations, although in gt2/3 patients in a small study 100% were cured. But gt1 remains the major concern where other combinations with more potent oral drugs besides RBV will be used. Here is a review of non nucleoside polymerase inhibitors. Gilead has 2 non-nucleoside polymerase inhibitors. Roche bought & has been developing ANA598, a non nucleoside polymerase inhibitor. BMS791325 is a non-nucleoside polymerase inhibitor. Abbott has 2 of these: ABT-072 & ABT-333. Boerhinger Ingelheim has a potent non nucleoside polymerase inhibitor BI207127, which has been studied in combination with their protease BI1335, which is currently in phase 3 completing in about 1 to 1.5 years, the most recent results were reported at EASL 2012. Vertex has a potent non nucleoside VX222. .

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 - (04/20/12)

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 - (04/22/1

Safety, pharmacokinetics and antiviral effect of BI 207127, a novel ... www.natap.org/2009/EASL/EASL_08.htm Safety, pharmacokinetics and antiviral effect of BI 207127, a novel HCV RNA polymerase inhibitor, after 5 days' oral treatme

VX-222 Vertex NNRTI Polymerase Inhibitor 3 Days Monotherapy www.natap.org/2010/EASL/EASL_02.htm VX-222 Vertex NNRTI Polymerase Inhibitor 3 Days Monotherapy. Reported by Jules Levin EASL Apr 14-18 2010. Vienna Austr

Patients of all IL28B Genotypes have High SVR Rates when Treated with VX-222 in Combination with Telaprevir/Peginterferon/Ribavirin in the ZENITH Study - (04/24/12)

Vertex QUAD Therapy Yielded 83-93% SVR with 12 weeks duration ... www.natap.org/2012/APASL/APASL_11.htm

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

EASL 2012: 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

Nonclinical and Cross-genotypic Profiles of GS-9669, a Novel HCV NS5B Non-nucleoside Thumb Site II Inhibitor - (04/06/1

Antiviral, pharmacokinetic and safety data for GS-9190, a non - NATAP www.natap.org/2007/AASLD/AASLD_39.htm Antiviral, pharmacokinetic and safety data for GS-9190, a non-nucleoside HCV NS5B polymerase inhibitor, in a phase-1 trial in HCV genotype

ANA598 HCV Polymerase Inhititor Safety & Activity + Peg/Rbv in ... www.natap.org/2010/EASL/EASL_20.htm At 8 weeks, ANA598 400 mg bid plus Peg/Rbv resulted in 72% of patients achieving undetectable levels of virus. No patient receiving ANA5

12-Week Effiacy and Safety of ABT-072 or ABT-333 with Pegylated ... www.natap.org/2011/APSL/APSL_02.htm In a previous clinical trial, subjects receiving two days of ABT-072 monotherapy had a mean maximum HCV RNA decrease from baseline of 1.3 log10 IU/mL

EASL: Gilead, Bristol Hep C Drug Data Arrives at EASL: 100% Cure Rate with Bristol's phase II study of daclatasvir plus Gilead's GS-7977 in patients with genotypes 1, 2, and 3: SVR4 (early cure) rate in the genotype 1 patients: 100%. In genotype 2/3 patients, the SVR4 rate was 91%. - (04/23/12)

EASL: 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) - (04/19/1

IDENTIFICATION AND CHARACTERIZATION OF PPI-383, A NEXT GENERATION HCV NS5BNON-NUCLEOSIDE INHIBITOR WITH POTENT ACTIVITY AGAINST ALL MAJORHCV GENOTYPES - (04/25/1

BMS-766, a Novel HCV NS5A Inhibitor With Enhanced Resistance Coverage - (04/06/11)

EASL 2012

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

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

GS-7977 Phase 2 Trials: Concordance of SVR4 with SVR12 and SVR24 in HCV Genotypes 1-3 - (04/20/1

The Effect of Hepatic Impairment on the Safety, Pharmacokinetics, and Antiviral Activity of GS-7977 in Hepatitis C Infected Subjects Treated for Seven Days - (04/24/1

GS-6620, A Liver-Targeted Nucleotide Prodrug, Exhibits Antiviral Activity and Favorable Safety Profile Over 5 Days in Treatment Naïve Chronic HCV Genotype 1 Subjects - (05/04/12)

EASL 2011

Gilead Studies

Four-Week Treatment with GS-9256 and Tegobuvir (GS-9190) +/- RBV +/- PEG, Results in Enhanced Viral Suppression on Follow-up PEG/RBV Therapy, in Genotype 1a/1b HCV Patients - (04/05/1

Therapeutic Efficacy of a TLR7 Agonist for HBV Chronic Infection in Chimpanzees - (04/07/1

Anti-Viral Efficacy and Induction of an Antibody Response Against Surface Antigen with the TLR7 Agonist GS-9620 in the Woodchuck Model of Chronic HBV Infection - (04/07/1

Three-Day, Dose-Ranging Study of the HCV NS5A Inhibitor GS-5885 - (04/06/1

A Phase 2b Trial Comparing 24 to 48 Weeks Treatment with Tegobuvir (GS-9190)/PEG/RBV to 48 Weeks Treatment with PEG/RBV for Chronic Genotype 1 HCV Infection - (04/06/1

GS-6620: A Liver Targeted Nucleotide Prodrug with Potent Pan-Genotype Anti-Hepatitis C Virus Activity In Vitro - (04/06/11)

Emergence and Persistence of NS5B Mutations Following Combination Treatment with Tegobuvir (GS-9190) plus Standard of Care--Long-Term follow-Up from the Phase 2b Study GS-US-196-0103 - (04/06/1

Preclinical Properties of the Novel HCV NS3 Protease Inhibitor GS-9451 - (04/06/1

GS-6620, A Novel Anti-Hepatitis C Virus Nucleotide Prodrug, Has A High In Vitro Barrier To Resistance - (04/06/1

Nonclinical and Cross-genotypic Profiles of GS-9669, a Novel HCV NS5B Non-nucleoside Thumb Site II Inhibitor - (04/06/1

Preclinical Characterization of GS-9620, A Potent and Selective Oral TLR7 Agonist - (04/06/1

A Phase-I, Randomized, Double-Blind, Placebo-Controlled Study To Evaluate The Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Escalating Oral Doses of GS-9620 In Healthy Subjects - (04/06/1

Genotypic and Phenotypic Characterization of HCV Resistance From a Multiple Dose Clinical Trial of GS-9451, a Novel NS3 Protease Inhibitor - (04/06/11)

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6 New HCV Drugs in Phase 3 Now

Provided by NATAP

  • "Rapid progress has been made with the HCV Research Program and we now have a comprehensive Phase III development program" John Martin CEO Gilead........"In May and June of this year, discussions were held with the U.S. FDA and 3 European regulatory agencies, and agreement has been achieved on a comprehensive Phase III development plan for GS-7977 and on a Phase III plan for GS-7977 in combination with the NS5A inhibitor, GS-5885.......we anticipate being able to file for regulatory approvals for GS-7977 by the middle of next year.......If successful, the initial indication will for 12 to 16 weeks of treatment with GS-7977 and Ribavirin in genotype 2/3 infected patients, and for 12 weeks of treatment with GS-7977, peg-interferon and Ribavirin in genotype 1, 4, 5 and 6 infected patients......we plan to advance the fixed dose combination of GS-7977 and 5885, currently in Phase I clinical testing, into Phase III in the fourth quarter of this year.....GS-7977 and GS-5885 were successfully co-formulated into a single pill, fixed dose combination......The fixed dose combination regulatory filings could, in that case, follow the initial GS-7977 filings a year later by mid-2014"....."The Food and Drug Administration is allowing a nonstandard-of-care controlled phase III study for 7977/5885" from Barron's online [we know the FDA is allowing this for all IFN-free therapy development studies from all companies

    Gilead Begins Single Pill Hepatitis C Study for 2014 Approval - (07/27/12)

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