August 31, 2013

If You Can't Make Own Drug, Take Gilead's

Provided by The Big Red Biotech Blog

08/31/2013

Fierce Biotech reports that Gilead is getting a lot of attention from rivals Merck and Roche as its hepatitis C drug, sofosbuvir, approaches expected approval by FDA in December of this year.  Idenix is also claiming its place in line to grab for sofosbuvir by including the drug in a list of metabolites it claims in ints patents. 

You may remember that Gilead bought Pharmasset for a startling $11B a few years ago to gain control of this very drug. The drug is considered to be a potential game changer in hepatitis C treatment.  Analysts variously estimate peak sales to be in $4B to $5B range. 

Gilead says Roche's claim has no merit.  It says any agreement that it had with Pharmasset ended several years before it even purchased the company.  Gilead also says its own patent cover sofosbuvir and dismisses merit of any Idenix patents.  That leaves Merck which claims Gilead should pay it 10% royalties on sofosbuvir sales due to two patents it holds that it claims Gilead would need to practice.  It gave Gilead until today to respond to its claims. 

It's clear that this property is valuable so anyone -- even with a tenuous claim -- may find it to be well worth the legal investment to try to get in on the action.  Legal costs are much likely to be far less than costs that would be incurred to actually invent ones own drug, right? 

Posted by Bruce Lehr Aug 31st 2013.

Source

Also See: Gilead Sues Merck Saying New Drug Won’t Infringe Patents

Journal of Hepatology

Article in Press

Coilly Audrey, Roche Bruno, Dumortier Jérôme, Leroy Vincent, Botta-Fridlund Danielle, Radenne Sylvie, Pageaux Georges-Philippe, Si-Ahmed Si-Nafaa, Guillaud Olivier, Antonini Teresa Maria, Haim-Boukobza Stéphanie, Roque-Afonso Anne-Marie, Samuel Didier, Duclos-Vallee Jean-Charles

Received 18 February 2013; received in revised form 16 July 2013; accepted 15 August 2013. published online 30 August 2013.
Accepted Manuscript

Abstract

Background

Protease inhibitors (PI) with peg-interferon/ribavirin have significantly improved SVR rates in HCV G1 patients. Their use to treat HCV recurrence after liver transplantation (LT) is a challenge.

Methods

This cohort study included 37 liver transplant recipients (male: 92%, age 57±11years), treated with boceprevir (n=18) or telaprevir (n=19). The indication for therapy was HCV recurrence (fibrosis stage > than or equal to F2 (n=31, 83%) or fibrosing cholestatic hepatitis (n=6, 16%).

Results

Eighteen patients were treatment-naive, five were relapsers and 14 were non-responders to dual therapy after LT. Twenty-two patients received cyclosporine and 15 tacrolimus. After 12 weeks of PI therapy, a complete virological response was obtained in 89% of patients treated with boceprevir, and 58% with telaprevir (P=0.06). The end of treatment virological response rate was 72% (13/18) in the boceprevir group and 40% (4/10) in the telaprevir group (P=0.125). A sustained virological response 12 weeks after treatment discontinuation was observed in 20% (1/5) and 71% (5/7) of patients in the telaprevir and boceprevir groups, respectively (P=0.24). Treatment was discontinued in 16 patients (treatment failures (n=11), adverse events (n=5)). Infections occurred in ten patients (27%), with three fatal outcomes (8%). The most common adverse effect was anemia (n=34, 92%), treated with erythropoietin and/or a ribavirin dose reduction; thirteen patients (35%) received red blood cell transfusions. The cyclosporine dose was reduced by 1.8±1.1-fold and 3.4±1.0-fold with boceprevir and telaprevir, respectively. The tacrolimus dose was reduced by 5.2±1.5-fold with boceprevir and 23.8±18.2-fold with telaprevir.

Conclusions

Our results suggest that triple therapy is effective in LT recipients, particularly those experiencing a severe recurrence. The occurrence of anemia and drug-drug interactions, and the risk of infections, require close monitoring.

Keywords: Abbreviations

Keywords: ALT, alanine aminotransferase, AFEF, French Association for the Study of the Liver, AUC, area under the curve, BID, twice daily (bis in die), BOC, boceprevir, cEVR, complete early virological response, CNI, calcineurin inhibitors, CYP, cytochrome P450, EPO, erythropoietin, EOT, end of treatment response rate, EVR, early virological response, F, female, FCH, fibrosing cholestatic hepatitis, G1, genotype 1, GGT, gamma-glutamyl transferase, HBV, hepatitis B virus, HCC, hepatocellular carcinoma, HCV, hepatitis C virus, HIV, human immunodeficiency virus, IL, interleukin, INR, International Normalized Ratio, IS, immunosuppressive drugs, Kg, Kilogram, LT, liver transplantation, M, male, MELD, Model for End-stage Liver Disease, MMF, mycophenolate mofetil, NA, not available, NR, non-response, PCR, polymerase chain reaction, PEG-IFN, pegylated interferon, PI, protease inhibitors, QD, once a day (quaque die), RBV, ribavirin, RVR, rapid virological response, SVR12, sustained virological response 12 weeks after the end of therapy, TBC, trough blood concentration, TID, three times a day (ter in die), TVR, telaprevir, VB, virological breakthrough, VL, viral load, VR, virological response.

Keywords: Boceprevir, Drug-drug interaction, Early virological response, HCV recurrence, Liver transplantation, Protease inhibitors, Sustained virological response, Telaprevir

PII: S0168-8278(13)00613-2

doi:10.1016/j.jhep.2013.08.018

© 2013 Published by Elsevier Inc.

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Provided by MedicalXpress

August 30, 2013

livercancerd

Immunohistochemical stainings of Ki67 and pancytokeratin (Ki67 is stained brown, pancytokeratin is stained pink) indicate proliferation of hepatocytes (arrowheads) and biliary epithelial cells (arrows) in TAK1/RIP3-deficient mice. Credit: Helmholtz Zentrum München

The death of numerous liver cells in the context of chronic inflammation due to apoptosis, a form of programmed cell death, can promote the formation of tumour cells in the liver. This insight significantly contributes to a better understanding of cellular processes in liver cancer development and thereby opens up new therapeutic approaches. A research team including scientists from the Helmholtz Zentrum München has reported this in the current issue of the scientific journal Cell Reports.

Liver cancer (Hepatocellular Carcinoma, HCC) usually arises as the result of a chronic, inflammatory liver disease. The most common causes here are excessive alcohol consumption as well as a high-fat diet and also chronic infection with the hepatitis viruses B and C. In the course of the inflammatory process, the liver cells (hepatocytes) die more frequently due to programmed cell death. The result is increased cell growth, also referred to as compensatory proliferation, which can lead to tumour development.

A distinction is made between the two most important forms of self-induced cell death, namely apoptosis (programmed cell death) and necroptosis (programmed necrosis), which are based on different cellular mechanisms. Until now, it was not clear which form of cell death is decisive for the development of malignant liver tumours. The team working with Professor Dr. Tom Luedde from the RWTH Aachen University Hospital and Professor Dr. Mathias Heikenwälder from the Institute of Virology at the Helmholtz Zentrum München (HMGU) has now been able to verify that apoptosis precedes the development of abnormal liver cells. The scientists, including Florian Reisinger from the Institute of Virology (HMGU) and Dr. Kristian Unger from the Research Unit Radiation Cytogenetics (HMGU) showed this using mouse models. Moreover they discovered that in contrast, necroptosis prevents uninhibited cell proliferation and consequently the development of liver cancer.

These findings could form the basis for new approaches to therapy for liver cancer, which until now has been a form of cancer that cannot be adequately treated and that kills 800,000 patients around the world each year. "We now know which cellular signalling pathways are involved in liver tumour development", explains Heikenwälder. "In a further step we want to develop new treatment options, for example, by attempting to pharmaceutically block the apoptosis itself or its signalling pathways. But any new therapy can also cause undesirable effects: In our experiments, we saw that blocking apoptosis under inflammatory conditions can result in bililary obstruction (cholestasis) in the context of liver inflammation."

In upcoming investigations, the scientists want to verify their findings on the development of liver cancer and search for active substances that inhibit apoptosis while simultaneously causing the mildest possible side effects. The objective is to further develop the acquired knowledge in the sense of translational research in order to provide concrete benefits for society.

 Explore further: US liver-related deaths underestimated for decades

More information: Vucur, M. et al. (2013), RIP3 inhibits inflammatory hepatocarcinogenesis but promotes cholestasis by controlling Caspase-8- and JNK-dependent compensatory cell proliferation, Cell Reports. DOI: 10.1016/j.celrep.2013.07.035

Journal reference: Cell Reports

Provided by Helmholtz Association of German Research Centres

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August 30, 2013

Hey Grandma, Let's Get You Checked for Hep C

Medscape Family Medicine > Best Evidence Review

Charles P. Vega, MD

Aug 30, 2013

Best Evidence Review of the USPSTF Screening Recommendations for Hepatitis C

The Study

Moyer VA; US Preventive Services Task Force. Screening for hepatitis C virus infection in adults: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2013 Jun 25. [Epub ahead of print]

Introduction

The prevalence of chronic hepatitis C virus (HCV) infection in the United States may have peaked over a decade ago, but there is convincing evidence that middle-aged and older adults born between 1945 and 1965 are at increased risk for infection. The most significant risk factor for chronic HCV infection is prior injection drug use, but the majority of adults with infection do not have this risk factor. Therefore, in additional to regular screening among high-risk groups, the US Preventive Services Task Force (USPTSF) now recommends 1-time screening for chronic HCV infection for adults born between 1945 and 1965.

While this recommendation may seem preposterous when thinking of your own Nana, do you really know what she was up to in 1968? There is good merit for the recommendation, which is discussed below.

Background to the Study

HCV infection is one of the most common chronic infections in the United States. Data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2002 indicated that the overall prevalence of HCV infection was 1.6% among adults aged 20-59 years.[1] This figure includes over 3 million adults with active infection, as defined by a positive HCV RNA test. Moreover, this testing probably underestimated the total prevalence of HCV infection because high-risk populations, including homeless and incarcerated adults, were not included in the research. In a study of over 400 homeless war veterans, the prevalence of HCV infection was 44.0%.[2]

Evidence of HCV infection is twice as common among women than men and among African Americans than white adults.[3] The most important risk factor for HCV infection is intravenous drug use. Nearly one half of the cohort that was positive for HCV infection in the NHANES study had this risk factor.[1] Other significant risk factors for HCV infection include receipt of blood transfusion before 1992, receipt of other blood products before 1987, and other drug use.[3] Sexual behavior is a less powerful risk factor HCV infection compared with HIV infection, but there is evidence that a history of multiple sexual partners is associated with a higher risk for HCV infection. Many individuals with HCV infection have overlapping risk factors for infection.

Why Screen All Baby Boomers?

Although the authors of the recommendations regarding screening for HCV infection note that the prevalence of HCV infection in the United States appeared to peak in 2001, there is another clear trend in the epidemiology of HCV infection that merits close attention. Persons born between 1945 and 1965 comprise approximately 27% of the total population of the United States, but they account for a disproportionate share of cases of HCV infection.[4] The prevalence of HCV infection in this age group is 3.25%, and approximately three quarters of active HCV infection cases are encountered among persons born between 1945 and 1965.

Moreover, and more important, persons who are currently in the fifth through seventh decades of life at this time are at the highest risk for complications from HCV infection. They account for 73% of mortality due to HCV infection, and this group is also at the highest risk for hepatocellular carcinoma and cirrhosis.[4] Therefore, the number of patients needed to treat with anti-HCV therapy in order to prevent additional cases of mortality is lower in this specific older cohort of adults compared with younger adults.

Therefore, it is not only the epidemiologic data that drive the new HCV screening recommendations from the USPSTF, but also an expectation that treatment of heretofore undiagnosed HCV infection can put a substantial dent in the broad clinical impact of HCV. The new recommendations call for 1-time screening for all adults born between 1945 and 1965 (B recommendation: high certainty that the net benefit is moderate, or moderate certainty that the net benefit is moderate to substantial). The anti-HCV antibody is test the best screening tool for these adults.

Limitations and Benefits of Age-Based Screening

Limitations

The authors identify the limitations of the new recommendations. Although age-based screening should identify more patients with HCV infection, they admit that this method may be less efficient than risk-based screening. The potential harms of screening include stigmatization, but also the more tangible and serious complications of the diagnostic work-up of liver disease.

The rate of major complications after percutaneous liver biopsy ranges between 0.09% and 2.3%, with a trend toward higher complication rates in older studies.[5] Use of ultrasonography to guide liver biopsy may reduce the risk for complications by 30%. However, the authors of the current review note that overall use of liver biopsy is declining with greater reliance on laboratory testing alone to guide treatment. This will reduce the potential harms of screening for HCV infection.

A more serious complication of a large screening campaign for HCV infection among older adults is overdiagnosis, meaning the discovery of infections which would have no impact on the course of the patient's life. Up to 25% of acute infections with HCV may be cleared and do not progress to chronic HCV infection.[6] Despite the high numbers of patients with chronic HCV infection, only 10%-15% develop cirrhosis. The mean interval from infection to cirrhosis is a matter of debate but is approximately 20 years, and patients without other cirrhosis risk factors, such as chronic alcohol misuse or hepatitis B infection, are less likely to develop cirrhosis.

Benefits of Screening

Nonetheless, acquiring HCV infection at an age older than 40 years is also associated with a higher risk for cirrhosis, making overdiagnosis less of an issue among older adults.[6] In addition, treatment of chronic HCV infection has resulted in significant improvements in morbidity and mortality outcomes.

In research from 5 large tertiary hospitals in which 530 patients were followed for over 8 years for mortality outcomes, patients with a sustained virologic response (SVR) experienced a 74% reduction in all-cause mortality and a 94% reduction in the risk for liver-related mortality or transplantation compared with patients who did not have an SVR to anti-HCV therapy.[7] The mean age of participants in this research was 48 years, meaning that many patients included in the new screening recommendation might receive these substantial benefits of anti-HCV treatment.

Furthermore, treatment of chronic HCV infection reduces the risk for hepatocellular carcinoma. In a meta-analysis of 18 studies, SVR reduced the relative risk for hepatocellular carcinoma to 0.24 compared with no SVR.[8] SVR was similarly effective in reducing the risk for hepatocellular carcinoma in an analysis confined to patients with advanced liver disease.

The new screening methods also appear to be cost-effective. In an analysis of the proposed birth-cohort HCV screening plan proposed by the USPSTF, researchers found that screening would result in over 800,000 new cases of HCV infection identified, at the cost of $2874 per case.[9] Subsequent treatment for HCV would result in costs of $15,000-$35,000 per quality-adjusted life-year gained, a favorable sum compared with other health interventions. In fact, another analysis found that age-based screening for HCV was more cost-effective than risk factor-based screening, although the authors stress that this is true only if all new cases receive standard triple therapy for their infection.[10]

Adding to the PCP Tasks

Primary care physicians are asked to do many things. The average number of patient requests of physicians per clinic visit was 5.5 in one study, and this information is now 14 years old.[11] These requests exclude other important elements of the office visit, such as addressing severe anemia or demonstrating empathy and patience when the patient bursts into tears upon being asked, "So, how's it going?"

Primary care physicians are also the stewards of preventive healthcare, which is a wonderful opportunity and distinct challenge. We need to get screening tests ordered on time for the right patients, and practice shared decision-making each step of the way as we do so.

At first glance, the new screening recommendations from the USPSTF may seem superfluous. However, after reviewing the epidemiology, treatment outcomes, and even cost-effectiveness data, this screening certainly appears to be prudent and beneficial. It should be embraced by primary care physicians. It should also evolve. As the demographics of HCV infection shift, the age-based screening approach will almost certainly need to change as well. An eventual move away from HCV screening will indicate a great victory for the public's health.

Clinical Pearls

  • Between 1% and 2% of the adult population in the United States has been found to have chronic HCV infection, although this may be an underestimation once high-risk groups are added to the equation.
  • Persons born between 1945 and 1965 bear a disproportionate share of the disease burden of chronic HCV infection, both in terms of higher prevalence and increased rates of complications.
  • Treatment that results in SVR among patients with chronic HCV infection substantially reduces the risks for cirrhosis, hepatocellular carcinoma, and mortality.
  • The new recommendations from the USPSTF support traditional screening for HCV among high-risk groups but also call for 1-time screening using anti-HCV antibody testing among adults born between 1945 and 1965. If used widely, this screening program should have a positive effect on morbidity and mortality among older adults.

References

  1. Armstrong GL, Wasley A, Simard EP, et al. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144:705-714.

  2. Desai RA, Rosenheck RA, Agnello V, et al. Prevalence of hepatitis C virus infection in a sample of homeless veterans. Soc Psychiatry Psychiatr Epidemiol. 2003;38:396-401.

  3. Rustgi VK. The epidemiology of hepatitis C infection in the United States. J Gastroenterol. 2007;42:513-521.

  4. Smith BD, Morgan RL, Beckett GA, et al. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR Recomm Rep. 2012;61:1-32.

  5. Sporea I, Popescu A, Sirli R. Why, who and how should perform liver biopsy in chronic liver diseases. World J Gastroenterol. 2008;14:3396-3402.

  6. Chen SL, Morgan TR. The natural history of hepatitis C virus (HCV) infection. Int J Med Sci. 2006;3:47-52.

  7. van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012;308:2584-2593.

  8. Morgan RL, Baack B, Smith BD, et al. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. Ann Intern Med. 2013;158:329-337.

  9. Rein DB, Smith BD, Wittenborn JS, et al. The cost-effectiveness of birth-cohort screening for hepatitis C antibody in U.S. primary care settings. Ann Intern Med. 2012;156:263-270.

  10. Liu S, Cipriano LE, Holodniy M, Goldhaber-Fiebert JD. Cost-effectiveness analysis of risk-factor guided and birth-cohort screening for chronic hepatitis C infection in the United States. PLoS One. 2013;8:e58975.

  11. Kravitz RL, Bell RA, Franz CE. A taxonomy of requests by patients (TORP): a new system for understanding clinical negotiation in office practice. J Fam Pract. 1999;48:872-878.

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Gilead Sues Merck Saying New Drug Won’t Infringe Patents

By Karen Gullo - Aug 30, 2013 9:16 PM ET

Gilead Sciences Inc. (GILD), the world’s largest maker of HIV medicines, sued Merck & Co. (MRK) seeking a court order that the experimental hepatitis C drug sofosbuvir won’t infringe patents.

Merck, which sold $502 million of its Victrelis hepatitis C drug last year, contacted Gilead this month requesting it license two patents Merck says are related to sofosbuvir, Gilead’s attorneys said a complaint filed today in federal court in San Francisco.

Merck, based in Whitehouse Station, New Jersey, asked Gilead to pay a 10 percent royalty on the net sales of the medicine until the patents expire, a request “meant to threaten Gilead” on the eve of U.S. regulatory approval of sofosbuvir, according to the complaint. Gilead seeks a judge’s declarations that the patents aren’t enforceable or infringed so it won’t have to license them to sell the medicine.

Gilead, based in Foster City California, said June 7 that sofosbuvir will receive a priority marketing review by U.S. regulators with a target review date of Dec. 8.

Hepatitis C attacks the liver and can lead to liver cancer. The virus affects about 150 million people worldwide and the market for new pills such as sofosbuvir is estimated at $20 billion.

Lainie Keller, a Merck spokeswoman, didn’t immediately respond to an e-mail after regular business hours seeking comment on the lawsuit.

The case is Gilead Sciences v. Merck, 13-04057, U.S. District Court, Northern District of California (San Francisco).

To contact the reporter on this story: Karen Gullo in San Francisco at kgullo@bloomberg.net

To contact the editor responsible for this story: Michael Hytha at mhytha@bloomberg.net

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Yes, Gilead Did It Again

Aug 30 2013, 14:39 | by: Prohost Biotech | about: GILD

Biotechnology accomplishments as we see them and love to write about them are those that act as rings in the chain of the fast advancement in the management of condemning diseases, not just developing and marketing more me-too drugs.

Here is a story told by the National Institute of health and posted in JAMA about an all-oral hepatitis C drug regimen where a majority of hepatitis C viral (HCV) infected patients with liver damage were cured following a six-month course of all-oral treatment. The combination therapy comprised the investigational drug sofosbuvir, with the antiviral drug ribavirin. The company behind the treatment is Gilead Sciences. (GILD).

The results were remarkable considering the fact that the patients had advanced disease with scarred liver and most were from a category known to be resistant to current treatments. The results were announced by the National Institutes Of Health (NIH), as scientists from the National Institute of Allergy and Infectious Diseases (NIAID) and the NIH Clinical Center, which are parts of the National Institutes of Health, have led the trial.

The findings, which appeared in the Aug. 28 issue of the Journal of the American Medical Association ((JAMA)) demonstrate that the regimen was highly effective in clearing the virus and was well tolerated in a group of patients who historically have had unfavorable prognoses.

The study involved 60 volunteers with genotype-1 HCV, which is less responsive to interferon-based treatment.

Fifty of the 60 participants were African-American. NIAID researcher Shyam Kottilil, M.D., Ph.D., the principal investigator of the trial said, "While African-Americans make up about 13 percent of the U.S. population, they represent more than 22 percent of people with chronic HCV infection and, compared to whites, have lower cure rates with traditional HCV therapy."

Dr. Kottilil tried to draw attention to the fact that several recently completed studies testing interferon-free regimens have yielded promising results, but unlike this study, most volunteers in those studies were white. Also, the new study enrolled people with severe liver damage as well as those with mild or moderately scarred livers.

The first part of the two parts study enrolled ten people with mild or moderate liver fibrosis. Volunteers received oral ribavirin at a dosage based on their weight along with the experimental drug sofosbuvir, also in pill form developed by Gilead Sciences taken daily for six months.

Nine of the ten volunteers completed the course of therapy. The hepatitis C virus was undetectable in all nine volunteers 12 weeks after the end of therapy and continued undetectable when they were tested again 24 weeks after finishing therapy.

Dr. Kottilil explained, "HCV does not integrate itself into human DNA. If the virus cannot be detected for a period of 12 weeks after stopping therapy, the patient is considered cured."

The second part of the study enrolled 50 volunteers, Thirteen had liver damage rated serious. Twenty-five received ribavirin based on their weight, and 25 received a low dose (600 milligrams per day). All received sofosbuvir.

At four, 12 and 24 weeks after the end of treatment, HCV levels were undetectable in 24 of the volunteers in the high dose arm when treatment ended. Of those, 17 continued to have undetectable virus levels 24 weeks later and were considered cured of infection. In the low-dose arm, three volunteers dropped out of the study. Of the remaining 22, all responded to the treatment, but only 12 were considered cured at 24 weeks after the end of treatment.

Commenting on the result in general, Dr. Kottilil said, "We saw an overall cure rate of about 70 percent using regimens that did not include interferon," He added, "This is an encouraging result, especially considering the proportion of volunteers who had characteristics such as being male, having HCV genotype-1 infection, being African-American and having advanced liver damage - all are recognized as predictors of poor response to treatment."

Additional trials are underway to further determine if regimens without interferon or ribavirin can help people with chronic HCV infection, particularly those who have both HIV and HCV infections, said Dr. Kottilil. These trials include two studies in which volunteers with or without HIV infection take a combination of HCV drugs (but no interferon or ribavirin) for periods of three months or less.

Information about these trials is available at clinicaltrials.gov using the identifiers NCT01805882 and NCT01878799.

Prohost Comments: This story might partially explain the reason why we consider Gilead as the model of firms that we seek to find and invest in. The firm specialized in Viral diseases and began by creating what amounted to miraculous achievement, turning a deadly killer disease, AIDS, into a chronic disease. It courageously paid a huge amount of money, over $11 billion, to put its hands on molecules for HCV infection, knowing in fact that it will develop these molecules in a way that extracts the best out of them, including treating hopeless cases with poor prognosis.

We agree with the NIAID Director and study co-author Anthony S. Fauci, M.D. that there is a pressing need for hepatitis C virus treatments that are less burdensome to the patient, have fewer side effects and take less time to complete.

The number of patients suffering from HCV infection is overwhelming. More than 3 million Americans suffer this liver infection - a major cause of cirrhosis, a leading cause for liver transplantation and in many cases end with liver cancer. People die from HCV and it seems that HCV claims the lives of 15,000 people every year in the U.S.

Gilead's success and fame is based on its strong scientific fundamentals, excellent management abilities and, more important, its persistent efforts towards improvement. Gilead is ready to spend enormous time and money and do whatever it takes to perfect its specialized treatments. It is one of the few largest biotech firms in spite of the fact that it is still at the beginning of the road towards fulfilling its ambitious goals.

Disclosure: Long GILD.

FORWARD-LOOKING: Material presented here is for informational purposes only. Nothing in this article should be taken as a solicitation to purchase or sell securities. Before buying or selling any stock you should do your own research and reach your own conclusion. Further, these are our "opinions" and we may be wrong. We may have positions in securities mentioned in this article. You should take this into consideration before acting on any advice given in this article. If this makes you uncomfortable, then do not listen to our thoughts and opinions. The contents of this article do not take into consideration your individual investment objectives so consult with your own financial adviser before making an investment decision. Investing includes certain risks including loss of principal.

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Chimp-free labs are bad news for fight against hepatitis C

by Elizabeth DeVita-Raeburn @devitaraeburn August 29, 2013 6:30AM ET

Vaccine researchers say an end to testing on chimpanzees would be a major setback

Topics: Disease, Science

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A NIH researcher studies DNA map of the hepatitis C virus

Richard T. Nowitz/Science Source

Earlier this summer, Francis Collins, the director of the National Institutes of Health, announced that the agency would significantly reduce the use of chimpanzees in scientific research. The Fish and Wildlife Service is now deliberating whether to add captive chimpanzees — a category that includes the 50 chimps the NIH set aside as a safeguard for research that could not be done any other way — to the endangered species list.

If that happens, it would mark the end of medical research using chimpanzees in the United States. Animal activists have long sought the end of chimp research, and many medical researchers also celebrated the NIH decision, saying research on the animals had become obsolete. For HIV studies, the chimps’ utility is nil; with research on malaria and other diseases, better approaches exist.

But the decisions have troubled a small number of scientists struggling to develop a vaccine for hepatitis C, a serious liver disease most common in intravenous drug users, but also found in baby boomers, veterans, health-care workers and babies born to hepatitis C–infected mothers. They say ending use of chimps will dramatically slow their research.

Hepatitis C researchers think one reason they failed to win their case with the NIH is because so many of the victims are, or have been, intravenous drug users. Some of the doctors who see patients say that the stigma associated with this disease is reminiscent of the early days of the AIDS epidemic, when research and patients suffered because of the perception that it was a "gay" disease that people had brought on themselves.

Hepatitis C, which six years ago surpassed AIDS as a cause of mortality in the United States, may have taken up the niche that AIDS once occupied. "It's stigmatized and totally lacks the advocacy and cachet of HIV," says David Thomas, director of the division of infectious disease at Johns Hopkins University. That's largely, he says, because of its link to drug use.

'A screeching halt'

In announcing the NIH decision, Collins said the chimps' "likeness to humans has made them uniquely valuable for certain types of research, but also demands greater justification for their use. After extensive consideration, with the expert guidance of many, I am confident that greatly reducing their use in biomedical research is scientifically sound and the right thing to do." A NIH spokesperson declined to comment on the specific concerns of hepatitis C researchers.

Those researchers say they have few alternatives. Chimps are the only creatures, other than humans, susceptible to the hepatitis C virus. Because of this, chimps have long been considered essential for studying the disease and potential treatments — particularly a vaccine.

Francis Chisari, a virologist with the Scripps Research Institute who has been working on a vaccine, said that more than 20 years of research came "to a screeching halt" with the NIH decision. The consequences for researchers who've devoted careers to this endeavor are devastating, says Chisari. Many, he says, are considering leaving the field.

But more troubling for researchers are the consequences for people who have the disease or are at risk. Hepatitis C afflicts between 3 and 4 million Americans, most of whom don’t know they have it until its later stages. Unchecked, the disease is a serious risk factor for liver failure and liver cancer. Experts attribute a recent spike in incidence of liver cancer in the U.S. directly to this virus.

Devon Nicholson, 30, who has had the virus since 2009, called the NIH decision "sad" for patients. "I’m an animal lover; I have a lot of empathy for them," he says, "but I do think our own species should be a priority. This is a widespread, infectious disease. The treatment is hard to take, it's expensive, and from what I understand, the number of people infected is growing. This is a serious health concern for the future."

Nicholson, a former wrestler, was on the verge of realizing his life's dream — a lucrative professional wrestling contract — when a blood test, given as part of the required physical for obtaining a license to wrestle professionally, turned up positive for hepatitis C. The deal was canceled. He suspected that he’d been infected when another wrestler "bladed him" — nicked him with a concealed razor — during a match to make it bloodier and more exciting.

Self-blading is not an uncommon practice for wrestlers who want to put on a good show. "It just produces a trickle of blood, and it seals up pretty easily," says Nicholson. But you don’t nick someone else without permission, he says. His theory was proved true, he says, when he watched a videotape of one of his matches and saw his opponent, who has since tested positive for the disease, take out a razor, blade himself, and then blade Nicholson four or five times on the forehead. "It was just the same as sharing a needle," says Nicholson.

New drugs

The last few years have seen an explosion of new and better drug options to treat hepatitis C, which may also be part of the reason hepatitis researchers lost their case with the NIH. Two new drugs, designed to be used in combination with existing therapies, were approved in 2011, and there are six more in the pipeline. This has led some to believe that researchers have conquered hepatitis C and a vaccine is no longer necessary.

But vaccine researchers say this isn’t true. The drug regimens may be capable of clearing the virus, but they don’t protect people from being reinfected, says Andrea Cox, a physician and researcher at Johns Hopkins University who is currently working on a trial of the one hepatitis C vaccine that was tested in chimps before the NIH decision. And the treatments themselves, at this point, are hard to take and quite expensive, about $88,000, according to Cox.

Nicholson has gone through two painful rounds of extensive drug treatment to try and get rid of the virus. The first round had to be stopped at 19 weeks, when he suffered a mild stroke. He doesn’t know yet if the second attempt, an arduous 37-week regimen that he documented via a blog and his Facebook page, has worked. He’ll be tested in mid-September to see if the virus is still in his system.

Predictions of an epidemic

Not all people with hepatitis C are drug abusers. Baby boomers are designated high risk because of potentially risky behavior experimenting with drugs in the era of sex, drugs and rock and roll, and their potential exposure to tainted blood before screenings for the virus became possible. Hepatitis C has even struck some celebrities, including Natalie Cole, Steven Tyler, Naomi Judd and Pamela Anderson. Though they have been open about their infection, their celebrity has, thus far, not changed perception of the disease.

Vets are at risk because of exposure to blood on the battlefield and transfusions before screening. Studies by the Department of Veterans Affairs have shown a hepatitis C prevalence rate of between 5 percent and 22 percent among military veterans.

And some experts, like Marian Major, a research microbiologist at the Food and Drug Administration who works on hepatitis C, predict another “sadly massive epidemic” coming in the form of young suburbanite teens casually experimenting with injectable drugs. “They think they’re safe as long as they’re with people they know,” says Major.

A vaccine could head off a lot of that. But not having chimps to test hepatitis C vaccines will “severely retard” the process, say Chisari and others. Without the chimp, researchers will have to conduct trials on humans earlier, with less assurance of efficacy. "You could end up recruiting patients for a vaccine that has no effect," says Major. And one large question is: will drug companies, faced with this inconvenience, bother with vaccine research when drug options are easier to produce?

The most likely alternative to chimps would be to create mice genetically engineered to be susceptible to the virus — a difficult and time-consuming project that has seen progress recently but by all accounts is nowhere close to being a stand-in for the chimp.

Meanwhile, patients are muddling through their options. Nicholson, who is Canadian, said he called researchers at the University of Alberta to see if a vaccine would be available after he completed his treatment. If he tests negative for the virus, he says, he wants the vaccine "to ensure I never get this disease again, no matter what." He was told it would be at least another 10 years.

Source

Studies: Marijuana May Help Hepatitis C Sufferers

Posted on August 30, 2013 at 9:14 am by David Downs in Health

Hepatitis C is an often-fatal viral disease of the liver afflicting about four million Americans. Chronic hepatitis C infection causes fatigue, depression, joint pain and liver impairment, including cirrhosis and liver cancer. There is no cure.

Interestingly, patients diagnosed with hepatitis C often report using cannabis to treat both symptoms of the disease and the nausea associated with antiviral therapy, and there’s some science to back it up.

“An observational study by investigators at the University of California at San Francisco (UCSF) found that hepatitis C patients who used cannabis were significantly more likely to adhere to their treatment regimen than patients who didn’t use it,” writes TheAnswerPage.com today. TheAnswerPage.com is co-sponsored by The Massachusetts Medical Society, publisher of the New England Journal of Medicine, as part of their continuing medical education of physicians.

“Preclinical data indicate that the endocannabinoid system may moderate aspects of chronic liver disease and that cannabinoids [– the active ingredients in pot -] may reduce inflammation in experimental models of hepatitis,” TheAnswerPage.com writes.

“Cannabis use improves retention and virological outcomes in patients treated for hepatitis C,” one study concludes.

“Writing in the October 2006 issue of the European Journal of Gastroenterology, investigators from Canada and Germany concluded that cannabis”potential benefits of a higher likelihood of treatment success [for hepatitis c patients] appear to outweigh [its] risks.’

“Nevertheless, no clinical trials assessing the use of cannabinoids for this indication are available in the scientific literature,” TheAnswerPage writes, and “some experts discourage the use of cannabis in patients with chronic hepatitis, until further studies are performed.”

Source

August 29, 2013

Journal of Viral Hepatitis

Early View (Online Version of Record published before inclusion in an issue)

Original Article

B. Baran1, M. Gulluoglu2, O. M. Soyer1, A. C. Ormeci1, S. Gokturk1, S. Evirgen1, S. Yesil2, F. Akyuz1, C. Karaca1, K. Demir1, S. Kaymakoglu1, F. Besisik1,*

Article first published online: 27 AUG 2013

DOI: 10.1111/jvh.12127

© 2013 John Wiley & Sons Ltd

Abstract

Keywords: fibrosis progression; gamma-glutamyl transferase; hepatitis C; nonresponder; treatment failure

Summary

Chronic hepatitis C (CHC) patients with treatment failure (TF) remain at risk of continuing fibrosis progression. However, it has not been investigated whether there is an increased risk of accelerated fibrosis progression after failed interferon-based therapy. We aimed to investigate long-term influence of TF on fibrosis progression compared with untreated patients with CHC. We studied 125 patients with CHC who underwent paired liver biopsies from 1994 to 2012. Patients with advanced fibrosis were excluded from the analysis. Sixty-three patients had TF, and 62 patients were treatment-naïve (TN). Annual fibrosis progression rate (FPR) was calculated, and significant fibrosis progression (SFP) was defined as ≥2 stage increase in fibrosis during follow-up. Multiple regression analyses were performed to find out independent predictors of FPR and SFP. Demographic characteristics and duration between paired liver biopsies were similar in TF and TN groups. Baseline alanine aminotransferase and gamma-glutamyl transferase (GGT) levels (71 ± 31 vs 47 ± 22, P < 0.001 and 49 ± 39 vs 36 ± 28, P = 0.027, respectively), baseline mean fibrosis stage (2.2 ± 0.7 vs 1.9 ± 0.7, P = 0.018) and histologic activity index (6.3 ± 1.9 vs 4.3 ± 1.6, P < 0.001) were higher in the TF group compared with the TN group. In regression analyses, the strongest independent predictor of fibrosis progression was the GGT level (OR: 1.03, 95%CI 1.01–1.5, P < 0.001). Treatment experience (OR: 5.97, 95%CI 1.81–19.7, P = 0.003) also appeared as an independent predictor of both FPR and SFP. Failed interferon-based CHC treatment may lead to accelerated FPR in the long-term compared with the natural course.

Source

Journal of Hepatology

Article in Press

M. Patrizia Carrieri, Caroline Lions,Philippe Sogni, Maria Winnock,  Perrine Rouxm Marion Moram Philippe Bonnard, Dominique Salmon, François Dabis, Bruno Spire, ANRS CO13 HEPAVIH Study Group

Received 12 March 2013; received in revised form 6 August 2013; accepted 16 August 2013. published online 26 August 2013.
Accepted Manuscript

Abstract

Background & aims

We used longitudinal data from the ANRS CO13 HEPAVIH cohort study of HIV-HCV coinfected individuals to investigate whether polyphenol rich foods intake through coffee and/or daily chocolate consumption could play a role in reducing liver enzymes levels.

Methods

Longitudinal data collection included self-administered questionnaires and medical data (ASpartate aminoTransferase (AST) and ALanine aminoTransferase (ALT) liver enzymes). Two analyses were performed to assess the association between coffee (> or equal to 3 cups a day) and daily chocolate intake and abnormal values of AST and ALT (AST or ALT >2.5x upper normal limit (UNL)) (N=990) over time, after adjustment for known correlates. Logistic regression models based on Generalised Estimating Equations were used to take into account the correlations between repeated measures and estimate adjusted odds ratio.

Results

After adjustment, elevated coffee consumption and daily chocolate intake were independently associated with normal ALT (OR = 0.65; p = 0.04 and OR = 0.57; p=0.04, for coffee and chocolate respectively), while only elevated coffee consumption was positively associated with normal AST values (p = 0.05). Nevertheless, the combined indicator of coffee and chocolate intake was most significantly associated with a 40-50% reduced risk of abnormal liver enzymes (p = 0.003 for AST; p = 0.002 for ALT).

Conclusions

Elevated coffee consumption and daily chocolate intake appear to be associated with reduced level of liver enzymes in HIV-HCV co-infected patients. Further experimental and observational research is needed to better understand the role that polyphenol intake or supplementation can play on liver disease and liver injury.

Abbreviations: ANRS, Agency for Research on Aids and Viral Hepatitis, ALT, ALanine aminoTransferase, ART, Antiretroviral Treatment, AST, ASpartate aminoTransferase, AU, Alcohol Units, AUDIT-C, Alcohol Use Disorders Identification Test, BMI, Body Mass Index, CDC, Centers for Disease Control and Prevention, CD4, Cluster of Differentiation 4, GEE, Generalized Estimating Equations, HCV, Hepatitis C Virus, HIV, Human Immunodeficiency Virus, IDU, Intravenous Drug Users, IQR, Interquartile Range, kPa, kilopascal, OR, Odds Ratio, PEG-IFN, Pegylated Interferon, RNA, RiboNucleic Acid, TGF-Beta, Transforming Growth Factor Beta, TRIPS, Trade-Related Aspects of Intellectual Property Rights

Keywords: Polyphenol, Coffee, Chocolate, Cocoa, Liver enzyme, Hepatitis C HIV

PII: S0168-8278(13)00608-9

doi:10.1016/j.jhep.2013.08.014

© 2013 Published by Elsevier Inc.

Source

FDA, academia and industry team up to end hepatitis C

Provided by the University of Florida

Published: August 29th, 2013

GAINESVILLE, Fla. — As doctors prepare to manage an influx of new hepatitis C patients and treatment options, a collaboration among academia, industry and the U.S. Food and Drug Administration is poised to deliver real-world data that can help doctors and patients optimize their treatment experience.

A research consortium known as the Hepatitis C Therapeutic Registry and Research Network, or HCV-TARGET, has joined forces with the FDA to share national data on how newly approved therapies for hepatitis C are used and managed in routine practice. HCV-TARGET is led jointly by investigators at the University of Florida and the University of North Carolina at Chapel Hill and is sponsored in part by multiple pharmaceutical companies.

The new partnership’s goal is to establish research collaborations using the HCV-TARGET database to better inform patients and clinicians about hepatitis C therapies.

“This collaboration will not only strengthen our ongoing efforts to monitor the safety and effectiveness of existing hepatitis C treatment regimens,” said Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, “it will also provide opportunities for FDA scientists to apply their research expertise in studying existing data held by HCV-TARGET to identify areas for improvement in clinical trial design that may help improve the future of HCV drug development programs.”

Hepatitis C is a viral liver disease that can lead to liver damage, cirrhosis, liver failure or liver cancer. It is transmitted through contact with infected blood. Because a person with chronic hepatitis C can live symptom-free for decades, many people do not know they are infected.

Two factors increase the significance of this collaboration:

  • More patients to be screened and treated — Within the last year, both the Centers for Disease Control and Prevention and the U.S. Preventive Services Task Force recommended all baby boomers be tested for hepatitis C. The CDC estimates baby boomers represent three-quarters of the more than 3 million Americans believed to be infected with hepatitis C. Among those at highest risk are individuals who received blood transfusions before 1992, when screening donated blood for the virus began.
  • New treatments on the horizon — The first all-oral hepatitis C treatment is moving through the final stages of FDA approval. If approved, it would be the first of a new generation of hepatitis C drugs that will improve what for many has been a grueling treatment regimen that can take up to 48 weeks and requires injections of interferon, a drug that can be difficult to tolerate. The introduction of new drugs will bring new questions about managing side effects, drug combinations and other clinical considerations.

“Leading liver doctors across the country have joined HCV-TARGET to study and navigate rapidly evolving treatment paradigms for hepatitis C. We see a healthier future for patients battling this virus and formed HCV-TARGET to help guide the way,” said Dr. David R. Nelson, co-principal investigator, director of the UF Clinical and Translational Science Institute and a professor of medicine at UF Health, which serves as the clinical coordinating center for HCV-TARGET.

Following close to 2,500 patients in North America who have agreed to participate in its study to date, HCV-TARGET includes populations underrepresented in clinical trials such as patients with cirrhosis, patients age 65 and older and African-Americans. The initial focus of the network’s observational study has been treatment with boceprevir and telaprevir, drugs newly approved by the FDA when HCV-TARGET launched in 2011. HCV-TARGET will expand its study this year to include the entire spectrum of antiviral hepatitis C therapeutics.

“Real-world data about how drugs perform outside of restricted clinical trials are extremely important. HCV-TARGET allows us to capture this information using novel approaches to ensure the integrity and quality of the data. Through our partnership with the FDA, we hope this information can be used to help doctors and their patients more readily determine the most beneficial treatment options across a broad spectrum of patients,” said Dr. Michael W. Fried, co-principal investigator and professor of medicine at the UNC School of Medicine, which serves as the HCV-TARGET data coordinating center.

HCV-TARGET and the FDA signed in May a memorandum of understanding to promote scientific research in the area of hepatitis C drug development. In mid-July, HCV-TARGET held meetings with representatives from the FDA Center for Drug Evaluation and Research’s division of antiviral products and offices of computational science, clinical pharmacology and biostatistics. Attendees agreed one of the first priorities should be to align how data elements of common interest are defined so the clinical trial data collected by the FDA can be reasonably compared to the real-world observational data collected by HCV-TARGET, a critical step in developing research collaborations and pilot projects. In addition, the agreement allows an FDA representative to join HCV-TARGET’s advisory council.

HCV-TARGET includes 103 academic and community sites in 31 states, Puerto Rico, Canada and Europe. HCV-TARGET currently receives ongoing industry support from Merck, Genentech, Kadmon and Vertex. Fried receives research grant support from and serves as ad hoc consultant to Genentech, Vertex, Merck, Gilead, Bristol Myers Squibb, Janssen Pharmaceuticals and Abbott. Nelson receives grant support from Genentech, Kadmon, Merck, Vertex, Gilead, Boehringer Ingelheim and Abbott/Abbvie; and payment for the development of educational presentations from Clinical Care Options, Rush University Medical Center, Practice Point Communications and the Chronic Liver Disease Foundation.

Credits

Media Contact
Claire Baralt (UF), cbaralt@ufl.edu, 352-273-8211
Media Contact
Michelle Maclay (UNC), maclay@med.unc.edu, 919-843-5365

Source

August 28, 2013

Provided by NATAP

Download the PDF here

Download the PDF here

(from jules: this was an initial small study with only GS7977+Rbv - 83% African-American/70-80% genotype 1a/23% advanced liver disease/96% undetectable in rbv wt-based group at the end of 24 weeks treatment with 7 relapsers after that)

JAMA August 28, 2013

Anuoluwapo Osinusi, MD, MPH1,2; Eric G. Meissner, MD, PhD1; Yu-Jin Lee1; Dimitra Bon, MS3; Laura Heytens, RN4; Amy Nelson, RN1; Michael Sneller, MD1; Anita Kohli, MD1; Lisa Barrett, MD, PhD1; Michael Proschan, PhD5; Eva Herrmann, PhD3; Bhavana Shivakumar, MS1; Wenjuan Gu, PhD6; Richard Kwan, PAC4; Geb Teferi, MD7; Rohit Talwani, MD8; Rachel Silk, RN2; Colleen Kotb, RN2; Susan Wroblewski, RN1; Dawn Fishbein, MD9; Robin Dewar, PhD6; Helene Highbarger, MS6; Xiao Zhang, MS1; David Kleiner, MD10; Brad J. Wood, MD11; Jose Chavez, MD7; William T. Symonds, PharmD12; Mani Subramanian, MD, PhD12; John McHutchison, MD12; Michael A. Polis, MD, MPH1; Anthony S. Fauci, MD1; Henry Masur, MD4; Shyamasundaran Kottilil, MD, PhD1

Gilead HCV Program, GS-7977 - (08/19/13)

"Participants were enrolled in this single-center, 2-part, randomized controlled trial conducted at the Clinical Research Center of the National Institutes of Health, Bethesda, Maryland, from October 2011 through April 2012. Eligible participants were infected with HCV genotype 1, had liver biopsy-proven chronic disease, and were naive to HCV treatment..........Eighty-three percent of the participants were black; 66%, men; and 48%, body mass index greater than 30 (calculated as weight in kilograms divided by height in meters squared); 81% had the IL28 CT or TT genotype; 70%, GT-1a genotype; 23%, advanced liver disease; and 62%, baseline HCV RNA levels greater than 800 000...........

In the first part of the study, 9 participants (90%; 95% CI, 55%-100%) achieved SVR24. In the second part, 7 participants (28%) in the weight-based group and 10 (40%) in the low-dose group relapsed after treatment completion leading to SVR24 rates of 68% (95% CI, 46%-85%) in the weight-based group and 48% (95% CI, 28%-69%; P = .20) in the low-dose group. Twenty individuals participated in a pharmacokinetic-viral kinetic substudy, which demonstrated a slower loss rate of infectious virus in relapsers than in participants who achieved SVR (clearance, 3.57/d vs 5.60/d; P = .009). The most frequent adverse events were headache, anemia, fatigue, and nausea. There were 7 grade 3 events including anemia, neutropenia, nausea, hypophosphatemia, and cholelithiasis or pancreatitis. No one discontinued treatment due to adverse events....... Bivariable analysis of baseline factors showed that in all randomized participants who completed treatment, the odds of relapse was significantly higher in participants who were male (odds ratio [OR], 6.09; 95% CI, 1.17-31.6), had advanced fibrosis (OR, 4.27; 95% CI, 1.10-16.54), and baseline HCV RNA greater than 800 000 IU/mL (OR, 5.74; 95% CI, 1.35-24.38; Table 4). Given the small number of events and the exploratory nature of the stepwise analysis that determined variables used in the model, only the bivariable model results are reported herein........ Deep sequencing of all baseline samples showed no S282T resistant mutant......Twenty-nine participants (58%) had paired liver biopsies with an improvement in inflammation in 27 participants (93%) with a median drop of 5 points (15-point scale; eFigure 3A and B in the Supplement). In parallel with HCV RNA decline, there was rapid improvement of alanine aminotransferase levels with 77% normalizing by day 7 and 98% by day 14. A similar pattern was observed with aspartate aminotransferase levels (eFigure 4A in the Supplement"

"........Twenty-four participants (96%) in each group achieved viral suppression by week 4. Four participants discontinued the study drug by week 8 due to nonadherence (1 in the weight-based group; 3 in the low-dose; Figure). One patient declined to continue study drug past week 12, but his viral load remained undetectable 24 weeks after stopping treatment. He is included in the final analysis. A total of 7 participants (28%) in the weight-based group and 10 (40%) in the low-dose group relapsed after treatment completion leading to SVR24 rates of 68% (95% CI, 46%-85%) in the weight-based group and 48% (95% CI, 28%-69%; P = .20) in the low-dose group (Table 2). A within-cohort comparison of baseline factors related to SVR was performed and is shown in eTable 3 in the Supplement. Deep sequencing of all baseline samples showed no S282T resistant mutant......."

"........All participants experienced a rapid decline in plasma HCV RNA. A viral kinetic model over the first 50 days of treatment of all randomized participants showed no differences in viral decay based on ribavirin dose or baseline characteristics (eFigure 1 and eFigure 2 in the Supplement). However, a fully fitted pharmacokinetics-viral kinetics model of a subset of 20 participants (10 in the low-dose group and 10 in the weight-based group) showed a significantly slower loss rate of free virus (clearance) in relapsers than participants who achieved SVR (clearance, 3.57 vs 5.60 per day; P = .009). There were no observable differences in viral decay, drug efficiency, loss rate of infected cells, or loss rate of infectious virus based on baseline characteristics (eTable 4 in the Supplement).......Twenty-nine participants (58%) had paired liver biopsies with an improvement in inflammation in 27 participants (93%) with a median drop of 5 points (15-point scale; eFigure 3A and B in the Supplement). In parallel with HCV RNA decline, there was rapid improvement of alanine aminotransferase levels with 77% normalizing by day 7 and 98% by day 14. A similar pattern was observed with aspartate aminotransferase levels (eFigure 4A in the Supplement)."

HCV1

(Click table to enlarge)

ABSTRACT

Importance The efficacy of directly acting antiviral agents in interferon-free regimens for the treatment of chronic hepatitis C infections needs to be evaluated in different populations.

Objective To determine the efficacy and safety of sofosbuvir with weight-based or low-dose ribavirin among a population with unfavorable treatment characteristics.

Design, Setting, and Patients Single-center, randomized, 2-part, open-label phase 2 study involving 60 treatment-naive patients with hepatitis C virus (HCV) genotype 1 enrolled at the National Institutes of Health (October 2011-April 2012).

Interventions In the study's first part, 10 participants with early to moderate liver fibrosis were treated with 400 mg/d of sofosbuvir and weight-based ribavirin for 24 weeks. In the second part, 50 participants with all stages of liver fibrosis were randomized 1:1 to receive 400 mg of sofosbuvir with either weight-based or low-dose 600 mg/d of ribavirin for 24 weeks. Main Outcomes and Measures The primary study end point was the proportion of participants with undetectable HCV viral load 24 weeks after treatment completion (sustained virologic response of 24 weeks [SVR24]).

Results In the first part of the study, 9 participants (90%; 95% CI, 55%-100%) achieved SVR24. In the second part, 7 participants (28%) in the weight-based group and 10 (40%) in the low-dose group relapsed after treatment completion leading to SVR24 rates of 68% (95% CI, 46%-85%) in the weight-based group and 48% (95% CI, 28%-69%; P = .20) in the low-dose group. Twenty individuals participated in a pharmacokinetic-viral kinetic substudy, which demonstrated a slower loss rate of infectious virus in relapsers than in participants who achieved SVR (clearance, 3.57/d vs 5.60/d; P = .009). The most frequent adverse events were headache, anemia, fatigue, and nausea. There were 7 grade 3 events including anemia, neutropenia, nausea, hypophosphatemia, and cholelithiasis or pancreatitis. No one discontinued treatment due to adverse events.

Conclusion and Relevance In a population of patients with a high prevalence of unfavorable traditional predictors of treatment response, a 24-week regimen of sofosbuvir and weight-based or low-dose ribavirin resulted in SVR24 rates of 68% and 48%, respectively.

Chronic infection with hepatitis C virus (HCV) is a major cause of chronic liver disease, end-stage liver disease, hepatocellular cancer and remains the leading indication for liver transplants in western countries.1- 2 The HCV epidemic in the United States is centered in large urban areas among populations with a high prevalence of unfavorable traditional predictors of treatment response.1,3- 4 The addition of the recently approved directly acting antiviral agents telaprevir or boceprevir to pegylated interferon-alfa and ribavirin has resulted in improved sustained virologic response (SVR) rates; however, adverse reactions, high pill burdens, and drug interactions continue to make treatment challenging.5- 7 Furthermore, certain host and viral factors including black race, advanced liver fibrosis, IL28B CT or TT genotypes, high baseline HCV viral loads, and prior treatment experience appear to remain associated with poorer treatment outcomes.5,7- 9

Recent studies show that interferon-free, directly acting antiviral agent-only regimens can successfully achieve SVR; however, populations traditionally associated with poorer treatment outcomes have been underrepresented.10- 12 Many studies also use ribavirin, currently a standard component of interferon-based HCV therapy, which is associated with significant adverse events including hemolytic anemia, nausea, and teratogenicity.13 Although ribavirin clearly improves SVR rates with interferon-based therapies,14- 15 the role and requirement for ribavirin in emerging directly acting antiviral agent regimens, including optimal dosing, have not been established.

In this study, we evaluated the safety and efficacy of sofosbuvir administered in combination with weight-based or low-dose once daily ribavirin for 24 weeks in a treatment-naive population with unfavorable characteristics of treatment success. We report the efficacy of this regimen as defined by SVR rates 24 weeks after completion of treatment as well as the host and viral factors associated with treatment relapse.

METHODS

Participants

Participants were enrolled in this single-center, 2-part, randomized controlled trial conducted at the Clinical Research Center of the National Institutes of Health, Bethesda, Maryland, from October 2011 through April 2012. Eligible participants were infected with HCV genotype 1, had liver biopsy-proven chronic disease, and were naive to HCV treatment. Additional eligibility criteria included seronegativity for human immunodeficiency virus (HIV) and hepatitis B; absolute neutrophil count of 750 cells/μLor more; platelet count of 50 000 cells/μL or more; and hemoglobin of 11 g/dL or more for women and 12 g/dL or more for men. Race/ethnicity was classified as white, black, or Hispanic using patient self-reported data. Written consent was obtained from all participants except for 2 patients with limited literacy who gave oral consent after the entire constent form had been read and explained to them.

Study Design

The study was performed in 2 parts. In the first part (proof of concept), participants with early to moderate liver fibrosis (Knodell histology activity index [HAI] fibrosis score, 0-1) were treated for 24 weeks with 400 mg/d of sofosbuvir and weight-based ribavirin (400 mg in the morning, 600 mg in the evening if <75 kg or 600 mg twice a day if >75 kg). In the second part, eligible participants with all stages of fibrosis (including compensated cirrhosis) were randomized in a balanced fashion to receive 400 mg/d of sofosbuvir in combination with either weight-based ribavirin or low-dose (600 mg/d) of ribavirin for 24 weeks. The randomization used a set of 60 random numbers, in which blocks of 4 numbers were selected. Within a block, the highest numbers were assigned to the weight-based protocol, and the lower numbers were assigned to the low-dose group. Once enrollment occurred, participants received a study number in sequential fashion. Participants who experienced treatment failure were offered the current standard of care.

Study Oversight

The study was approved by the institutional review board of the National Institute of Allergy and Infectious Diseases (NIAID) and was conducted in compliance with the Good Clinical Practice guidelines, the Declaration of Helsinki, and regulatory requirements. An independent safety monitor participated in the interim safety and efficacy analysis.

Efficacy Assessments

Plasma HCV RNA levels were measured using the real-time HCV assay (Abbott Molecular), with a lower limit of quantification of 12 IU/mL and a lower limit of detection of 3 IU/mL. The Abbott assay was used to measure HCV RNA levels in all participants at all time points. Plasma HCV RNA levels were also measured using the COBAS TaqMan HCV RNA assay, version 1.0 (Roche), with a lower limit of quantification of 43 IU/mL and a lower limit of detection of 12 IU/mL at specified clinical time points.

Safety Assessments

Adverse events and clinical laboratory results were recorded throughout the study. Adverse events were graded from 1 (mild) to 4 (severe) by a standardized scale using the Division of AfIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (Division of AIDS toxicity table version 1.0). Patient adherence was determined by pill counts at each visit and during patient interviews. A missed dose was defined as any component of the medication regimen not taken on a given day.

Viral Kinetics, Pharmacokinetics, and Pharmacodynamics

Early viral kinetics, pharmacokinetics, and pharmacodynamics of sofosbuvir and its metabolite GS-331007 were obtained and calculated. Levels of sofosbuvir and its metabolite GS-331007 in serum were measured at 0, 1, 2, 4, 8, 12, 24, and 36 hours after administration of sofosbuvir and ribavirin using a high-performance liquid chromatography-mass spectrometry bioanalytical technique (QPS LLC).

IL28B Genotyping

Genotyping of the IL28B single-nucleotide polymorphism rs12979860 has been previously shown to be associated with treatment outcome.16- 17Whole blood was collected using PAXgene Blood DNA tubes (Qiagen) and stored at -80°C until DNA extraction. DNA was extracted using the Paxgene Blood DNA Kit (PreAnalytiX, a Qiagen/BD Company). The IL28B genotype was conducted in a blinded fashion on DNA specimens using the 5' nuclease assay with IL28B-allele-specific TaqMan probes (ABI TaqMan allelic discrimination kit) and the ABI7500 Real-Time PCR system (Applied Biosystems). The IL28B genotyping was classified as either favorable (CC genotype) or unfavorable (CT or TT genotypes).18

454 Deep Sequencing for the Detection of S282T NS5B Mutation

The major mutation shown to confer resistance to NS5B drugs including sofosbuvir is an S282T mutation.19 The HCV viral RNA was extracted from baseline plasma using QIAamp Viral RNA Mini (Qiagen) followed by reverse transcription-polymerase chain reaction to amplify complementary DNA. Using the Genome Sequencer FLX system, 454 Deep sequencing was then performed in the NS5B region to determine the presence of putative resistance-associated variants to sofosbuvir, including S282T.

Liver Biopsy

All participants had undergone a liver biopsy within 3 years of enrollment, and an optional research biopsy was offered after treatment completion (within 2 weeks of drug cessation). Histopathological assessments were performed by a single pathologist in a nonblinded fashion at the time of biopsy and staged according to the Knodell-HAI scoring system.20

Clinical End Points

The primary study end point was the proportion of participants with undetectable HCV viral load 24 weeks after treatment completion (SVR24). Secondary efficacy end points included the proportion of participants with undetectable HCV viral load at specified time points during and after treatment. Safety end points included frequency and severity of adverse events, discontinuations due to adverse events, and safety laboratory changes.

Modeling Viral Kinetics, Pharmacokinetics, and Pharmacodynamics

Pharmacokinetics, pharmacodynamics, and viral kinetic modeling of sofosbuvir in the 20 randomized participants in the substudy were calculated using previously described techniques.21- 23 An estimation of mean and maximum drug efficacy, infected cell loss rate, and loss rate of free virus was generated with this model.

Statistical Analysis

Although the primary interest was the per-protocol analysis, we also present the intention-to-treat analysis of all randomized participants because these results are more readily generalizable. The per-protocol analysis included all participants who received at least 8 weeks of the study drug. For efficacy analysis, missing data points were deemed a success if the immediately preceding and subsequent time points were successful; otherwise, data points were termed as failures. Participants who had missing data due to premature discontinuations were considered failures from the point of discontinuation. Comparisons were analyzed using the nonparametric Wilcoxon rank sum test for continuous outcomes and Fisher exact test for binary outcomes. A bivariable logistic regression model of baseline characteristics was used to identify factors associated with relapse. All P values were 2-tailed and were considered significant only when lower than .05. Analysis was performed using PRIZM 8.0 (GraphPad Software), SAS (SAS Institute Inc), STAT-CRUNCH, and S-Plus 8.0 (Statistical Sciences Inc). Sample size was calculated using an assumed early response rate of 90% for the weight-based group vs 85% for the low-dose group. With 50 participants, the study would be able to estimate the difference in early virologic response proportions to within plus or minus 0.18. There was a substantial gain in precision (from an accuracy of ± 0.24 to ± 0.18) from increasing the sample size from 15 to 25 per group but diminishing returns after a sample size of 25.

RESULTS

Seventy-nine participants were screened and 60 were enrolled in this study (10 participants in part 1 [proof of concept] and 50 participants in part 2 [randomized portion]; Figure). All results including treatment response and safety in the 10 nonrandomized participants are shown in eTable 1 and eTable 2 in the Supplement.

Figure.

Study Flow Diagram

The first 10 were sequentially enrolled from eligible participants in an open-label exploratory group. Relapse is determined at any time after end of treatment response but brior to sustained virologic response at 24 weeks.The patient who discontinued at week 12 was still included in both analyses as having reached sustained virologic response at 24 weeks.

HCV2

(Click table to enlarge)

Baseline Characteristics of Participants

Baseline characteristics were similar among treatment groups (Table 1). Eighty-three percent of the participants were black; 66%, men; and 48%, body mass index greater than 30 (calculated as weight in kilograms divided by height in meters squared); 81% had the IL28 CT or TT genotype; 70%, GT-1a genotype; 23%, advanced liver disease; and 62%, baseline HCV RNA levels greater than 800 000.

HCV3

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Virologic Response

Twenty-four participants (96%) in each group achieved viral suppression by week 4. Four participants discontinued the study drug by week 8 due to nonadherence (1 in the weight-based group; 3 in the low-dose; Figure). One patient declined to continue study drug past week 12, but his viral load remained undetectable 24 weeks after stopping treatment. He is included in the final analysis. A total of 7 participants (28%) in the weight-based group and 10 (40%) in the low-dose group relapsed after treatment completion leading to SVR24 rates of 68% (95% CI, 46%-85%) in the weight-based group and 48% (95% CI, 28%-69%; P = .20) in the low-dose group (Table 2). A within-cohort comparison of baseline factors related to SVR was performed and is shown in eTable 3 in the Supplement. Deep sequencing of all baseline samples showed no S282T resistant mutant.

Viral Kinetic, Pharmacokinetic, and Pharmacodynamic Modeling

All participants experienced a rapid decline in plasma HCV RNA. A viral kinetic model over the first 50 days of treatment of all randomized participants showed no differences in viral decay based on ribavirin dose or baseline characteristics (eFigure 1 and eFigure 2 in the Supplement). However, a fully fitted pharmacokinetics-viral kinetics model of a subset of 20 participants (10 in the low-dose group and 10 in the weight-based group) showed a significantly slower loss rate of free virus (clearance) in relapsers than participants who achieved SVR (clearance, 3.57 vs 5.60 per day; P = .009). There were no observable differences in viral decay, drug efficiency, loss rate of infected cells, or loss rate of infectious virus based on baseline characteristics (eTable 4 in the Supplement).

Histologic Response

Twenty-nine participants (58%) had paired liver biopsies with an improvement in inflammation in 27 participants (93%) with a median drop of 5 points (15-point scale; eFigure 3A and B in the Supplement). In parallel with HCV RNA decline, there was rapid improvement of alanine aminotransferase levels with 77% normalizing by day 7 and 98% by day 14. A similar pattern was observed with aspartate aminotransferase levels (eFigure 4A in the Supplement).

Safety

The combination of sofosbuvir and ribavirin was safe and well tolerated with no death or discontinuation of treatment due to adverse events. The most frequent adverse events were headache, anemia, fatigue, and nausea, the severity of which ranged from mild to moderate (Table 3). There were 7 grade 3 events.

Participants in the weight-based group experienced a higher incidence of hemoglobin decline, which was maintained through week 12, than did participants in the low-dose group (week 4, 37% vs 4%; P = .005; week 12, 39% vs 4%; P = .01; eFigure 4B, in the Supplement). Eight participants (5 in the weight-based group) underwent ribavirin dose reduction for decreased hemoglobin including 3 with a history of coronary artery disease with ribavirin reduction instituted at a hemoglobin level of less than 12 g/dL. There was no use of erythropoietin-stimulating agents in this study. No major biopsy-related complications were observed.

Characteristics Associated With Relapse

Bivariable analysis of baseline factors showed that in all randomized participants who completed treatment, the odds of relapse was significantly higher in participants who were male (odds ratio [OR], 6.09; 95% CI, 1.17-31.6), had advanced fibrosis (OR, 4.27; 95% CI, 1.10-16.54), and baseline HCV RNA greater than 800 000 IU/mL (OR, 5.74; 95% CI, 1.35-24.38; Table 4). Given the small number of events and the exploratory nature of the stepwise analysis that determined variables used in the model, only the bivariable model results are reported herein.

HCV4

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DISCUSSION

Although the treatment of HCV is rapidly evolving, several questions remain unanswered. This study demonstrates the efficacy of an interferon-free regimen in a traditionally difficult-to-treat population while exploring the reasons for treatment relapse. In this study, treatment of chronic HCV infection with a single directly acting antiviral agent (sofosbuvir) and weight-based ribavirin resulted in a high SVR rate in a population with unfavorable traditional predictors of treatment response compared with reported rates with currently used interferon-based therapy in similar populations.7- 8Compared with previous trials testing boceprevir and telaprevir, this population had a higher prevalence of unfavorable traditional predictors of treatment response including black race (80% vs 7%-15%); genotype 1a (70% vs 60%-64%); advanced fibrosis (24% vs 9%-20%); and body mass index greater than 30 (49% vs 22%).7- 8 The overall SVR rate achieved by participants who received sofosbuvir in combination with weight-based ribavirin in our study was 68% compared with the 84% reported in a recent New Zealand study of sofosbuvir and weight-based ribavirin in a predominantly white, treatment-naive population.11 Because treatment of HCV is evolving from an interferon-based combination therapy to an all-oral, interferon-free directly acting antiviral agent regimen, these results are encouraging and provide important information regarding the expected treatment responses in a population representative of the US epidemic.

In an exploratory bivariable model, we found that the baseline factors of male sex, advanced liver disease, and high baseline HCV RNA were associated with relapse. The association of advanced liver disease with higher odds of relapse is similar to that described with direct-acting antiviral agent interferon-based regimens.6- 8 In this regard, 7 of the 13 participants (54%) with advanced liver fibrosis treated in this study relapsed including all 4 participants with cirrhosis. Future studies are warranted to evaluate the efficacy of sofosbuvir and ribavirin regimens in participants with advanced fibrosis.

There were no cases of viral breakthrough while receiving therapy in participants treated with sofosbuvir and ribavirin similar to what has been reported in prior studies.11 Comprehensive analysis of baseline plasma HCV quasi-species by 454 deep sequencing failed to detect the characteristic S282T mutants previously associated with resistance to sofosbuvir.

The kinetics of HCV decline during interferon and ribavirin therapy has been previously described as a predictor of SVR.21- 22 Because interferon-free directly acting antiviral agent therapy is entirely based on achieving maximum suppression of HCV replication, we sought to explore the effect of early HCV viral kinetics, pharmacokinetics, and pharmacodynamics on therapeutic response. Although there were no significant differences in viral kinetics or pharmacokinetics between the weight-based ribavirin and low-dose ribavirin groups, the viral kinetics-pharmacodynamics model demonstrated a significantly slower loss rate of infectious virus in participants who subsequently relapsed. The mechanism of viral relapse in these participants remains elusive and future research will be focused on identifying the biological basis for incomplete clearance of HCV in these participants.

Limitations of this study include the relatively small sample size in each group and a higher, though small, increase in the number of discontinuations with low-dose ribavirin. Due to the small size, associations described are preliminary in nature and require further evaluation in larger studies.

Ribavirin is associated with significant adverse events13,23 but appears to be essential for optimal response to interferon-based and certain directly acting antiviral agent therapies.11,14- 15 Although our study did not show a significant association between treatment response and ribavirin dosing, it remains important to determine the optimal dose and role of ribavirin in the treatment of chronic HCV infection in larger interferon-free studies. In conclusion, treatment with a 24-week regimen of sofosbuvir and ribavirin resulted in an SVR rate of 68% in the weight-based ribavirin regimen and 48% in the low-dose ribavirin regimen among patients with chronic HCV and unfavorable traditional predictors of treatment response who are representative of the demographics of the US HCV epidemic. The delineation of the host and viral factors associated with treatment relapse with different directly acting antiviral agent interferon-free regimens needs to be further assessed. As new direct-acting antivial agent regimens are being evaluated, it is important that these studies involve populations most affected by the disease.

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