Costly Pills Put Financial Burden on Health Systems

Provided by Roll Call

By Kerry Young
Roll Call Staff
Jan. 13, 2014, 4:43 p.m

The new Sovaldi hepatitis C drug, which has a wholesale cost of $1,000 a pill, will pose a challenge to Medicare, Medicaid and prison systems during a time of austere budgets.

Sovaldi’s price already has sparked controversy among activist groups and could, in time, accelerate serious debate about how federal and state agencies buy medicines. Advocates for people with hepatitis C have welcomed Sovaldi as a true medical breakthrough while decrying the high price that its owner, Gilead Sciences Inc., intends to charge.

Gilead has said that a 28-pill bottle of Sovaldi will have a wholesale cost of $28,000, or $1,000 a pill. Many patients will take the drug for 12 weeks, or 84 days; such a course of Sovaldi would cost $84,000.

Sovaldi is seen as a leader in an expected new wave of drugs with the potential to replicate some of the rarest victories in medical science, the near total containment of a disease.

“We’ve got the first of many tools that will allow us to seriously have the discussion about eradicating hepatitis C,” said Michael Ninburg, executive director of the Hepatitis Education Project in Seattle. “In the next few years, there will be very few people living with hepatitis C who won’t be able to be cured by taking a pill, or a couple of pills, a day for 12 weeks, or in some cases maybe a little bit longer.”

The Food and Drug Administration called Sovaldi a “significant shift” in how hepatitis C will be treated. It can be used for some patients without requiring a combination of interferon injections, which are known to frequently cause side effects.

Sovaldi was the third medicine to win the FDA’s relatively new designation as a breakthrough therapy, meaning that it’s considered a substantial improvement over available treatments for a serious and potentially fatal condition.

The FDA noted in a news release that Sovaldi worked for some people who couldn’t tolerate interferon, although the new pill will be combined with injections of the older drug for some patients in other regimens. It’s intended to be taken with the generic pill ribavirin.

“It’s absolutely to be applauded,” Ninburg said. “The price, on the other hand, is an issue.”

It’s certainly a problem for government health programs. Officials at the Federal Bureau of Prisons warned Congress last year about an expected spike in the cost of treating inmates infected with hepatitis C, also called HCV, due to the introduction of new, more expensive medicines.

“More patients will be candidates for treatment and drug regimens will become more and more expensive,” the bureau said in its fiscal 2014 budget request to Congress. “As treatment indications broaden in the future and multi-drug regimens become the standard of care, the drug costs for managing HCV will grow significantly.”

Prisons host a disproportionate share of people infected with hepatitis C, according to the Centers for Disease Control and Prevention. About 3.2 million people in the United States have chronic hepatitis C, meaning that their bodies didn’t clear the liver-damaging virus on their own without treatment. The infection is primarily linked to a history of injections of illegal drugs, such as heroin, although it can be transmitted in other ways.

About 12 percent to 35 percent of inmates are chronically infected with hepatitis C, compared with 1 percent to 1.5 percent of the population outside of prisons, the CDC said. The infection can sometimes cause people to need costly organ transplants.

As it stands now, the bureau spends $4 million a year on testing for hepatitis C. More than 11,000 inmates with the infection have been identified, most of whom have not been treated yet, the bureau said.

The current course of therapy, which costs about $6,600, lasts for 48 weeks and includes injections of interferon. Many would-be patients don’t have enough time on their sentences to complete the full course by the time the treatment is offered.

When the budget request was submitted, there were two recently introduced pills — Merck & Co.’s Victrelis and Vertex Pharmaceuticals Inc.’s Incivek — that could be added to a combination of interferon and ribavirin.

“These newer agents are very expensive and could add $20,000 to $40,000 to the cost of treating one patient,” the bureau said.

Now, more expensive drugs have arrived. The Fair Pricing Coalition, which lobbies on behalf of people with HIV and hepatitis C, in November protested against the expected $66,000 price for a course of treatment with Johnson & Johnson’s recently approved Olysio hepatitis C drug. Now the Bureau of Prisons is facing the potential tab for that, plus Sovaldi.

“They dodged a bullet with the old medicines, but now the marketplace will have new, more expensive medicines with a much shorter course of treatment,” Anne Spaulding, an Emory University researcher who has studied HIV and hepatitis C in prisons, said in an interview.

In a recent paper, she and other researchers suggested modifying the current rules on the federal 340B drug discounting program, which could open the way for more prison systems to participate.

Having deeper discounts on drugs would make it easier for prison systems to manage the cost of the new wave of hepatitis therapies. For now, the requirements associated with the 340B program, such as the need for an entity other than the prison to have control of the medical records of covered patients, have prevented many states from trying this option, Spaulding said.

“Hepatitis C treatment has a high price tag,” she said. “Prisons don’t want to pay the high price tag up front when they will not recoup the downstream benefits of avoiding the expensive treatment for end-stage liver disease.”

A change in Medicare policy also could spur demand for Sovaldi. The agency appears likely to act on a June 2013 recommendation from the U.S. Preventive Services Task Force, which advocated for a one-time screening for hepatitis C in people born between 1945 and 1965.

About 2.1 million of those infected with the disease in the United States are baby boomers, with perhaps 1.5 million unaware that they have this condition, according to the CDC. Many may have contracted it before 1992, when screening began of blood donations for the hepatitis C virus. Getting these people appropriate care and treatment could prevent more than 120,000 deaths.

There could be a quick uptake of Sovaldi in the United States, according to a December report from Phil Nadeau, a biotechnology analyst with Cowen and Company. He said that as many as 50,000 people could be treated in the United States with Sovaldi in 2014 alone, helping drive global sales of the drug to $3 billion for the year.

The haggling currently allowed for drugs in the United States in private plans and some Medicaid plans could lower the price for treatment with Sovaldi to about $70,000 a patient for a 12-week course.

Medicaid programs may also be another major market for Sovaldi and the newer hepatitis drugs.

A study presented in May at one of the world’s largest gatherings of liver specialists, known as Digestive Disease Week, found the rate of hepatitis C infection was more than twice as high among people on Medicaid compared with those with private insurance, with 663 cases for every 100,000 people on the state-federal health program and 302 for every 100,00 in the other group. People in the Medicaid group also were less likely to have had treatment for hepatitis than those with private health insurance, 20 percent versus 27 percent.

“The development of interferon-free regimens may increase eligibility for treatment,” concluded the paper, whose lead writer was an employee of the drugmaker AbbVie, which is developing a competitor pill to Sovaldi.

kerryyoung@cqrollcall.com

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Also See: What Is a Hepatitis C Drug Worth?

amfAR Launches Hep C Study in Asia

by Winnie McCroy
EDGE Editor
Tuesday Jan 14, 2014

amfAR’s new study will help how how to treat hepatitis C in a resource-limited setting
(Source:amfar.org)

In an effort to implement care for those suffering from hepatitis C in Asia, amfAR’s Therapeutic Research, Education and AIDS Training (TREAT Asia) is conducting a study on how to implement care in a resource-limited setting that can be replicated in the region, where treatment is very costly and rarely accessible. Two hundred HIV-positive patients with hepatitis C infection and signs of liver disease will be offered free treatment.

"As rates of hepatitis C and HIV co-infection continue to rise around the world, managing co-infection is one of the most important clinical challenges we face today," said amfAR CEO Kevin Robert Frost.

It is estimated that approximately five million people worldwide are co-infected with HIV and the hepatitis C virus (about 15 percent of all those living with HIV). People co-infected with HIV and hepatitis C have higher rates of progression to hepatitis C-related liver disease, which has become a significant cause of death in people living with HIV.

This is the first time a study is being done in Asia to show how to implement care in a resource-limited setting that can be replicated in the region, where treatment is very costly and rarely accessible.

Led by amfAR’s TREAT Asia program, the study will be implemented in four partner HIV treatment centers: Cipto Mangunkusumo General Hospital in Jakarta, Indonesia; the HIV-NAT/Thai Red Cross AIDS Research Center in Bangkok, Thailand; the National Hospital for Tropical Diseases in Hanoi, Vietnam; and the University of Malaya Medical Centre in Kuala Lumpur, Malaysia.

In this study, a total of 200 HIV-positive patients with confirmed chronic hepatitis C infection and signs of liver disease will be offered free hepatitis C treatment. The treatment model will include the integration of hepatitis C treatment within routine HIV care, use of a simplified treatment protocol, intensive patient disease education, treatment preparedness and adherence support, as well as peer support.

"The resources needed to effectively treat them remain out of reach for most due to the high cost of hepatitis C medicines and the overall lack of experience with treating co-infected patients in the region," said Annette Sohn, M.D., amfAR vice president and director of TREAT Asia.
The study is sponsored by amfAR, the study drugs are provided by Merck Sharp and Dohme under its Investigator-Initiated Study Program, and hepatitis C molecular viral load and genotyping tests are provided by Abbott.

"This is the first time a study is being done to show how we can implement treatment of hepatitis C in routine HIV care in Asia," said Nicolas Durier, M.D., M.P.H., TREAT Asia’s director of research and one of the study’s principal investigators. "We hope that the model of care we have developed and our study findings will lead to replication and scale-up of hepatitis C treatment across the region, as well as bolster advocacy efforts aimed at expanding the availability of treatment."

Launched in 2001, TREAT Asia (Therapeutics Research, Education, and AIDS Training in Asia) is a cooperative network of clinics, hospitals, and research institutions working together with civil society to ensure the safe and effective delivery of HIV/AIDS treatments throughout Asia and the Pacific, and now encompasses 23 adult and 21 pediatric clinical sites and HIV support programs across the region.

amfAR, The Foundation for AIDS Research, is one of the world’s leading nonprofit organizations dedicated to the support of AIDS research, HIV prevention, treatment education, and the advocacy of sound AIDS-related public policy. Since 1985, amfAR has invested more than $366 million in its programs and has awarded grants to more than 2,000 research teams worldwide.

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Prevalence of hepatitis C infection found to vary widely among Hispanics

PUBLIC RELEASE DATE:14-Jan-2014

Contact: Kim Newman
sciencenews@einstein.yu.edu
718-430-3101
Albert Einstein College of Medicine

January 14, 2014 - (BRONX, NY) - The first study of hepatitis C infection among different Hispanic groups in the U.S. has found that infection with the virus varies widely, with Puerto Rican Hispanics much more likely than other groups to be infected. The study, led by researchers at Albert Einstein College of Medicine of Yeshiva University, highlights which Hispanic populations would benefit most from increased hepatitis C testing and treatment. It was published today in the online edition of the Journal of Infectious Diseases.

Hepatitis C is a viral disease that primarily affects the liver and is caused by the hepatitis C virus. The virus is usually spread through contact with the blood of an infected person, often from sharing needles to inject drugs. Many people were also infected through blood transfusions before testing of donated blood began in 1992. About 150 million people worldwide are now infected with hepatitis C, including three to four million in the U.S., according to the Centers for Disease Control and Prevention (CDC). The majority of infected people don't know they're infected, since it may take decades for the virus to cause liver damage severe enough to cause symptoms.

"Until now, national health surveys that assessed hepatitis C's prevalence among U.S. Hispanics have looked only at Mexican-Americans," said Mark Kuniholm, Ph.D., lead author of the study and assistant professor of epidemiology & population health at Einstein. "As a result, no one knew whether the rates were higher or lower in other Hispanic populations. It turns out that there's a dramatic variation in prevalence, with infection rates ranging from less than 1 percent in Hispanic men of South American or Cuban background to 11.6 percent in men of Puerto Rican background – a more than 10-fold difference. This suggests that it's not appropriate to lump all U.S. Hispanics into a single, broad at-risk group."

The prevalence of hepatitis C infection found for men in other Hispanic groups are: Mexican (1.9 percent), Dominican (1.5 percent), Central American (1 percent), South American (.4 percent), and Cuban (0.8 percent). Hispanic women generally had a lower prevalence of hepatitis C infection than men, with Puerto Rican background women having the highest prevalence (3.9 percent) among Hispanic women. The overall prevalence of hepatitis C among men and women in the U.S. is 1.3 percent, according to the National Health and Nutrition Examination Survey (NHANES). The researchers said it was not clear why the prevalence of hepatitis C was highest among Hispanic men and women of Puerto Rican background compared with Hispanics of other backgrounds.

The Einstein study used data collected on 11,964 individuals as part of the Hispanic Community Health Study/Study of Latinos, a National Institutes of Health-funded study of Hispanic adults from four communities (Bronx, Miami, Chicago and San Diego). It was led by Robert Kaplan, Ph.D., the Dorothy and William Manealoff Foundation and Molly Rosen Chair in Social Medicine and professor of epidemiology & population health, and by Gloria Ho, Ph.D., professor of epidemiology & population health, both at Einstein.

"Clearly, our findings strongly support the need for community-based campaigns to increase testing and treatment in the Hispanic population," said Dr. Kuniholm. "But in our view, outreach efforts should be redoubled in those communities with large numbers of people of Hispanic background and a high prevalence of the disease.. For example, if you're in Miami with its mostly Cuban Hispanic population, the cost effectiveness of extra screening may be less than in the Bronx or Chicago, which both have large Puerto Rican communities. Extra efforts to increase screening may be warranted in those communities."

In 2012, the Centers for Disease Control and Prevention recommended that all Baby Boomers (people born from 1945 through 1965) be tested for hepatitis C. Those at increased risk for hepatitis C infection should also be tested, including people who ever injected illegal drugs (even if they did so only once or many years ago), have abnormal liver tests, received donated blood or organs before 1992, have been exposed to blood at work through needle sticks or injury with a sharp object, or were ever on hemodialysis.

The study's findings take on added importance with the development of a new class of hepatitis C drugs, recently approved by the FDA that can potentially cure more than 80 percent of people infected with hepatitis C. "In the past, treating hepatitis C was often very difficult and was associated with severe side effects," said Dr. Kuniholm. "The newer treatments cause far fewer side effects and are more effective and more convenient to take."

###

The paper is titled "Prevalence of Hepatitis C Virus Infection in US Hispanic/Latino Adults: Results from the NHANES 2007-2010 and HCHS/SOL Studies." In addition to Drs. Kuniholm, Kaplan and Ho, other Einstein contributors are Molly Jung, M.P.H., Ryung Kim, Ph.D., and Howard Strickler, M.D., M.P.H. Additional contributors are James E. Everhart, M.D., M.P.H., at National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD; Scott Cotler, M.D., at Loyola University Medical Center, Maywood, IL; Gerardo Heiss, M.D., Ph.D., and Marston Youngblood, M.A., M.P.H. at University of North Carolina, Chapel Hill, NC; Geraldine McQuillan, Ph.D., at U.S. Centers for Disease Control and Prevention, Hyattsville, MD; and Bharat Thyagarajan, M.D., at University of Minnesota, Minneapolis, MN.

The Hispanic Community Health Study/Study of Latinos is supported by contracts from the National Heart, Lung, and Blood Institute to the University of North Carolina (N01-HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236), and San Diego State University (N01-HC65237). The following Institutes/Centers/Offices contribute to the HCHS/SOL through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, National Institute on Deafness and Other Communication Disorders, National Institute of Dental and Craniofacial Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, NIH Institution-Office of Dietary Supplements. Dr. Kuniholm is supported in part by the National Center for Advancing Translational Sciences, through CTSA grants UL1RR025750 and KL2RR025749.

The authors report no conflicts of interest.

About Albert Einstein College of Medicine of Yeshiva University

Albert Einstein College of Medicine of Yeshiva University is one of the nation's premier centers for research, medical education and clinical investigation. During the 2013-2014 academic year, Einstein is home to 734 M.D. students, 236 Ph.D. students, 106 students in the combined M.D./Ph.D. program, and 353 postdoctoral researchfellows. The College of Medicine has more than 2,000 full-time faculty members located on the main campus and at its clinical affiliates. In 2013, Einstein received more than $155 million in awards from the NIH. This includes the funding of major research centers at Einstein in diabetes, cancer, liver disease, and AIDS. Other areas where the College of Medicine is concentrating its efforts include developmental brain research, neuroscience, cardiac disease, and initiatives to reduce and eliminate ethnic and racial health disparities. Its partnership with Montefiore Medical Center (http://www.montefiore.org/), the University Hospital and academic medical center for Einstein, advances clinical and translational research to accelerate the pace at which new discoveries become the treatments and therapies that benefit patients. Through its extensive affiliation network involving Montefiore, Jacobi Medical Center–Einstein's founding hospital, and five other hospital systems in the Bronx, Manhattan, Long Island and Brooklyn, Einstein runs one of the largest residency and fellowship training programs in the medical and dental professions in the United States.

For more information, please visit http://www.einstein.yu.edu and follow us on Twitter @EinsteinMed.

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Bristol-Myers Ties Hepatitis C Success to Gilead’s Pill

By Drew Armstrong Jan 14, 2014 8:25 AM ET

Bristol-Myers Squibb Co. will try to grab an early share of the multibillion-dollar market for new hepatitis C treatments by piggybacking its experimental drug with Gilead Sciences Inc.’s approved pill.

Bristol-Myers and Gilead are among several companies developing new hepatitis C therapies relying on combinations of two or more drugs. Those regimens are being approved by regulators one drug at a time for a hepatitis C market analysts estimate may reach $100 billion over a decade.

Bristol-Myers is seeking European approval of its drug, daclatasvir, and wants to pair it with Gilead’s Sovaldi before Gilead gains clearance for its second hepatitis C treatment. They will do the same in the U.S. if they can get a broad approval from regulators, said Charles Bancroft, the chief financial officer for Bristol-Myers, in an interview at the JPMorgan Chase & Co. health-care conference in San Francisco.

In “the potential approval of daclatasvir in Europe, the label should be expansive enough to use with sofosbuvir,” Bancroft said, referring to Solvadi by its scientific name. “Hopefully what we do in Europe, we can parlay some of that to here in the U.S.,”

Bristol-Myers, based in New York, is focusing its effort on antiviral treatments, cancer drugs and specialty medicines. It ended its work on diabetes treatments last month, selling a stake in a joint venture with London-based AstraZeneca Plc for as much as $4.3 billion.

Bristol-Myers shares fell 1.4 percent to $55.42 in New York trading yesterday. Gilead, based in Foster City, California, dropped 2.3 percent to $73.41.

4 Million Americans

The move on the hepatitis C pills is a part of a competition by drugmakers to reach the market with new treatments that are more convenient and produce fewer side effects than current therapies including injections. About 4 million Americans have the viral infection, which can cause liver cirrhosis, and U.S. health officials recommended every American born from 1945 to 1965 get tested for the disease.

Gilead’s Sovaldi became the first all-oral treatment for certain hepatitis C patients when it was approved in December by the U.S. Food and Drug Administration. Johnson & Johnson and Medivir AB won FDA approval in November for their pill, Olysio, to be used in combination with other medicines including current treatments.

Gilead is testing other drugs to produce a full combination treatment, which may not be available until the end of 2014 or the beginning of 2015. Bristol-Myers’s combination may not be ready until later.

The drugs from Gilead and Bristol-Myers have been studied together. In a trial of 41 patients released last year, every patient who took the drugs and was followed up with was free of the virus 12 weeks later. The companies haven’t been able to reach an agreement on further testing, though.

Sales Estimates

The combinations are projected to be blockbusters once approved. Gilead’s Sovaldi is priced at $84,000 per treatment, and is projected to sell $8.22 billion in 2016, according to an average of 11 analysts’ estimates compiled by Bloomberg. Abbvie Inc. and Merck & Co. are also developing treatments.

“My personal view is that Gilead is going to get the lion’s share, bni ushealth strut there is room for other players,” Bancroft said. Once combinations from Bristol-Myers and rivals are cleared for the market, competition will drive prices down, he said.

Gilead said it is moving ahead with its combination out of necessity.

“We believe that we have been able to advance the development of this fixed-dose combination much more quickly than would have been possible with any inter-company collaboration,” Norbert Bischofberger, Gilead’s head of research and development, said in an e-mail. “Gilead remains focused on delivering the simplest and safest all-oral treatment regimen to patients as quickly as possible.”

To contact the reporter on this story: Drew Armstrong in New York at darmstrong17@bloomberg.net

To contact the editor responsible for this story: Reg Gale at rgale5@bloomberg.net

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What Is a Hepatitis C Drug Worth?

Provided by Roll Call

By Kerry Young
Roll Call Staff
Jan. 13, 2014, 4:41 p.m

The founder of the company that discovered the Sovaldi hepatitis C drug, which has been listed with a cost of $1,000 for a single pill, says that it’s fairly cheap to make the basic ingredients for this well-regarded new medicine. It may cost only about $1,400 to manufacture a 12-week supply, or 84 pills, of the key ingredient in Sovaldi, excluding the costs of manufacturing plants, solvents, formulation, encapsulating and marketing.

That’s the estimate that Raymond F. Schinazi, a founder of Pharmasset Inc. and a noted infectious-disease researcher at Emory University, put forward in a paper published in December in the journal Trends in Microbiology.

By now, Gilead Sciences Inc., which bought Pharmasset in January 2012 for $11.4 billion, may have brought down the production cost further, Schinazi said in a recent interview. “It could be even less than that,” Schinazi said.

Pharmaceutical companies have long experience with making pills, with some products having been made in large scale for more than a century.

“Even aspirin, but they still charge you a significant markup for that,” Schinazi said. “With new drugs like Sovaldi, or sofosbuvir as we used to call it, the company needs to recover its investment in research.”

Gilead has argued that spending for Sovaldi now will save programs such as Medicaid and Medicare and the Department of Veterans Affairs on future health costs, because people whose hepatitis C infections are treated with the drug will not need future treatment for serious liver damage or organ transplants.

The nonprofit AIDS Healthcare Foundation has accused Gilead of “unbridled greed,” and some activists have pointed to the high price that Gilead paid for Pharmasset as a reason for Sovaldi’s pricing. Schinazi, who said he has no stake in Gilead, says there was a “bidding war” for Pharmasset with the aim of capturing Sovaldi. The drug, intended to be combined with the generic ribavirin, is considered a breakthrough in hepatitis C treatment.

There’s little consensus about how much it costs to develop drugs, with estimates ranging as high as $1.7 billion for a new product.

Pharmasset, though, had an accumulated deficit of about $325 million for its roughly 13 years as an independent company, a time in which it worked on several other potential drugs in addition to advancing Sovaldi as far as testing in patients, according to a filing with the Securities and Exchange Commission.

“We were very efficient, extremely efficient. We have a lot of experience,” said Schinazi, whose other biotechnology ventures included Triangle Pharmaceuticals, which Gilead bought in 2003.

But Schinazi stressed that biotechnology of all sizes, startups such as Pharmasset and giants like Gilead, face long odds in their work with Sovaldi. The high prices charged for the products that make it to market compensate for failures unknown to most of the public, he said.

“There’s a whole cemetery full of drugs that have failed in this particular class of compounds, a huge cemetery. You have got to look at that,” Schinazi said. “We got a bit lucky but we also did amazingly good science.”

kerryyoung@cqrollcall.com

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Also See: Costly Pills Put Financial Burden on Health Systems

Hepatitis C: More Affordable Treatment Possible

Medscape Medical News

Jennifer Garcia

January 13, 2014

Large-scale manufacture of drugs used to treat patients infected with the hepatitis C virus (HCV) can be accomplished at much lower costs than current pricing schemes, according to a study published online January 6 in Clinical Infectious Diseases.

The US Food and Drug Administration (FDA) recently approved new drugs for HCV, including sofosbuvir and simeprevir. The drugs are expected to dramatically improve care for patients with HCV.

However, the cost of these game-changing drugs may put them out of reach of many patients. At this time, in the United States, the cost of 12 weeks of HCV therapy with simeprevir is $66,000, and with sofosbuvir it is $84,000.

In a new study, Andrew Hill, PhD, from the University of Liverpool, United Kingdom, and colleagues, estimated the cost of HCV treatment, using similar market dynamics as those used to dispense antiretroviral therapy to patients with HIV in developing countries.

Given their similar chemical structure and mechanism of action, the researchers compared 5 direct-acting antiviral HCV drugs (DAAs) — daclatasvir, sofosbuvir, simeprevir, faldaprevir, and ribavirin — with their closest analogues used in the treatment of HIV and used these data to estimate manufacturing costs per gram of drug.

The authors determined that the cost of a 12-week course of HCV therapy could be as little as $100 to $250 a person. These estimated treatment costs were based on an intended treatment population of at least 1 million patients and included a 40% margin for finished production.

The authors note that 12 of the 20 countries with the largest HCV epidemics are classified as low- or lower-middle-income countries and point out that their results demonstrate that more affordable therapy is possible. "These low prices coupled with the high [sustained virological response] rates established in several trials [show] the potential for large-scale, low cost HCV treatment in developing countries, with the potential to repeat the model of low-cost HIV treatment that has benefitted millions of people," write Dr. Hill and colleagues.

In an interview with Medscape Medical News, Dr. Hill said, "We need the health authorities in the highest-burden countries to work with the World Health Organization for a plan for large-scale treatment of hepatitis C. Eradication of this disease is possible, if there is the political will."

When asked whether he felt the current price for new DAAs for HCV therapy is justified, Dr. Hill responded: "We need to separate the cost of treatment in North America and Europe from the cost in low- and middle-income countries. There should be large-scale access programs set up to treat people with hepatitis C at minimum cost in high-burden countries such as India, Egypt, Indonesia, and Nigeria."

Already, legal initiatives have been filed in India in an effort to prevent a major pharmaceutical company from obtaining a patent on one of these new HCV drugs. This would allow for production of a low-cost generic formulation and drastically reduce the cost of treatment in that country.

Dr. Hill and colleagues acknowledge there are limitations to their analysis, including a lack of detailed production information about specific DAAs and the fact that these estimates assume no patent restrictions on production. They note that voluntary or compulsory licenses that allow for the production of generic formulations will be necessary to make these cost estimates a reality.

"Every company developing drugs for hepatitis C needs a plan for ensuring access to their drugs in low- and middle-income countries," concluded Dr. Hill. "In the future, access to treatment for hepatitis C should be available together [with] treatment for HIV," he said.

One author has received consultancy payments from Janssen Pharmaceuticals that are not connected with this project. Another author has received consultancy and travel grants from other pharmaceutical companies that are also not associated with this project. The other authors have disclosed no relevant financial relationships.

Clin Infect Dis. Published online January 6, 2014. Full text

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Also See: Minimum costs for producing Hepatitis C Direct Acting Antivirals, for use in large-scale treatment access programs in developing countries

Treatment of Chronic Hepatitis C Virus Infection: Some Remaining Obstacles in the United States

Liver International

Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)

Review Article

You have free access to this content

Gloria Searson¹, Ellen S. Engelson²,  Damaris Carriero^1,3, Donald P. Kotler^1,2,*

DOI: 10.1111/liv.12467

This article is protected by copyright. All rights reserved.

Publication History
Accepted manuscript online: 13 JAN 2014 01:05AM EST
Manuscript Accepted: 6 JAN 2014
Manuscript Revised: 25 DEC 2013
Manuscript Received: 27 JUN 2013

Keywords: effectiveness research;  health disparities;  substance abuse; alcoholism;  chronic liver disease

Abstract

Hepatitis C infection is an important problem in inner city neighborhoods, which suffer from multiple health disparities. Important factors in this population include alcoholism and substance abuse, mental illness, and homelessness, which may be combined with mistrust, poor health literacy, limited access to health care, and outright discrimination. Systemic barriers to effective care include a lack of capacity to provide comprehensive care, insufficient insurance coverage, poor coordination among caregivers and between caregivers and hospitals, as well as third party payers. These barriers affect real world treatment effectiveness as opposed to treatment efficacy, the latter reflecting the world of clinical trials. The components of effectiveness include efficacious medications, appropriate diagnosis and evaluation, recommendation for therapy, access to therapy, acceptance of the diagnosis and its implications by the patient and adherence to the recommended therapy. Very little attention has been given to assisting the patient to accept the diagnosis and adhere to therapy, i.e., care coordination. For this reason, care coordination is an area in which greater availability could lead to greater acceptance/adherence and greater treatment effectiveness.

This article is protected by copyright. All rights reserved.

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Achillion Reports HCV Pipeline Progress and Outlines 2014 HCV Milestones

Jan. 13, 2014

NEW HAVEN, Conn., Jan. 13, 2014 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) today reported progress on the Company's portfolio of proprietary compounds for the treatment of chronic hepatitis C (HCV) and outlined its 2014 milestones.

"We believe that we have the broad portfolio of HCV compounds necessary to succeed in achieving our primary goal of developing commercially competitive short duration therapies for the treatment of HCV that are once-daily and ribavirin-free. With the emerging safety and in vitro data on ACH-3422, a uridine nucleotide inhibitor of NS5B polymerase, and the 12-week clinical activity reported with ACH-3102, our Phase 2, pan-genotypic, second-generation NS5A inhibitor, we believe that our HCV compounds are well-positioned to achieve positive results in the clinical studies we plan to initiate throughout 2014," commented Dr. Milind Deshpande, President and Chief Executive Officer of Achillion. "With our 2013 year-end cash balance projected to exceed $150 million, we believe we have sufficient capital to fund our operations into 2016 and achieve a number of value-creating milestones throughout this year with our HCV assets."

2014 Milestones

• ACH-3422: HCV Nucleotide NS5B Polymerase Inhibitor

-  To date, all of the Company's preclinical studies support the advancement of ACH-3422 into clinical trials. Achillion expects to initiate a Phase 1 first-in-human trial ex-US during the second quarter of 2014, subject to regulatory approval, followed by a Phase 1 proof-of-concept trial in mid-2014. Achillion anticipates reporting initial results from HCV-infected patients in the third quarter of 2014.

• ACH-3102 + sofosbuvir

-  Achillion plans to initiate a pilot Phase 2 study early in the second quarter of 2014 evaluating the combination of ACH-3102, a second-generation NS5A inhibitor in Phase 2, with sofosbuvir in treatment-naive HCV patients over treatment durations of 8 weeks or less. The study aims to optimize the use of ACH-3102 in nucleotide-based regimens and to expedite the development of the combination of ACH-3102 and ACH-3422. 

• ACH-3422 + ACH-3102 ± NS3/4A protease inhibitor

- Achillion anticipates the initiation of an all-oral Phase 2 combination study evaluating ACH-3422 by year-end 2014, and anticipates the initiation of a Phase 2 combination study evaluating ACH-3422 and ACH-3102, with and without an Achillion NS3/4A protease inhibitor, in treatment-naive HCV patients over treatment durations of 8 weeks or less in early 2015.

• ACH-3102 + ACH-2684

- Achillion intends to evaluate the combination of its NS5A inhibitor ACH-3102, and next-generation NS3/4A protease inhibitor, ACH-2684, in a Phase 1 drug-drug interaction study that is expected to begin in the first quarter of 2014.

- The Company also plans to initiate a proof-of-concept study evaluating this combination in genotype 1b HCV-infected patients over a treatment duration of 8 weeks in mid-2014 to enable future combination studies.

Sovaprevir: NS3/4A Protease Inhibitor

- Achillion is preparing a complete response package on the previously disclosed sovaprevir clinical hold and anticipates a response from the FDA by the end of the first half of 2014.

- In the ongoing Phase 2 -007 trial evaluating 12-week treatment with sovaprevir, ACH-3102, and ribavirin in combination, to date all patients with chronic genotype 1b HCV infection have maintained 100% virologic response despite the presence of multiple resistant mutations at baseline in the NS5A protein. As anticipated by the viral breakthroughs previously reported in genotype 1a patients, the combination of sovaprevir and ACH-3102 is not being pursued as a treatment for chronic genotype 1a HCV infection. Achillion intends to submit these study results for presentation at a scientific conference in 2014.

"We are very pleased with the overall progress across our broad HCV portfolio. We believe that the clinical strategy outlined for 2014 will enable us to move toward delivering commercially competitive treatment regimens for HCV," commented Dr. David Apelian, M.D., Ph.D., Chief Medical Officer at Achillion. "Furthermore, with Achillion's broad portfolio of assets, we believe that the addition of an NS5B nucleotide inhibitor, such as ACH-3422, could achieve very competitive cure rates across broad patient populations with a treatment regimen of 8 weeks or less."

About Achillion Pharmaceuticals

Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's discovery, clinical development, and commercial teams have advanced multiple novel product candidates with proven mechanisms of action into studies and toward the market. Achillion is focused on solutions for the most challenging problems in infectious disease including HCV and resistant bacterial infections. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.

Cautionary Note Regarding Forward-Looking Statements

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other important factors that could cause actual results to differ materially from those indicated by such forward-looking statements, including statements with respect to: the potential benefits and prospects for Achillion's portfolio of HCV compounds; expectations regarding clinical study results in 2014; Achillion's projected year-end cash balance, its expectations as to the period in which such cash will be available to fund its operations, and the prospects for such cash enabling it to achieve milestones; the Company's 2014 milestone goals, including with respect to advancing compounds into and through clinical development and obtaining data readouts from trials of its compounds; and its plans and timing with respect to the FDA clinical hold on sovaprevir. Achillion may use words such as "expect," "anticipate," "project," "intend," "plan," "aim," "believe," "seek," "estimate," and "may" and similar expressions to identify such forward-looking statements. Among the important factors that could cause actual results to differ materially from those indicated by such forward-looking statements are risks relating to, among other things Achillion's ability to: demonstrate in any current and future clinical trials the requisite safety, efficacy and combinability of its drug candidates; advance the preclinical and clinical development its drug candidates, including ACH-3422, ACH-3102 and ACH-2684, under the timelines it projects in current and future clinical trials; satisfactorily respond to the clinical hold placed on sovaprevir by the FDA; obtain and maintain necessary regulatory approvals; obtain and maintain patent protection for its drug candidates and the freedom to operate under third party intellectual property; establish commercial manufacturing arrangements; identify, enter into and maintain collaboration agreements with appropriate third-parties; compete successfully with other companies that are seeking to develop improved therapies for the treatment of HCV; manage expenses; manage litigation; raise the substantial additional capital needed to achieve its business objectives; and successfully execute on its business strategies. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Quarterly Report on Form 10-Q for the fiscal quarter ended September 30, 2013 and its subsequent SEC filings.

In addition, any forward-looking statement in this press release represents Achillion's views only as of the date of this press release and should not be relied upon as representing its views as of any subsequent date. Achillion disclaims any duty to update any forward-looking statement, except as required by applicable law.

Company Contact:

         Glenn Schulman

         Achillion Pharmaceuticals, Inc.

         Tel. (203) 624-7000

         gschulman@achillion.com 

         Media:

         Emily Johnson

         Ogilvy PR

         Tel. (212) 880-5316

         emily.johnson@ogilvy.com

         Investors:

         Mary Kay Fenton

         Achillion Pharmaceuticals, Inc.

         Tel. (203) 624-7000

         mfenton@achillion.com

         Investors:

         Lee Stern

         The Trout Group, LLC

         Tel. (646) 378-2922

         lstern@troutgroup.com

Contact

 

Source

Interim results (SVR4) from a phase II all-oral combination study of Simeprevir and Samatasvir (IDX719) for the treatment of hepatitis C

Stockholm, Sweden—Medivir AB (OMX: MVIR), announces that Idenix Pharmaceuticals, Inc. today released interim data from the ongoing phase II HELIX-1 clinical trial evaluating an all-oral, direct-acting antiviral (DAA) HCV combination regimen of samatasvir (IDX719), Idenix’s once-daily pan-genotypic NS5A inhibitor, and simeprevir , a once-daily protease inhibitor jointly developed by Janssen R&D Ireland and Medivir AB, and ribavirin.

The combination regimen of the study was well-tolerated. In the treatment-naïve, non-cirrhotic, genotype 1b or 4 HCV-infected patients receiving 50 mg of samatasvir and 150 mg of simeprevir plus ribavirin for 12 weeks, 85 percent (n=17/20) of the patients achieved SVR4 (undetectable HCV RNA four weeks after end of treatment). The 50 mg dose of samatasvir is the selected dose in the ongoing 3-DAA HELIX-2 clinical trial. The HELIX-1 study results are expected to be presented at a scientific meeting in 2014.

HELIX-1 study design
The HELIX-1 trial is the first study in HCV-infected patients to commence under a non-exclusive collaboration agreement between Idenix and Janssen which was established in January 2013. The HELIX-1 trial is a phase II 12-week, randomized, parallel group study evaluating the antiviral activity, safety and tolerability of samatasvir and simeprevir in treatment-naïve, non-cirrhotic, genotype 1b or 4 HCV-infected patients.

Patients in part A of the study (n=63) were enrolled in one of three treatment groups receiving 50, 100, or 150 mg samatasvir once-daily for 12 weeks in combination with 150 mg of simeprevir plus a weight-based dose of ribavirin. In part B of the ongoing HELIX-1 study, exploratory cohorts of patients have been added to evaluate the safety and antiviral activity of a 25 mg dose of samatasvir in genotype 1b-infected patients and of a 100 mg dose of samatasvir in genotype 6-infected patients.

A second phase II trial (HELIX-2) was initiated in December 2013 evaluating samatasvir, simeprevir and TMC647055, a once-daily non-nucleoside polymerase inhibitor plus a low-dose ritonavir being developed by Janssen, with and without ribarivin in genotype 1-infected patients who are either treatment-naïve or have previously relapsed after treatment with pegylated interferon and ribavirin.

For additional information about the HELIX-1 study, please visit www.clinicaltrials.gov

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

Medivir is required under the Securities Markets Act to make the information in this press release public. The information was submitted for publication at 13.15 p.m. CET on 13 January 2014.

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

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

About Samatasvir (IDX719)
Samatasvir is an NS5A inhibitor with low picomolar, pan-genotypic antiviral activity in vitro. To date, samatasvir has been safe and well-tolerated after single and multiple doses of up to 150 mg in healthy volunteers up to 14 days duration, and in HCV-infected patients up to 12 weeks duration. There have been no treatment-emergent serious adverse events reported in the program. Samatasvir has demonstrated potent pan-genotypic antiviral activity in HCV-infected patients with mean maximal viral load reductions up to approximately 4.0 log10 IU/mL across HCV genotypes 1-4 in a proof-of-concept, three-day monotherapy study.

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

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

Source

Physicians’ practices for diagnosing liver fibrosis in chronic liver diseases: A nationwide, Canadian survey

Original Articles
January 2014, Volume 28 Issue 1: 23- 30

G Sebastiani | P Ghali | P Wong | MB Klein | M Deschenes | RP Myers

OBJECTIVE: To determine practices among physicians in Canada for the assessment of liver fibrosis in patients with chronic liver diseases.

METHODS: Hepatologists, gastroenterologists, infectious diseases specialists, members of the Canadian Gastroenterology Association and/or the Canadian HIV Trials Network who manage patients with liver diseases were invited to participate in a web-based, national survey.

RESULTS: Of the 237 physicians invited, 104 (43.9%) completed the survey. Routine assessment of liver fibrosis was requested by the surveyed physicians mostly for chronic hepatitis C (76.5%), followed by autoimmune/cholestatic liver disease (59.6%) and chronic hepatitis B (52.9%). Liver biopsy was the main diagnostic tool for 46.2% of the respondents, Fibroscan (Echosens, France) for 39.4% and Fibrotest (LabCorp, USA) for 7.7%. Etiology-specific differences were observed: noninvasive methods were mostly used for hepatitis C (63% versus 37% liver biopsy) and hepatitis B (62.9% versus 37.1% liver biopsy). For 42.7% of respondents, the use of noninvasive methods reduced the need for liver biopsy by >50%. Physicians’ characteristics associated with higher use of noninvasive methods were older age and being based at a university hospital or in private practice versus community hospital. Physicians’ main concerns regarding noninvasive fibrosis assessment methods were access/availability (42.3%), lack of guidelines for clinical use (26.9%) and cost/lack of reimbursement (14.4%).

CONCLUSIONS: Physicians who manage patients with chronic liver diseases in Canada require routine assessment of liver fibrosis stage. Although biopsy remains the primary diagnostic tool for almost one-half of respondents, noninvasive methods, particularly Fibroscan, have significantly reduced the need for liver biopsy in Canada. Limitations in access to and availability of the noninvasive methods represent a significant barrier. Finally, there is a need for clinical guidelines and a better reimbursement policy to implement noninvasive tools to assess liver fibrosis.

Canadian physicians | Chronic liver diseases | Liver biopsy | Liver fibrosis | Noninvasive fibrosis methods

Conitnue reading full article (PDF) here ….. [Free]

Chronic hepatitis C in Western Canada: A survey of practice patterns among gastroenterologists in Alberta and British Columbia

Original Article (Online only)
January 2014, Volume 28 Issue 1: e 1-e 4

R Pai | A Ramji | SS Lee | WW Wong | EM Yoshida

OBJECTIVE: To survey gastroenterologists in British Columbia and Alberta with regard to awareness of chronic hepatitis C virus (HCV) management and practice patterns among physicians who treat and do not treat HCV-infected patients.

METHODS: An anonymous two-page mail survey was distributed to actively practicing adult gastroenterologists in British Columbia and Alberta. Among physicians who treated HCV patients, respondents answered assessment of fibrosis pretreatment, measurement of rapid virological response, prescription of protease inhibitors (PIs), barriers to using these agents and referral patterns. For those who did not treat HCV, referral of patients for treatment and to whom was assessed.

RESULTS: Seventy-seven of 166 individuals completed the survey (46% response rate). Most (49%) practiced in academic or large community (42%) settings. Chronic liver disease comprised <25% of individual practice in 71%. Forty-eight (62%) treated HCV and two-thirds prescribed a PI. Barriers to prescription included unfamiliarity (six of 16), lack of allied health (five of 16) and few suitable patients (seven of 16). Pretreatment liver biopsy was performed by 33% (16 of 48) and 69% (33 of 48) used noninvasive measures. Rapid virological response was measured in 83% (40 of 48). Referral patterns changed in 46% (22 of 48) of physicians who treated HCV. All respondents who did not treat HCV referred patients for consideration, with 90% (26 of 29) made to hepatologists.

CONCLUSIONS: Chronic liver disease comprised <25% of practice in the majority of surveyed respondents. Among those who treated HCV, one-third have not prescribed a PI. Barriers to prescription and referral pattern changes are noted by those currently treating patients with HCV infection.

Barriers | Guidelines | HCV | Practice | Rapid virological response | Referral | Survey

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Hepatitis C virus infection in dialysis patients

REVIEW ARTICLE

Year : 2014  |  Volume : 25  |  Issue : 1  |  Page : 1-8

Hossein Khedmat¹, Mohsen Amini¹, Mohammad Ebrahim Ghamar-Chehreh¹, Shahram Agah^2
1 Baqiyatalah Research Center for Gastroenterology and Liver Disease, Baqiyatallah University of Medical Sciences, Tehran, Iran
² Colorectal Research Center, Tehran University of Medical Sciences, Tehran, Iran
Click here for correspondence address and email

Date of Web Publication 7-Jan-2014

Abstract

Despite the introduction of strict hygienic precautions preventing infection spread of hepatitis C virus (HCV) in dialysis settings, this infection is still prevalent among dialysis patients due to procedures making the patients vulnerable to infection through blood contamination. Treatment of HCV infection in dialysis patients is also less successful than that in the non-uremic population due to contraindication of using ribavirin, a main drug, in the infected patients. In this review article we aim to investigate the feasibility of the current antiviral therapies in dialysis patients infected with HCV infection.

How to cite this article:
Khedmat H, Amini M, Ghamar-Chehreh ME, Agah S. Hepatitis C virus infection in dialysis patients. Saudi J Kidney Dis Transpl 2014;25:1-8

How to cite this URL:
Khedmat H, Amini M, Ghamar-Chehreh ME, Agah S. Hepatitis C virus infection in dialysis patients. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2014 Jan 12];25:1-8. Available from: http://www.sjkdt.org/text.asp?2014/25/1/1/124455

Introduction

The World Health Organization estimates the global prevalence of chronic infection with hepatitis C virus (HCV) to be 3%, with wide epidemiological variation. ^[1] In patients under going maintenance hemodialysis (HD), the prevalence of HCV infection substantially increases to up to 90%, ^[1],[2] and this disease has been shown to be associated with severe complications from chronic hepatitis to fatal cirrhosis and hepatocellular carcinoma. ^[3] Furthermore, there are other malignancies associated with

HCV infection in some patient populations. ^[4] Moreover, data on the natural history of HCV infection in kidney disease patients demonstrate that these patients may have significant liver disease on liver biopsy, despite normal serum liver enzymes, ^[5] and it also reportedly impairs the quality of life of chronic HD patients. ^[6] Accordingly, eradication of HCV infection in this specific population is highly recommended. ^[7]

Interferon-based therapy, a standard treatment for HCV infection, has many drawbacks in HD patients, such as poor tolerance and marginal response. ^[8] Prescription of ribavirin in HD patients is generally contraindicated due to a risk of hemolytic anemia. ^[9] Pegylated interferon (PEG-IFN), which has a large polyethylene glycol moiety bound to IFN, has higher stability and prolonged systemic bio-availability ^[10] with more efficiency compared with regular IFN. ^[9] However, data on the efficiency and safety of PEG-IFN in end-stage renal disease (ESRD) patients are limited. There are also newly introduced agents, including telaprevir and boceprevir, which have been successfully employed to manage HCV infection in the non-dialysis context. ^[10],[11] However, there is an absolute scarcity of data on the efficacy and/or safety of these drugs in dialysis patients, although one study suggested that renal dysfunction does not affect the serum levels of boceprevir. ^[12]

We aim in this review article to discuss the course and management of HCV-positive patients on maintenance HD.

HCV Infection Course in HD Patients

Because of the chronic nature of HCV infection and the high rate of morbidities and mortalities in dialysis patients owing to their renal disease, the long-term evaluation of the natural history of HCV infection in this patient population has several limitations. However, evidence suggests that HCV infection increases all-cause mortality in dialysis patients, ^{[13],[14],[15],[16],[17]} and this risk of death exists irrespective of the type of dialysis. ^[18] In a meta-analysis, Fabrizi et al. ^[19] reported that the presence of anti-HCV antibody was an independent factor for death, with a relative risk of 1.57 in patients on maintenance dialysis. They also reported that dialysis patients with HCV infection are significantly more likely to develop hepatocellular carcinoma and liver cirrhosis. ^[19] On the other hand, renal transplantation has been recommended for HCV-positive dialysis patients because of its survival advantage over patients remaining in the waiting list, ^[20] although, not surprisingly, viral replication of HCV has been shown to adversely affect renal graft survival. ^[21] The proposed explanation for this observation is that HCV-induced hepatic necro-inflammation would be accelerated, especially after renal transplantation, due to immunosuppression therapy. ^[22]

 Diagnosis of HCV Infection in ESRD Patients

There are two types of assays that measure the anti-HCV antibodies: Enzyme immunoassay (EIA) and recombinant immunoblotting assay (RIBA). Although RIBA is a known confirmative test for the diagnosis of HCV infection in case of positive EIA samples, molecular assays detecting circulating HCV-RNA have thoroughly replaced it. It has been demonstrated that the false-negative rates of EIA-2 were too high, rendering the HCV-RNA polymerization as the gold standard test to confirm the HCV infection. ^[23],[24] However, the EIA-3, as a serological assay, has a high sensitivity in patients on maintenance dialysis and can be effectively used for HCV diagnosis in the HD population. ^[3]

Detection of serum aminotransferase levels in HCV-infected HD patients is of less value because it is suggested that ESRD itself lowers the aminotransferase levels; however, some authors suggested different cut-off levels for them in this patient population. , Although some authors suggested some clinical values for elevated aminotransferase levels in dialysis patients, multivariable analysis in one of them showed no independently significant relationship. ^[27]

The distribution of HCV genotypes widely varies in different geographical areas, although HCV genotype 1 predominates in dialysis patients with chronic HCV infection, regardless of geographic area. ^{[28],[29],[30]} Detection of HCV-RNA is the direct method of evaluating HCV infection. Moreover, this method enables us to estimate the viral replication rate in the liver; thus, it is a reliable test to assess the response to antiviral treatment and helps physicians determine the optimal duration and dosage of anti-viral agents. Most studies indicate that the HCV-RNA levels decrease transiently during HD sessions. ^[31] Several mechanisms have been suggested for this observation, including the adsorption of HCV onto the dialysis membrane, destruction of HCV particles, escape of HCV into the dialysate and an increase of plasma IFN-α levels during dialysis. ^[32],[33] However, recent studies have reported different observations such as a steady state or an increasing rate of HCV-RNA concentration during HD sessions. ^[34],[35] Interestingly, this observation was independent from HD procedures, dialysis membrane, heparin concentration and uremic toxins. ^[35]

Role of Histological Evaluation of the Liver

The histopathological evaluation of a liver biopsy specimen is of substantial value in determining the severity of liver fibrosis and necro-inflammation in chronic HCV infection. This also rules out other disorders, including the very prevalent non-alcoholic fatty liver disease, which may be able to induce similar damages to the liver. ^[36] However, liver biopsies are limited by complications including potentially mass bleeding events, patients' unwillingness and technical errors in obtaining the specimen or its evaluation. Compared with HCV patients with normal renal function, dialysis patients with HCV infection have milder hepatic necro-inflammation and fibrosis. The predictors of a hepatic damage in this patient population include a longer duration of infection, advanced age at infection, elevated serum aspartate aminotransferase (AST) and severe hepatic necro-inflammation on liver biopsy. ^[37] Clinical relevance of evaluating liver histopathology in dialysis patients includes the necessity for IFN-based therapy, the long-term prognosis and the eligibility for kidney transplantation. ^{[38],[39],[40]}

For dialysis patients on a transplantation waiting list, the Kidney Disease Improving Global Outcomes (KDIGO) recommends liver biopsies in the HCV-infected patients, while the American Association for the Study of Liver Diseases (AASLD) limits the biopsies to only the dialysis patients with genotypes 1 and 4 HCV infection. ^[42]

There is an increased risk of bleeding in patients with chronic kidney disease because of platelet dysfunction and anticoagulation therapies. Accordingly, the preferred method of a liver biopsy in HD patients is the trans-jugular or transfemoral routes. Moreover, through this method, one can also estimate the hepatic venous pressure gradient as well as the portal hypertension.

Treatment of Acute Infection with Hepatitis C Virus

Despite the introduction of a new generation of anti-HCV agents, IFN-α is still considered a very effective treatment in dialysis patients developing acute HCV infection according to recent publications. In a recent meta-analysis of eight clinical studies including 173 unique patients, Fabrizi et al ^[7] reported that IFN-based therapy of acute hepatitis C in dialysis populations results in a sustained virological response (SVR) in almost half of the patients. The patients who received higher doses of IFN developed higher rates of SVR. ^[44],[45]

In non-uremic patients, PEG-IFN-α-2b increases the SVR rate up to 94% in acute hepatitis C infection. ^[46] Nevertheless, data on the efficacy of PEG-IFN in dialysis patients are limited and suggestive of less-promising results than in non-uremic individuals. A recent study by Liu et al ^[47] on 35 HD patients who developed acute hepatitis C and did not have spontaneous HCV clearance by 16 weeks concluded that treatment with PEG-IFN-α-2a at a dosage of 135 μg weekly for 24 weeks was associated with almost 90% virological response, while this rate in 36 control patients who did not receive therapy was only 17%. In another study, 32 ESRD patients with acute HCV infection were followed and ten of them received PEG-IFN-α-2b, and only 40% developed SVR and one died. ^[48]

Treatment of Chronic Hepatitis C Virus Infection in Dialysis Patients

[Table 1] summarizes the data of previous metaanalyses on the treatment of chronic HCV infection in HD patients. Despite the introduction of more potent drugs and combination therapies of HCV infection in dialysis patients, IFN monotherapy is still considered a very effective therapeutic option in patients on maintenance dialysis. Conventional IFN monotherapy at a dose of 1-6 MU daily or three times per week for 12-48 weeks has been associated with SVR rates of 20-71% in dialysis patients. ^{[3],[49],[50],[51]} The predictive factors of SVR in these patients include a low baseline HCV-RNA level, mild liver histology and treating patients by IFN at a dose of 3 MU for at least six months.^[3],[52] Previous review articles have excellently included articles published earlier on the efficacy and safety of IFN monotherapy for chronic HCV infection in dialysis patients. ^[3] In our review, we only found one more article published recently to add. Fucuta Pereira Pda et al, ^[53] evaluating 40 HD patients, reported septal fibrosis or cirrhosis in 38% of patients. HCV-RNA was undetectable at Week 12 in 68% and SVR was observed in 30% of patients.

Table 1: Meta-analyses investigating efficacy of chronic HCV treatment in dialysis patients.

Peg-IFN has also been extensively used to treat chronic HCV infection in HD patients. Among recent studies, Kose et al. ^[5] investigated the largest patient population. PEG-IFN-α-2a 135 mcg/week was given for 48 weeks, which was administered in 41 patients, of whom 38 completed the study. Virological response rates for Weeks 12 and 72 were 60% and 50%, respectively. Furthermore, Alsaran et al. ^[2]treated 13 patients with PEG-IFN for 48 weeks, with no drop-out. After 24 weeks of therapy, 76% of patients responded to therapy and 24% of patients were resistant. Six months after termination of therapy, nine (69%) patients had SVR. ^[2] [Table 2] summarizes the recent studies investigating anti-HCV therapy in ESRD patients.

Table 2: Recent studies investigating treatment of HCV infection in dialysis patients.

Resistant Cases of Hepatitis C Virus-Infected Dialysis Patients to Interferon Therapy

Although treatment of HCV infection with IFN-based regimens in dialysis patients has been reportedly considered a safe and feasible method of therapy, many ESRD patients with HCV infection show resistance toward it. Intolerance to IFN due to its side-effects is the most significant cause of resistance to this therapy. There is a wide spectrum of side-effects associated with IFN therapy, which includes loss of appetite, fatigue, dry skin, influenzalike symptoms and gastrointestinal disturbances as well as neuropsychiatric symptoms and hematological abnormalities. ^[64] These side-effects often result in discontinuation or dose reduction of the drug, which can endanger viral response in HCV-infected dialysis patients. ^[55],[56] The incidence of these side-effects can be as high as 30% in patients using PEG-IFN, with lower rates in those using standard IFN. ^[64] Data on the efficacy and safety of PEG-IFN in ESRD patients are more limited and future studies are required to extend our knowledge on this issue.

References

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2.Alsaran K, Sabry A, Shaheen N. Pegylated interferon alpha-2a for treatment of chronic HCV infection in hemodialysis patients: A single Saudi center experience. Int Urol Nephrol 2011;43:865-73.  [PUBMED]   

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