Achillion's Hep C Pipeline Likely Can't Compete

By Adam Gefvert, Contributor

Thursday, 19 January 2012 08:16

Hepatitus C drug developers have been drinking champagne and eating caviar lately. Companies in this space that have shown little to no revenues for years have been getting acquired at huge premiums to their share price and for billions of dollars.

Pharmasset (VRUS) was offered $11 billion by Gilead Pharmaceuticals (GILD) in November 2011, for an over 100% premium to the share price. Gilead bought it for its PSI-7797 anti-HCV (Hepatitis C Virus) nucleoside. Bristol-Meyers Squibb (BMY) made a tender offer for Inhibitex over the January 7^th weekend for $2.5 billion, a 160% premium over its share price. Also for its anti-HCV nucleoside.

With the recent heavy M&A action in the Hepatitis C space, drug development company stocks that are focusing on Hepatitis C drugs have taken off. Since the Inhibitex buyout on Jan 9, Achillion (ACHN) has gone from $7.92 to $12.95, for a 64% gain. It has since settled down to about $11.

However, Inhibitex and Pharmasset HCV drugs: INX-189, and PSI-7977, respectively, are nucleosides which are a different type of anti-viral drug than those currently used to fight HCV. Nucleosides are believed to be the next generation drug to fight HCV because they have shown in clinical trials to be able to destroy the HCV virus on their own without the aid of other drugs.

Achillion is at a disadvantage to its competitors because none of its HPV drugs in development are nucleosides.

The type of drugs currently used to fight HCV are protease inhibitors which are not able to fight the HCV alone. HCV’s mutations are able to resist protease inhibitors, so they must be used along with the standard of care treatment of pegylated interferon and ribavirin (PR) in order to cure patients. Use of a protease inhibitor along with PR gives a 75% chance to cure HCV, while treatment of only PR, the old method of fighting HCV, gives only a 50% chance to cure it.

The problem is, the side effects of interferon are so bad, that many patients would rather have the disease or wait for a better solution than deal with the treatment. Many patients say the side effects are worse than the disease itself.

The fact that big pharmaceutical companies paid so high a price for Pharmasset and Inhibitex nucleosides is a testament to the thesis that the future of HCV treatment is going to be done without interferon.

“We believe the interferon free era will come late 2015 and early 2016 and we would anticipate, from a time perspective, being competitive with that," said Inhibitex's chief executive Russell Plumb.

In the following picture, Pharmasset illustrates the contrast between the present and future of Hepatitis C treatment.

Achillion’s most advanced HPV drug that is currently going through phase II trials, is ACH-1625, which is a protease inhibitor. It has been going through preclinical trials since 2008 before it was discovered that nucleosides can efficiently fight the HCV. If ACH-1625 won’t work without the help of interferon, then it will pretty much be worthless. By the time it gets to market in 2015 or 2016, if it gets approved, there won’t be any HCV patients willing to do a treatment with interferon.

There is a glimmer of hope for protease inhibitors though. In October 2011, Abbott Laboratories and partner Enanta Pharmaceuticals announced positive results from a phase 2 study of ABT-450, their oral protease inhibitor against HCV, without the use of interferon.

“In the trials, 44 previously untreated patients with hepatitis C were given ritonavir with Abbott's ABT-450 and one of two Abbott polymerase inhibitors, ABT-333 or ABT-072, and ribavirin for 12 weeks. All patients who remained in the studies achieved an early virologic response at 12 weeks, and of the 10 patients to date who were tested 24 weeks after completing the treatment course, nine had achieved a sustained virologic response”, the company said.

Abbott said it could have this shorter duration combination therapy for hepatitis C on the market in 2015 with annual sales potential of about $2 billion.

Early virologic response is a reduction of 2 or greater log in HCV RNA (hepatitis C ribonucleic acid) at week 12 of therapy, and this predicts sustained virologic response, which is an undetectable level of HCV RNA, at further treatments.

"We are seeing there is another way of achieving a regimen without interferon that looks like it will be competitive, it will eventually all boil down to who has the better data,” said Leerink Swann analyst Howard Liang.

However, Brean Murray Carret & Co. analyst Brian Skorney noted that "I continue to believe Pharmasset's [therapy] will be better." (FYI - this was stated before Gilead made the offer to acquire Pharmasset).

Merck is also working on an interferon-free regimen with their protease inhibitor MK-5172. From the company website: “MK-5172 suppressed HCV in patients infected with HCV genotypes 1 and 3. In addition, new in vitro data shows antiviral activity against a wide range of resistant mutant HCV types. The company is actively pursuing the use of MK-5172 in an interferon-free regimen for HCV.”

Achillion’s ACH-1625 drug hasn’t been proven to work without the help of PR. The drug has quite a few obstacles to climb to be worth anything. It would not only have to show effectiveness against HCV without interferon, but it would also have to compete with the nucleosides’ data when they come to market, as well as Abbott’s ABT-450 if it becomes successful, and Merck’s protease inhibitor and those of other big pharma companies. Then there’s all the resources and expenses necessary to get it through the trials. Phase III trials alone would likely cost over $100 million.

Besides ACH-1625, all its other drugs in the pipeline are in the preclinical stage or are starting phase 1 trials. It wouldn’t make any sense for a big pharmaceutical company to acquire Achillion at its current elevated price. Most of them are already working on their own HCV drugs. For example, Vertex and Alios BioPharma have teamed up to do clinical trials of their nucleoside drugs ALS-2200 and ALS-2158.

As shown in the Q3 2011 report, Gilead Sciences had entered into a research collaboration and license agreement with Achillion in 2004, and is continuing to do a minimal amount of collaborative research with the company, only paying $64K last quarter. Then Gilead went ahead and acquired Pharmasset for $11 billion totally snubbing Achillion. If any big pharma was going to buy Achillion, it would seem that Gilead would’ve been a good candidate since they have worked together for awhile. Achillion’s market cap was only about $400 million in late November when Gilead bought Pharmasset.

It’s unlikely that Achillion will be able to find an interferon-free treatment for HPV with ACH-1625 because when the drug was first designed, it didn’t have that goal in mind. Now, going through its phase 2 trials, with all the competition, I’m giving it a 15% chance that it will be able to develop an interferon-free regimen and become a top HPV drug with $2 billion a year in revenues like Abbott predicts its ABT-450 drug will peak at.

Achillion’s other two HCV inhibitors, ACH-2684 and ACH-2928, are going through phase 1 trials, so I’m giving them a 10% chance to succeed and reach the $2 billion annual sales number. I’m not including in the value calculation Achillion’s drugs still going through preclinical trials.

Even if Achillion managed to develop and commercialize a $2 billion a year in sales drug, it would need help to market it as it doesn’t have any experience selling drugs. That’s why the company is looking for an acquirer, or a big pharma to continue with the trials from here, take on the expenses, and give Achillion royalty payments once the drug hits the market. The latter is the scenario I use in my discounted cash flows analysis.

Continue Reading …

New Combo KOs HCV Without Interferon, Ribavirin

By Michael Smith, North American Correspondent, MedPage Today
Published: January 18, 2012
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston.

A combination of direct-acting antiviral agents aimed at hepatitis C -- and given without standard therapy -- can lead to sustained virologic response in patients with a difficult-to-treat strain of the virus.

In an "exploratory" phase II study, four of 11 patients treated with the two agents daclatasvir and asunaprevir had undetectable levels of the virus 12 and 24 weeks after the end of treatment, according to Anna Lok, MD, of the University of Michigan Ann Arbor, and colleagues.

All of the patients had previously failed standard therapy with pegylated interferon and ribavirin, Lok and colleagues reported in the Jan. 19 issue of the New England Journal of Medicine.

The finding is a "proof-of-concept" that combining agents that directly target the virus through different mechanisms can yield good outcomes even without the standard therapy, the researchers argued.

On the other hand, results were even better in the second arm of the study, in which 10 patients were given all four drugs: all had a sustained virologic response 12 weeks after stopping treatment and nine still had undetectable levels of hepatitis C RNA after 24 weeks.

Sustained virologic response – defined as a plasma level of viral RNA of less than 10 IU per milliliter 12 weeks after treatment ends – is regarded as the functional equivalent of a cure, since the virus rarely rebounds after that.

In clinical trials, standard therapy with pegylated interferon and ribavirin yields sustained virologic responses in no more than half of patients with the difficult to treat genotype 1 and in no more than 80% of those with genotypes 2 or 3.

Adding either of the approved direct-acting agents – telaprevir (Incivek) and boceprevir (Victrelis) – improves those outcomes markedly.

But regimens including pegylated interferon and ribavirin are difficult to take and real-world effectiveness is much lower, leading to a growing interest in other agents that attack viral replication directly and may be used without interferon and ribavirin.

That's why the current study is a "watershed moment" in hepatitis C therapy, according to Raymond Chung, MD, of Massachusetts General Hospital in Boston.

In an accompanying editorial, Chung said that researchers can "certainly" do even better than Lok and colleagues by adding other direct-acting agents into the mix.

With other classes in development – such as nucleotide polymerase inhibitors – "we are on the threshold of a treatment revolution," Chung argued.

"There has never been a more exciting time for patients and providers who grapple with this silent killer," he concluded.

The two drugs under study both attack the viruses' ability to replicate inside cells. Daclatasvir inhibits the NS5A replication complex, while asunaprevir blocks the activity of the NS3 protease enzyme.

For this study, Lok and colleagues enrolled 21 patients with genotype one hepatitis C who had not responded to previous therapy and assigned them randomly to get the two drugs alone or in combination with standard therapy for 24 weeks.

The primary endpoint was a sustained virologic response 12 weeks after therapy ended.

Lok and colleagues reported:

• Four patients in the two-drug group (36%) met the primary endpoint, including two of the nine with viral genotype 1a and both of those with genotype 1b.
• Six patients -- all with genotype 1a -- had viral breakthrough while receiving therapy, and in all of them the researchers found resistance mutations to both antiviral agents.
• All 10 patients in the four-drug group had a sustained virologic response 12 weeks after treatment, and nine maintained that for another 12 weeks.

The most common adverse event in both groups was diarrhea, and six patients had transient elevations of alanine aminotransferase levels to more than three times the upper limit of the normal range.

The study is not the first to find such a result; Japanese researchers have also shown that the two drugs in combination – but without interferon -- can lead to promising outcomes.

But in that open-label, single-arm study, all the patients had genotype 1b virus, which appears to respond better to therapy than genotype 1a.

The study was supported by Bristol-Myers Squibb.

Lok reported financial links with Abbott, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck–Schering-Plough, and Roche. Other authors also reported financial links with industry and several are either employees of or hold stock in Bristol-Myers Squibb.

Chung reported financial links with Merck, Gilead, Pfizer, Roche, and Schering.

Primary source: New England Journal of Medicine
Source reference:
Lok AS, et al "Preliminary study of two antiviral agents for hepatitis C genotype 1" N Engl J Med 2012; 366: 216-224.

Additional source: New England Journal of Medicine
Source reference:
Chung RT "A watershed moment in the treatment of hepatitis C" N Engl J Med 2012; 366: 273-275.

Source

Also See:

1. First Hepatitis C Treatment Data Demonstrating Proof of Principle with Direct-Acting Antiviral-only Therapy Published
2. Hepatitis C treatment with antivirals is effective: study
3. Bristol-Myers Hepatitis C Pills Clear Virus Without Interferon

Where Drug Names Come From

Naming Convention Drugmakers propose generic names for new drugs by starting with stems that describe structure, function, and targets, then tacking on syllables of their choice.

Chemical & Engineering News Volume 90 Issue 3 | January 16, 2012 | pp. 36-37

Behind every generic name lies a specific process

By Carmen Drahl

It isn’t every day that a molecular moniker is on the docket at Illinois’ Cook County Circuit Court. But then, the 2002 case of cis-8-methyl-N-vanillyl-6-nonenamide was most unusual.

The trouble wasn’t with the compound’s International Union of Pure & Applied Chemistry-approved name. It was that cis-8-methyl-N-vanillyl-6-nonenamide also happens to be a medication. Drug molecules get an additional, simpler name called a nonproprietary name or generic name. Winston Pharmaceuticals, a company that develops products based on cis-8-methyl-N-vanillyl-6-nonenamide, sought to change that molecule’s generic name, which an independent body had chosen in-line with decades of drug-naming conventions. If the case went Winston’s way, more than a name on a box would have been at stake.

Drug naming rarely involves drama. But this example illuminates a little-talked-about layer in drug development, one that affects doctors, pharmacists, and patients.

Unlike IUPAC-sanctioned chemical names, generic names usually describe a drug’s physiological function rather than its chemical structure. Today’s regimented generic-naming process got its start in the 1960s, a time when drugs had grown complex in structure and IUPAC names had grown to unwieldy lengths. In 1961, the American Medical Association, the U.S. Pharmacopeial Convention, and the American Pharmacists Association created the U.S. Adopted Names (USAN) Council to select concise generic names. The Food & Drug Administration joined the effort in 1967.

Today, the USAN Council names the active ingredients in drugs, biologics, vaccines, and even contact lenses and sunscreens. The council recommends names to the World Health Organization’s (WHO) International Nonproprietary Names (INN) program, which ultimately chooses a single name for each new drug that’s acceptable worldwide. For drugmakers, obtaining a generic name is a required part of bringing new products to market. Choosing a brand, or trade, name is an entirely separate process.

USAN Council members believe it’s important to develop drug names that are free for anyone to use, says Ruta Freimanis, who served as associate executive secretary and then as executive secretary of the USAN Council between 1978 and 2000. Brand names might be handy at first, “but eventually drugs do go off patent,” she says. A generic name “can go in the literature, on package labels, or even in educational materials” without copyright issues related to brand names, she explains.

The naming process itself “is an evolving type of science,” says Stephanie C. Shubat, the current director and secretary to the USAN Council. Generic names have evolved from being truncated versions of chemical terminology to being largely independent of it, she explains.

A list of naming rules, some of them quirky, has evolved as well. The letters h, j, k, and w are off-limits because they lead to pronunciation problems in other languages. Drugmakers can suggest names to the USAN Council, but any name with an implication that a drug is better, newer, or more effective than the competition heads straight for the reject pile, Shubat says. When a prospective name reaches the WHO stage, international connotations come into play. A name that sounds perfectly fine in English might have bad or even obscene connotations elsewhere. No one wants to sell the Chevy Nova of the drug world.

The crux of the generic-naming system is a collection of short name fragments called stems. Each stem has a meaning connected to a particular drug class or mode of action. The official list of USAN and INN stems and substems has grown and changed over time as companies come up with new classes of drugs, Shubat explains.

Understanding drug names through stems is a lot like learning English vocabulary by studying Greek and Latin roots. Learn what the stems mean, and you’re most of the way to figuring out what a drug does. Take top-selling drug Nexium, which has a generic name of esomeprazole. The stem in that name is -prazole, which means the drug is a benzimidazole antiulcer agent. The drug’s es- prefix describes the nature of the drug’s chirality—esomeprazole is dextrorotatory and contains a chiral center in the S configuration.

A prefix, in fact, was a player in the Winston case. The generic name Winston wanted to change, zucapsaicin, contains the prefix “zu,” which comes from German chemical nomenclature and indicates a cis isomer. Zucapsaicin is the cis isomer of capsaicin, a compound in chili peppers. The molecule targets a specific ion channel and can be used to treat pain, inflammation, or itch, says Joel E. Bernstein, a physician and Winston’s chief executive officer. Winston requested a name change from zucapsaicin to civamide, which according to the company was commonly used in hospitals and pharmacies.

It’s possible to change generic names, but only on rare occasions, and usually only for safety reasons. In 2009, for instance, the entire family of botulinum toxin drugs, which includes the popular cosmetic Botox, got a generic-name makeover in light of reports of serious side effects and deaths from dosage mix-ups.

Winston did not win its court case. A 2004 petition to FDA to change the name didn’t work out either. The name zucapsaicin was found to be in-line with established naming precedents. As for name confusion among physicians and pharmacists, the USAN Council concluded Winston was partly to blame.

The name zucapsaicin had been on the books since 1994. The council negotiated the name with a company called GenDerm, which owned the rights to the drug at the time. Civamide was a generic name GenDerm suggested. After that name was rejected, GenDerm continued to use the name civamide in the literature and its documentation. Winston continued the practice when it acquired the rights to the drug in 1999.

Most of the documents Winston cited to support its claim are dated after 1994, wrote then-USAN program director Sophia V. Fuerst in a letter to Winston. It’s both Winston and GenDerm’s “use of the name civamide after the name zucapsaicin was adopted that has caused the confusion,” she wrote.

Bernstein disputes that idea. Still, he says, “we weren’t able to get USAN to change their mind, nor FDA, so we have zucapsaicin.”

Most of the time, a simple back-and-forth between a company and the USAN Council is enough to settle any name disputes, says John E. Kasik, professor emeritus at the University of Iowa Carver College of Medicine and a longtime member of USAN’s review board, which settles naming spats. In fact, the review board has only had to step in to resolve five disputes throughout its decades-long existence.

Sometimes small disagreements occur when a manufacturer asks for a new stem to be created, Shubat says. It’s the council’s job to keep naming as streamlined as possible, which means being conservative when it comes to adding new stems, she explains.

“Manufacturers have to supply concrete arguments as to what differentiates their compound to qualify for a new stem,” Freimanis says. Drugs within the same category are different, she says, “otherwise manufacturers wouldn’t be selling them.”

Once the council builds in stems, prefixes, and other conventions, “a lot of times a name is three-quarters predetermined,” Shubat says. Once in a while, though, companies get to do something special with the syllable or two they supply. Onyx Pharmaceuticals’ experimental multiple myeloma treatment carfilzomib is named after molecular biologist Philip Whitcome and his wife, Carla, who both succumbed to cancer. (The ph in Philip was changed to an f to make the name compatible with multiple languages.) Philip Whitcome was a founder of the company Proteolix, which first developed carfilzomib, says Onyx spokeswoman Lori Melançon. With the name, the company “wanted to celebrate both Phil and Carla’s legacy,” she says.

Bristol-Myers Squibb’s experimental hepatitis C drug asunaprevir gets part of its name from Li-Qiang Sun, the chemist who first made it, says Joel C. Barrish, BMS’s vice president of medicinal chemistry.

And dasatinib, a chronic myelogenous leukemia medication BMS markets under the brand name Sprycel, is named for research fellow Jagabandhu Das. Das, or Jag, as he’s known around the labs, didn’t discover dasatinib. “What Jag did was challenge dogma,” Barrish explains. On two separate occasions, Das’s discoveries pulled his teammates out of medicinal chemistry ruts.

Long after a drug’s patent expires, “it’s the generic name that will always be remembered,” Barrish says. “Being able to recognize Jag that way for his accomplishments made the whole team feel good.”

Chemical & Engineering News

ISSN 0009-2347

Copyright © 2012 American Chemical Society

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A Glucose Meter That Detects Viruses

Virus Meter? By making glucose a signal for viral DNA, researchers repurposed a glucose meter into a virus detector. Credit: Shutterstock

January 18, 2012

Medical Diagnostics: Researchers convert device for monitoring diabetes into one that can spot hepatitis B

By Erika Gebel

Although scientists have developed a variety of cheap, portable instruments for doctors to use in the field to pinpoint viruses, none have hit the market. To speed things along, researchers have now converted a commercially available device—a glucose meter—into one that can spot viral DNA (Anal. Chem., DOI: 10.1021/ac203014s).

“Our idea was to start with a technology that is already mature,” says Yi Lu of the University of Illinois, Urbana-Champaign. He and his team repurposed glucose meters, which people with diabetes commonly use to monitor their blood sugar, into virus meters by using glucose as a proxy for viral DNA. The scientists designed a chain of biomolecular interactions to link the two.

With hepatitis B as the virus they chose to detect, they first made two DNA probes that each would recognize half of the virus’s DNA sequence. The researchers then attached one probe to a tiny magnetic bead and the other to invertase, an enzyme that turns sucrose into glucose.

They tested their system by adding both probes to a solution of hepatitis B DNA at a known concentration. As the mixture incubated for a couple of hours, each strand of viral DNA bound both probes, thereby linking the enzymes to the beads. The researchers then isolated the beads with a magnet and placed them in a sucrose solution, where the enzymes slowly produced glucose. After three hours, the scientists removed the beads and measured the solution’s glucose concentration with a glucose meter.

Based on the measurement, they could determine how much invertase was present and, in turn, the amount of viral DNA in the original solution. Their system could detect hepatitis B DNA down to 40 pM, a level adequate to diagnose the disease at some stages, but not all. To improve the method’s sensitivity, Lu wants to increase incubation times and possibly engineer an enzyme that produces more glucose.

Chemical & Engineering News

ISSN 0009-2347

Copyright © 2012 American Chemical Society

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Effort Improves Outcomes for Liver Transplants

Written by Elizabeth Witherspoon

Nationally there are 17,000 people on the waiting list for a liver transplant. Yet according to A. Sidney Barritt, IV, M.D., M.S.C.R., surgeons are able to perform only about 6,000 transplants annually. And, unfortunately, the obesity and diabetes epidemics in this country may be reducing the number of viable organs for transplantation each year. Thus, science which advances the understanding of how best to treat patients and prevent mortality while they wait for transplants is vital.

Barritt and colleagues from UNC-Chapel Hill funded, in part, by an NIH KL2 grant through the North Carolina Translational and Clinical Sciences (NC TraCS) Institute studied one of the factors that may affect mortality of patients awaiting transplant – the density of gastroenterology (GI) specialists in their home communities. He presented his findings at the annual Liver Meeting of the American Association of the Study of Liver Disease and received an AASLD Presidential Poster of Distinction award in November.

Previous studies have looked at patients’ geographic distance from the transplant center, hypothesizing that the greater the distance, the lower the transplant rate. Instead, Barritt and his team considered the density of GI subspecialists in communities and found a correlation: the more GI subspecialists patients have in their home communities, regardless of how far they lived from the transplant center, the better the outcome.

This study showed that among patients referred for liver transplant, the number of gastroenterologists in their home hospital service area independently increases the odds of receiving a liver transplant by 16% for each additional gastroenterologist per 100,000 population. Increasing Model for End-stage Liver Disease (MELD) score and hepatocellular carcinoma also increase the odds of receiving a transplant. Medicaid and Medicare insurance coverage are detrimental to a patient’s odds of receiving a liver transplant, but are better than no insurance coverage at all.

“We were not looking at referral patterns. We were not looking at whether a gastroenterologist was more likely to send you to UNC,” said Barritt. “We were looking at whether the number of gastroenterologists in a community helps keep you alive and a viable transplant candidate from referral to ultimately getting a transplant.”

“Access to local subspecialty care improved the odds of transplant for our patient population most likely because we are a centrally located tertiary care transplant center and many of our patients continue to receive medical care locally. Access to local experts is a great boon to our center in co-managing these patients and we rely heavily on their expertise to get chronically and often critically ill patients through to liver transplant. As our referral base measures more than 500 miles in diameter, we are unable to follow some of our patients on a weekly basis. Additionally, when our medical center has no available beds for inpatient transfers, our colleagues around the state help facilitate patient care locally,” said Barritt.

The project also tested a clinical transplant database at UNC to see whether it is valid for use as a research database. The investigators hope that in the future they can combine these data with that of certain other transplant centers so they can conduct studies with more generalizable findings than research currently available from large single-center studies or from the United Network of Organ Sharing database, which lacks some patient specific data.

Barritt is an assistant professor in the Department of Medicine, Division of Gastroenterology and Hepatology, UNC School of Medicine. He is also a KL2 Scholar, in the second year of three years of support by NC TraCS. The KL2 program objective is to train and develop junior investigators who will become the next generation of successful translational researchers. It does this by providing classroom and experiential training, mentoring, funding for research and, perhaps most importantly, protected research time.

His colleagues on the project are: Stephen A. Telloni, M.D., Department of Medicine; Clarence W. Potter, M.S., NC TraCS; David A. Gerber, M.D., associate professor, Department of Surgery, Division of Abdominal Transplant; and Paul H. Hayashi, M.D., M.P.H., assistant professor and medical director of liver transplantation.

Source

Bristol-Myers Hepatitis C Pills Clear Virus Without Interferon

January 18, 2012, 6:08 PM EST

By Drew Armstrong and Robert Langreth

Jan. 18 (Bloomberg) -- Two experimental pills from Bristol- Myers Squibb Co. cleared the hepatitis C virus in 36 percent of patients who failed existing drugs, in a small study that may lead to a new oral-therapy approach against the liver disease.

The study released today is the first to suggest that difficult hepatitis C cases may be cured without using the injected drug interferon, said Anna Lok, the lead study author and director of hepatology at the University of Michigan in Ann Arbor. Interferon, a mainstay of existing treatment, causes unpleasant side effects including fatigue and flu-like symptoms.

Drug companies including Bristol-Myers, Merck & Co., Gilead Sciences Inc., and Vertex Pharmaceuticals Inc. are racing to come up with interferon-free treatment. The new results in 21 patients show that such a therapy will be possible, Lok said.

Oral treatments with fewer side effects would vastly increase the number of patients treated, according to an editorial in the New England Journal of Medicine, where the study was published.

“We are on the threshold of a treatment revolution that will greatly improve the effectiveness of HCV therapy,” wrote Raymond Chung, a gastroenternologist at Massachusetts General Hospital in Boston. He called it “a watershed moment in the annals of HCV therapy.”

The study compared Bristol-Myers’s two pills in combination with interferon to the pills alone in 21 hepatitis C patients who weren’t helped by existing therapy. It found that 4 of 11 patients had undetectable virus 24 weeks after treatment with Bristol’s experimental oral drugs daclatasvir and asunaprevir.

Adding injectable drugs, however, boosted the response rate. Results showed that 9 of 10 patients who got the two oral drugs plus interferon and a fourth drug, ribavirin, for 24 weeks had no detectable virus 24 weeks after stopping therapy.

“The combination of drugs we picked may not be the best, and we need to tweak it and find the best combination,” Lok said in a telephone interview from Ann Arbor.

Bristol-Myers, based in New York, sponsored the clinical trial.

--Editors: Angela Zimm, Andrew Pollack

To contact the reporters on this story: Drew Armstrong in New York at darmstrong17@bloomberg.net ; Robert Langreth in New York at rlangreth@bloomberg.net

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

Source

Also See:

1. Hepatitis C treatment with antivirals is effective: study
2. First Hepatitis C Treatment Data Demonstrating Proof of Principle with Direct-Acting Antiviral-only Therapy Published

Hepatitis C treatment with antivirals is effective: study

Hepatitis C can be spread through blood and infected needles. (Centers for Disease Control and Prevention)

By Shari Roan, Los Angeles Times / For the Booster Shots blog

January 18, 2012, 2:12 p.m.

A major advance in treating hepatitis C appears to be on the horizon. Researchers reported Wednesday that combining two antiviral medications was effective in stopping the infection in some patients who were not helped by the traditional treatment.

Progress in fighting hepatitis C infection is of high importance because millions of Americans have the virus. However, the standard treatment with the medication interferon, while effective in many people, is linked to severe side effects. "The challenge ... has been to identify regimens that are more effective, shorter, and have a better side-effect profile," said Dr. Raymond T. Chung, director of hepatology at Massachusetts General Hospital.

Hepatitis C is an infectious disease that can cause liver inflammation and damage. It's spread through exposure to infected blood, such as via contaminated needles or through sexual contact.

The new study, published in the New England Journal of Medicine, is a phase-2 trial of 21 people with hepatitis C who had not responded to previous therapy. They were randomly assigned to receive the two antiviral drugs daclatasvir and asunaprevir or those two antivirals with interferon and ribavirin (another drug used to treat hepatitis C infection).

The study showed that virus activity was halted in 36% of the patients receiving only the two antiviral medications over 24 weeks of treatment. Stopping the virus from replicating halts the infection. All but one of the patients in the second group, who were receiving the combination of four medications, showed a positive response to the medication after 24 weeks.

The research, while preliminary, proves that it may be possible to treat hepatitis C infection with antivirals only. Patients with a type of virus called genotype 1b had a particularly strong response to the antivirals. "Overall, these results suggest that further research with combinations of direct-acting antiviral agents, with or without [interferon] and ribavirin, is warranted," wrote the authors, led by Dr. Anna S. Lok, at the University of Michigan Medical Center.

Chung, who wrote a commentary accompanying the study, said: "We are on the threshold of a treatment revolution that will greatly improve the effectiveness of hepatitis C virus therapy by dramatically increasing the number of persons treated."

Studies are underway to further evaluate the effect of combining antiviral medications for hepatitis C treatment.

Source

Also See: First Hepatitis C Treatment Data Demonstrating Proof of Principle with Direct-Acting Antiviral-only Therapy Published

First Hepatitis C Treatment Data Demonstrating Proof of Principle with Direct-Acting Antiviral-only Therapy Published

January 18, 2012 05:01 PM Eastern Time

Study also Demonstrated 100% Sustained Virologic Response 12-Weeks Post Treatment with Quadruple Therapy

Phase II Investigational Data Published Today in the New England Journal of Medicine

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE: BMY) today announced the full results, published in the New England Journal of Medicine, from a Phase II clinical trial in patients with hepatitis C virus (HCV) genotype 1 who had not responded to prior therapy with PEG-interferon alfa and ribavirin (‘null responders’¹). The study demonstrated that its primary endpoint of the achievement of sustained virologic response 12-weeks post-treatment (SVR12) is possible with a direct-acting antiviral (DAA)-only combination containing daclatasvir and asunaprevir (4/11 patients, including two of two patients infected with HCV genotype 1b). This study was the first study to demonstrate the possibility that hepatitis C can be cured (defined as sustained virologic response 48 weeks post-treatment or SVR48) without the use of interferon. The study also demonstrated that 100 percent (10/10) of these difficult-to-treat patients dosed with quadruple therapy containing daclatasvir and asunaprevir in combination with PEG-Interferon alfa and ribavirin achieved SVR12.

In this study there were no serious adverse events on treatment or discontinuations due to adverse events. Diarrhea was the most common adverse event in both groups (73% and 70%).

“Even with the recent approval of two protease inhibitors, treatment of hepatitis C patients who have not responded to PEG-interferon alfa and ribavirin has limited success. Because of this high unmet medical need, there is a necessity for new combination regimens that can increase response rates in null responders,” said lead investigator Anna Lok, MD, FRCP, director of clinical hepatology and professor in the department of internal medicine at the University of Michigan Medical School in Ann Arbor. “The data seen in this study with Bristol-Myers Squibb’s investigational DAAs daclatasvir and asunaprevir, either as DAA-only therapy or as part of quadruple therapy, are encouraging as we work to advance hepatitis C therapy for this difficult-to-treat patient population. This study also shows for the very first time that sustained viral responses can be achieved without the use of interferon and ribavirin.”

Daclatasvir is the first NS5A replication complex inhibitor to be investigated in HCV clinical trials and is currently in Phase III development. Asunaprevir is an investigational, oral, selective NS3 protease inhibitor.

Study Results

Viral Response: Dual DAA Therapy with daclatasvir and asunaprevir (Group A)

Eleven patients were randomized to receive dual DAA therapy for 24 weeks. Seven of the 11 patients (64%) in Group A achieved undetectable viral load by week four, and five patients remained undetectable at the end of treatment. Of these 11 patients, one patient relapsed at four (4) weeks post treatment while four patients (36%) had sustained virological response at 12 weeks post-treatment (SVR12). In follow-up to 48-weeks post treatment, no additional cases of viral relapses were observed.

Six patients, all with HCV genotype 1a, experienced viral breakthrough on dual DAA therapy, and analysis of HCV sequences following breakthrough confirmed resistance to both antivirals. With the addition of PEG-interferon alfa and ribavirin to their regimen (rescue therapy), four of the six patients achieved undetectable viral load. Two of these patients relapsed following the treatment period and two remained undetectable, one with 14 weeks and one with 42 weeks of post treatment follow-up. Two of the six patients did not achieve undetectable HCV RNA and treatment was discontinued.

Viral Response: Quadruple Therapy with daclatasvir, asunaprevir and PEG-Interferon alfa and ribavirin (Group B)

Ten patients were randomized to receive quadruple therapy for 24-weeks. Six of the 10 patients (60%) in Group B achieved undetectable HCV RNA by week four. Ten of the 10 patients (100%) were undetectable by the end of treatment, and all 10 achieved SVR12. No patients experienced viral relapse during 48 weeks of post-treatment observation.

Safety

In the study, there were no serious adverse events on treatment, no deaths, and no treatment discontinuations due to adverse events. Most adverse events were mild to moderate, and the most common AEs were diarrhea (group A: 8/11, 73%; group B: 7/10, 70%), fatigue (group A: 6/11, 55%; group B: 7/10, 70%), headache (group A: 5/11, 45%; group B: 5/10, 50%), and nausea (group A: 2/11, 18%; group B: 5/10, 50%).

Six patients (four from group A, including two receiving rescue therapy, and two from group B) experienced elevated liver enzymes [ALT >3x upper limit of normal (ULN)] which did not require treatment discontinuation or dose interruptions, and all patients stabilized or improved with continued therapy. Six patients, all of whom received PEG-interferon alfa and ribavirin, experienced Grade 3 or 4 neutropenia, a blood disorder characterized by an abnormally low number of white blood cells.

About the Study

This open-label, phase IIa study evaluated the antiviral activity and safety of the combination of daclatasvir and asunaprevir with and without PEG-Interferon alfa and ribavirin in 21 HCV genotype 1 null responders. Patients in the study were randomized to receive one of two treatment regimens for 24 weeks. The 11 patients in Group A received dual-DAA therapy with daclatasvir 60 mg once daily and asunaprevir 600 mg twice daily, both taken orally. The 10 patients in Group B received quadruple therapy with daclatasvir 60 mg once daily, asunaprevir 600 mg twice daily, PEG-interferon alfa 180 µg once weekly, and ribavirin 1000-1200 mg daily (according to body weight) in two divided doses. The primary study objective was to determine the proportion of patients achieving undetectable viral load (HCV RNA <10 IU/mL) 12 weeks post-treatment (SVR12). This dual-DAA combination is now in Phase III development.

About Bristol-Myers Squibb’s Commitment to Liver Disease

Bristol-Myers Squibb is advancing a portfolio of compounds that aims to address unmet medical needs across the liver disease continuum, including hepatitis C, hepatitis B and liver cancer. The Company’s hepatitis C pipeline includes a portfolio of compounds with different mechanisms of action, pursuing both biologics as well as small molecule antivirals. These compounds are being studied as part of multiple novel treatment regimens with the goal of increasing SVR rates across diverse patient types and geographies. Discovered by Bristol-Myers Squibb through a genomics approach, daclatasvir, also known as BMS-790052, is the first NS5A replication complex inhibitor to be investigated in hepatitis C clinical trials and is currently in Phase III development. Asunaprevir, also known as BMS-650032, is an NS3 protease inhibitor in Phase III development for hepatitis C.

About Hepatitis C

Hepatitis C is a virus that infects the liver and is transmitted through direct contact with infected blood and blood products. An estimated 170 million people worldwide are infected with hepatitis C, with genotype 1 being the most prevalent genotype. Up to 90 percent of those infected with hepatitis C will not clear the virus and will become chronically infected. Twenty percent of people with chronic hepatitis C will develop cirrhosis and, of those, up to 25 percent may progress to liver cancer. Although there is no vaccine to prevent hepatitis C, it is a potentially curable disease.

About Bristol-Myers Squibb

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

Bristol-Myers Squibb Forward Looking Statement

This press release contains “forward-looking statements” as that term is defined in the Private Securities Litigation Reform Act of 1995, regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that the compound described in this release will move from exploratory development into full product development, that clinical trials of this compound will support a regulatory filing, or that the compound will receive regulatory approval or become a commercially successful product. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb’s business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2010, in our Quarterly Reports on Form 10-Q, and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise.

¹ Null responders – patients whose virus did not respond to prior treatment with PEG-interferon alfa and ribavirin (HCV RNA decrease <2 log₁₀ at 12 weeks).

Contacts

Bristol-Myers Squibb Company
Media:
Cristi Barnett, 609-252-6028
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or
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Source

Rituximab Helpful Against HCV Cryoglobulinemic Vasculitis

From Reuters Health Information

By David Douglas

NEW YORK (Reuters Health) Jan 13 - Research funded by the National Institutes of Health shows that rituximab is an effective treatment for refractory mixed cryoglobulinemic vasculitis in patients with hepatitis C.

"Unlike conventional forms of immunosuppressive therapy often used to treat this disease, rituximab was well tolerated and did not worsen the underlying viral hepatitis," said lead investigator Dr. Michael C. Sneller in email to Reuters Health.

Mixed cryoglobulinemic vasculitis is a relatively uncommon complication of hepatitis C virus (HCV) infection, as Dr. Sneller and his colleagues noted online December 6th in Arthritis & Rheumatism.

It's characterized by clonal expansion of B cells that produce IgM rheumatoid factor. The major manifestations are cutaneous vasculitis, arthralgia/arthritis, peripheral neuropathy, and membranoproliferative glomerulonephritis.

Pegylated interferon alpha and ribavirin can result in sustained remission, according to the researchers, but more than 50% of patients with HCV genotype 1, the most common in Europe and the Americas, do not respond.

Rituximab, however, can potentially deplete the expanded population of B cells - although there's been some concerns that it may increase HCV replication.

In an open label study, Dr. Sneller - based at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland - and colleagues randomly assigned 24 patients to four weekly infusions of rituximab, or to continue with best available therapy. Everyone in the trial had either failed attempts to control the lymphoproliferative disease with interferon alpha and ribavirin, or they were intolerant of those drugs.

Patients in the rituximab group could continue on their immunosuppressive medications, but they could not increase the dose or receive new immunosuppressants or plasma exchange.

In the control group, patients were maintained on their current regimen and were allowed to increase or initiate new immunosuppressive treatments as needed.

At six months, 10 of the 12 rituximab patients (83.3%) were in remission, compared to only one control subject (8%).

Of the two rituximab patients not in remission at that point, one had to withdraw after two infusions because of febrile reactions. The other was in remission at four months but subsequently relapsed.

There were no adverse effects in terms of viremia or transaminase levels.

The researchers conclude that rituximab can induce sustained remissions, and "was well tolerated and did not appear to increase HCV replication or worsen the underlying hepatitis."

Dr. Sneller added in his email: "Rituximab may be a safer, more effective alternative to standard immunosuppressive therapy for patients with HCV-associated cryoglobulinemic vasculitis in whom antiviral therapy was not effective."

SOURCE: http://bit.ly/zeAest

Arthritis Rheum 2012.

Source

Immunosuppression, Liver Injury and Post-transplant HCV Recurrence

From Journal of Viral Hepatitis

S. Ciesek; H. Wedemeyer

Posted: 01/17/2012; J Viral Hepat. 2012;19(1):1-8. © 2012 Blackwell Publishing

Abstract and Introduction

Abstract

Hepatitis C virus (HCV) infection is a major cause for liver transplantation worldwide. Still, HCV re-infection of the graft occurs in almost all cases. Most liver transplant recipients experience episodes of graft hepatitis associated with fibrosis progression and graft failure. Clinical management of graft hepatitis can be challenging as in addition to rejection and HCV-induced hepatitis various other factors might be involved including toxic liver injury, steatohepatitis, ischaemic bile duct lesions or infections with other pathogens. Treatment options are often contradictory for different causes of graft hepatitis, and the role of distinct immunosuppressive drugs has been discussed controversially. Corticosteroids increase the infectivity of HCV by altering expression levels of entry factors and other immunosuppressive agents may have diverse effects on HCV replication and fibrosis progression. Interferon alpha-therapy of hepatitis C shows limited efficacy and tolerability in liver transplant recipients and may also cause rejection. In this review we summarize the current knowledge on mechanisms of liver injury in post-transplant hepatitis C, discuss the pros and cons of immunosuppressive agents in this specific setting and describe potential novel approaches to prevent HCV reinfection.

Introduction

Around 160 million people are chronically infected with the hepatitis C virus (HCV), representing 2.2% of the world population.^[1,2] The geographic distribution of HCV-infected individuals varies largely between 0.1% in Northern Europe and up to 20% in Egypt.^[3–6] HCV is a highly variable enveloped RNA virus that infects hepatocytes. Based on sequence analyses, HCV can be grouped into seven different genotypes and more than 100 subtypes within the Flaviviridae family.^[7,8]

Patients with acute HCV infection stay asymptomatic in the majority of cases and fail to clear the virus spontaneously.^[9,10] Chronic hepatitis C can lead to hepatic inflammation, fibrosis, cirrhosis (10–20%) and hepatocellular carcinoma (HCC; 1–4% per year in cirrhotic patients).^[4,9,11] Until 2011 the standard of care for chronic HCV infection has been combination therapy with pegylated interferon alpha (PEGIFN-α) and ribavirin inducing a sustained virological response (SVR), i.e. HCV RNA negativity 6 months after completion of therapy,^[12] in 40–50% of patients infected with the most prevalent HCV genotype 1.^[13,14] Successful treatment is associated with an improved clinical long-term outcome even though HCC can still develop in cirrhotic patients after HCV has been eliminated.^[11,15] Very recently, two inhibitors of the HCV NS3/4A protease, boceprevir and telaprevir have been approved for the treatment of chronic hepatitis C. Triple therapy with a protease inhibitor, PEG-IFNa and ribavirin has substantially improved response rates now approaching 70%-80% for HCV genotype 1 infection.^[16]

HCV Recurrence After Liver Transplantation

Chronic infection with HCV is a major cause of end-stage liver disease and a leading indication for orthotopic liver transplantation (OLT) worldwide. However, re-infection of the graft by HCV particles present in the blood stream is almost universal and at least 25% of patients will develop liver cirrhosis after transplantation within 5–10 years.^[17,18] Once cirrhosis is established, transplanted patients show an accelerated natural history with decompensation rates of as high as 40% after 12 months.^[19] To date, there is no safe and effective way to prevent HCV recurrence. Moreover, patients with recurrent hepatitis can develop a severe cholestatic hepatitis C syndrome characterized by jaundice shortly after transplantation in the absence of biliary obstruction, particular high HCV RNA levels and a very high risk for liver failure.^[18] Subsequently, graft loss caused by recurrent HCV infection is the most important reason to consider re-transplantation. Some data suggest that the outcome of hepatitis C after liver transplantation has worsened during the last decades.^[20] Across different countries and transplantation programs, the 5-year post-transplantation survival rate for hepatitis C patients is significantly lower as compared to patients who underwent liver transplantation for other chronic liver diseases. Factors being associated with graft loss in HCV-infected patients included an older donor age, steatosis of the donor organ, specific immunosuppressive regimens (discussed later), female sex, a high necroinflammatory activity in the allograft 1 year after transplantation and high HCV viral loads (Table 1).^[21–23] In addition, several additional factors have been discussed to influence the long-term outcome of graft hepatitis C such as herpes virus infections,^[24] the degree of human leucocyte antigen (HLA) matching^[25] or the IL28b genotype of the donor and the recipient.^[26,27]

Cellular immune responses by both T cells and NK cells are thought to play a major role in the pathogenesis of chronic hepatitis C after transplantation. HCV-specific T-cell responses have been linked with improved histological and clinical outcomes^[28,29] and are also associated with spontaneous HCV clearance after liver transplantation.^[30] Genotypes of killer cell immunoglobulin-like receptors and their donor HLA ligands which determine NK cell activities may also play an important role in the recurrence and progression of hepatitis C in liver transplant recipients.^[31] An interesting study from Japan showed that adoptive immunotherapy 3 days after liver transplantation with activated lymphocytes extracted from the liver allograft perfusate can result in markedly reduced HCV RNA titres of the recipient confirming the importance of immune cells to control HCV infection after liver transplantation.^[32]

In general, HCV RNA levels are higher after OLT than before and high virus titres are associated with a worse long-term outcome of these patients.^[33] More specifically, serum HCV RNA levels increase rapidly from the second-week post-transplantation and peak by the fourth postoperative month. HCV RNA levels at 1 year after liver transplantation are 10- to 20-fold higher than pretransplant levels.^[34] Viral quasispecies composition differs after liver transplantation as compared to pretransplant sera^[35] and may also be involved in the long-term outcome of graft hepatitis.^[36] However, detailed mechanisms of how high viral loads and distinct viral compositions contribute to the accelerated disease progression in graft hepatitis C are still poorly defined.

Prevention of HCV Re-infection After Liver Transplantation

Considering the severe clinical course of post-transplant hepatitis C, one of the major unmet needs is the development of strategies to prevent re-infection of the liver graft after transplantation. Pretransplant treatment with PEG-IFNa and ribavirin of patients on the waiting list to prevent HCV reinfection is possible only in few individuals as PEG-IFNa treatment can induce severe infectious complications in decompensated liver disease.^[37,38] Moreover, no prophylactic vaccine is yet available to prevent HCV infection.^[39] Thus, alternative strategies to prevent HCV reinfection during or very early after transplantation should be explored.

In general, agents preventing viral cell entry should be of particular value (Fig. 1). These include antibodies against one or all essential HCV cellular entry factors, neutralizing antibodies against the HCV envelope proteins E1 and/or E2 envelope or drugs targeting HCV entry by interaction with the virion or a cellular entry factor.

Figure 1. Targets to prevent hepatitis C virus recurrence.

Four cellular factors have been described as essential for HCV entry: the tetraspanin molecule CD81, the scavenger receptor class B member I (SR-BI) and the tight junction proteins claudin-1 and occludin.^[40] Interestingly, neutralizing antibodies against CD81 are able to block HCV entry in vitro and also in immunodeficient mice transplanted with human hepatocytes, the best currently available small animal model of HCV infection.^[41] Anti-CD81 antibodies are currently in early clinical development but programs using antibodies against the other three entry factors are less advanced.

Neutralizing antibodies against the HCV envelope proteins E1 and E2 could also represent a promising approach to avoid HCV re-infection. However, efforts to elicit neutralizing antibody responses by immunization with E1E2 envelope proteins have had limited success. The main challenge here is the enormous genetic variability of the virus. Present within the chronically infected host is not a single isolate of HCV but rather a population of related yet different viral variants that has been referred to as a 'quasispecies swarm'. The swarm contains a vast repertoire of preformed variants that allow rapid escape from selective pressures such as neutralizing antibodies or anti-viral drugs. It has been shown that during chronic infection, HCV continuously escapes from the host's neutralizing antibody response.^[35,42] Nonetheless, efforts to target HCV glycoproteins continue and recently, Garrone et al.^[43] reported the development of a vaccine platform to generate HCV-neutralizing antibodies that are based on retrovirus-derived virus-like particles pseudotyped with heterologous E1 and/or E2 proteins. These particles induced neutralizing antibodies in mice and also in macaques and cross-neutralized other HCV genotypes. Overall, the application of broad cross-neutralizing anti-HCV antibodies to prevent HCV reinfection still seems to be reasonable approach. This strategy has been highly successful in hepatitis B virus infection where the combination of passive immunization with anti-HBs antibodies and HBV polymerase inhibitors is able to prevent HBV reinfections in all patients.^[44]

Another possibility to inhibit HCV entry is the development of small molecules targeting one of the four cellular entry factors. ITX 5061 is an orally bioavailable compound blocking the HCV receptor scavenger receptor BI protein.^[45] ITX-5061 had a good safety profile in animal toxicology studies and also in clinical studies. Currently, the potency of ITX-5061 is evaluated in an open-label, proof-of-concept Phase 1b study in liver-transplanted patients (http://www.clinicaltrials.gov).

Silibinin, a major component of silymarin, is a plant-derived compound that is used for the treatment of HCV infection although its precise mechanism of action is still not known in detail.^[46] In 2010, it was shown for the first time that high doses of intravenous silibinin monotherapy prevented graft re-infection after OLT in a patient with chronic hepatitis C^[47] which has been confirmed in another case report.^[48] However, a much larger controlled study is needed to verify that intravenous silibinin is indeed safe and effective to prevent HCV re-infection after liver transplantation.

Recently, two other already well-known molecules have been shown to inhibit HCV entry: the green tea catechin EGCG and the tyrosine kinase inhibitor erlotinib. Erlotinib blocks HCV entry by inhibition of the activity of the EGF-receptor which is required for formation of CD81-claudin-1 co-receptor associations.^[49] EGCG inhibits viral attachment to the target cell as well as cell-to-cell transmission between adjacent cells.^[50] Both drugs are already FDA approved for other clinical applications; and EGCG is known to be innocuous in humans, readily available and cheap. Both inhibitors may provide a new approach to prevent HCV infection in the setting of liver transplantation, and future clinical studies are needed to test these in vitro observations in patients.

Besides entry blockers, more advanced direct acting antivirals (DAA) targeting other phases of the replication cycle may also be useful to prevent HCV re-infection. However, almost all DAAs in development have only been tested in compensated chronic HCV infection and their role in the peri-transplant setting remains to be defined. Clearly, this is challenging as the peri-transplant population is more vulnerable. Rapid emergence of drug resistance will prevent monotherapy with certain classes of DAAs including HCV protease inhibitors.^[51] However, nucleoside or nucleotide analogous inhibiting the HCV polymerase as well as cyclophilin inhibitors show a very high resistance barrier and thus will likely be part of interferon-free regimens aiming to prevent HCV replication in the transplanted graft.^[16,52] Potential drug–drug interactions have to be considered as several DAAs in clinical development for HCV infection are metabolized via the cytochrome P450 3A4 and thus may interfere with immunosuppressive agents.

Thus, several approaches to prevent graft re-infection are currently being pursued. At this stage, no clear favourite has emerged and the goal to prevent HCV reinfection may well remain elusive for several years to come.

Treatment of HCV Re-infection After Transplantation

As long as no potent drugs or neutralizing antibodies are available to prevent HCV recurrence after liver transplantation, re-infection can still be treated with a combination of pegylated interferon alpha and ribavirin. However, the efficacy of this treatment is limited mainly by the poor tolerability in liver transplant recipients, and thus SVR rates are lower than in immunocompetent nontransplanted individuals.^[12] Overall, SVR rates after liver transplantation for HCV genotype 1 infection are around 25–30%.^[53] Furthermore, prolonged therapy seems to be required even in patients infected with the easier to treat genotypes 2 and 3 and extending antiviral therapy for more than 48 weeks might prevent virological relapse in many patients.^[54,55] IL28B genotypes of both the donor and the recipient are associated with response to PEG-IFNa-based treatment after liver transplantation, and determination of the IL28b genotype may therefore be useful in clinical practice to decide which patient should receive antiviral therapy.^[27] Importantly, successful treatment reduces liver-related complications in recurrent HCV infection.^[56]

Even though interferon alpha can be beneficial for many patients, it has to be considered that antiviral therapy can promote rejection especially in the early phase after transplantation.^[57] Thus, liver transplant recipients receiving standard antiviral therapy need to be monitored for acute cellular rejection and chronic ductopenic rejection. In addition, de novo autoimmune hepatitis may develop and immunological phenomena may even occur after treatment has been stopped. As the clinical course of HCV infection is largely influenced by co-factors, it is of particular importance in liver transplant recipients to avoid co-morbidities including ischaemic-type bile duct lesions and liver steatosis.

The use of the novel NS3/4A protease inhibitors seems to be limited in patients after liver transplantation as it has been shown that telaprevir increases tacrolimus blood levels by approximately 70-fold – precluding its use outside of clinical trials.^[58] Co-administration with telaprevir also affected cyclosporine exposure and cyclosporine half-life, but to a lesser extent. No data on drug–drug interactions between calcineurin inhibitors (CNI) and boceprevir are currently available. Clinical trials are under way to determine the safety of efficacy of triple therapy of hepatitis C in liver transplant recipients. Whether combinations of PEG-IFNa with other NS3/4A protease inhibitors or with calcineurin inhibitor-free immunosuppressive regimens are feasible remains to be determined.

Currently, more than 100 novel HCV inhibitors are under preclinical and clinical investigation. These can broadly be divided in direct antiviral agents (DAA) and host factor targeting antivirals (HTA).^[59] While DAAs target the virus directly and include NS3/4A protease inhibitors (first & second generation), NS5B polymerase inhibitors and NS5A inhibitors, HTAs target essential cellular factors like cyclophilin A, microRNA122 and CD81 antibodies. Disadvantages of some but not all DAA classes are that they are not effective against all HCV genotypes and that viral resistance is anticipated to become a major problem. HTAs may show broad activity across HCV genotypes and pose a higher barrier to drug resistance in comparison with DAA.^[16] It is expected that some of the novel drugs will reach the market in 2015; however, none of the new anti-HCV drugs are currently being evaluated in HCV-infected liver transplant recipients. The ultimate goal will be to introduce safe interferon-free combination therapies without significant drug–drug interactions leading to cure from HCV infection within a limited time frame.

Immunosuppression and Graft Hepatitis C

As HCV re-infection cannot be prevented and curative treatment is unsuccessful in the majority of cases, the question arises whether there are ways to optimize post-transplant management, most notably the immunosuppressive regimen used, to minimize the risk of transplant hepatitis and graft loss. Advances in the development of novel immunosuppressive drugs have resulted in an improved clinical outcome after transplantation and transformed liver transplantation into a routine clinical procedure with overall reasonable long-term results. However, individualization of immunosuppressive therapy owing to the underlying disease is still a major goal to enhance graft survival especially in HCV-positive individuals. Furthermore, it has been suggested that the type of immunosuppressive therapy might be responsible for the worse outcome of HCV-positive individuals after liver transplantation observed in recent years.^[60]

Calcineurin inhibitors form the backbone of immunosuppression in the majority of liver transplant recipients. The discovery of CNI in the early 1970s and the FDA approval of cyclosporine A (CsA) in 1983 were major milestones for the immunosuppressive management of transplant recipients and increased 1-year graft survival rates from 24% in the late 70s to up to 60% in the 80s.^[61] Two CNIs, tacrolimus (Tac) and CsA, are currently approved for immunosuppression after liver transplantation. There is a large experience with both compounds and some differences in efficacy and the side effect profile became evident over the years. Therapy with Tac is associated with a higher incidence of post-transplant diabetes mellitus, while CsA treatment leads more frequently to dyslipidaemia, hypertension, hirsutism and gingival hyperplasia.^[62] Tacrolimus treatment may also cause more often hearing impairments, which is a common phenomenon in liver-transplanted patients.^[63] Tac is about 100 times more potent than CsA and exerts its action by binding to the FK binding protein 12 (FKBP12), while CsA binds to cyclophilins (e.g. cyclophilin A). Importantly, both of these complexes inhibit calcineurin, a pivotal enzyme in T-cell receptor signalling and activation, which dephosphorylates the transcription factor NF-AT (nuclear factor activating T cell). NF-AT regulates the activity of genes coding for IL-2 and other cytokines in T cells^[62] and thus inhibition of calcineurin prevents T-cell activation. Effects on other immune cells have also been noted, e.g. the function of regulatory T cells may be altered by both CsA and Tac.^[64]

Cyclophilin A, the target protein of CsA, is not only involved in T-cell activation but also serves HCV as an essential host factor for viral replication.^[65] For this reason, CsA very efficiently suppresses HCV RNA replication in vitro. In contrast, treatment with Tac has no effect on HCV RNA levels.^[66] This observation has led to the clinical development of non immunosuppressive CsA analogues for the treatment of HCV infection. The cyclophilin A inhibitor alisporivir is currently the most advanced HTA in development, phase II studies have shown good efficacy and very low rates of viral resistance^[52,67] and phase III studies for the treatment of chronic hepatitis C patients are ongoing. While alisporivir seems promising in the nontransplant population, the antiviral effect of CsA did not lower HCV viremia in patients after liver transplantation^[68] or in a humanized mouse model.^[69] Even though, some earlier studies suggested that immunosuppression with cyclosporine might be associated with a better histological outcome of graft hepatitis C.^[70] However, the far majority of several subsequent studies did not identify major differences between CsA and Tac in the outcome of HCV infection after liver transplantation as nicely summarized by Berenguer et al. already in 2007.^[71] Conversely, a recent retrospective study with more than 8000 HCV-positive liver-transplanted individuals showed that patient death, graft failure, failure owing to recurrent disease and acute cellular rejection were slightly enhanced in the CsA-treated group in comparison with the Tac group.^[72] These results may cast doubt on the targeted long-term administration of CsA to HCV-infected liver transplant recipients. However, as part of strategies to avoid HCV re-infection, it might be helpful to employ a CsA-based immunosuppressive regimen in the early phase after transplantation as CsA has a clear additive antiviral effect in vitro.^[73] Moreover, some studies suggested that immunosuppression with CsA enhances SVR rates in liver transplant patients treated with interferon alpha and ribavirin.^[53,74] Finally, CsA may have advantages concerning drug–drug interactions if novel HCV protease inhibitors are explored as CsA drug levels were less affected than Tac levels when co-administered with telaprevir.^[58]

Besides the question of the optimal CNI for HCV-positive liver transplant recipients, the use of steroids after transplantation of HCV patients has been a matter of debate for several years. While it is widely accepted that steroids should be avoided in individuals with HBV infection after liver transplantation, conflicting data have been published for hepatitis C. Clearly, repeated administration of high doses of corticosteroids to treat rejection is associated with more rapid fibrosis progression and poor long-term outcome of graft hepatitis C.^[75] Several studies confirmed that there is a strong correlation between steroid bolus therapies of acute rejection episodes and severe recurrence of hepatitis C.^[76–78] Moreover, an interim analysis of the American HCV-3 study showed that a steroid-free immunosuppression regime was superior to steroid containing regimes regarding fibrosis progression which is in line with European experience demonstrating that immunosuppression without steroids reduces bacterial infections and improves histological short-term evolution of HCV recurrence.^[79] Besides the immunosuppressive effects of glucocorticoids, a recent in vitro study has revealed a direct stimulation of HCV infection by steroids. This was mediated through an upregulation of SR-BI and occludin, two crucial HCV entry factors, suggesting a novel direct mechanism of steroid-dependent exacerbation of HCV infection after liver transplantation.^[66] Taken together, it is widely accepted that immunosuppressive regimens after liver transplantation for hepatitis C should avoid steroid boli therapies, if possible. Overall, immunosuppression without steroids is safe after liver transplantation and has been shown to reduce infectious and metabolic complications. However, low-dose corticosteroids may not necessarily have to be avoided in HCV infection after liver transplantation. If steroids are used, slow rather than rapid tapering should be preferred.^[80]

The impact of other immunosuppressive agents including mycophenolate mofetil, azathioprine or interleukin-2 inhibitors on HCV recurrence remains controversial. For all of these drugs, conflicting studies have been published indicating both positive and negative effects on the course of HCV re-infection after transplantation. However, large high-quality prospective studies with a long-term follow-up are lacking. Thus, no recommendation can be given at this stage for preferential usage or avoidance of any of these compounds in the context of graft hepatitis C.

Conclusion

Prevention and treatment of HCV re-infection after liver transplantation remains a major unsolved clinical challenge. HCV-positive patients have poorer long-term outcomes after liver transplantation in comparison with patients with other underlying liver diseases. While treatment with pegylated interferon alpha and ribavirin can cure up to one-third of HCV-positive liver-transplanted patients, there are many promising drugs in clinical and preclinical development targeting either the virion or essential host factors. Strategies to prevent HCV re-infection include neutralizing antibodies or drugs targeting cellular HCV entry factors. Unfortunately, it will take at least several years until most of these drugs will reach routine clinical practice. Immunosuppressive medications may alter the course of hepatitis C after transplantation but conclusive data on the use of distinct regimens for HCV-infected transplant recipients are lacking. Thus, almost 30 years after the approval of the first calcineurin inhibitor and 23 years after the discovery of HCV, the optimal immunosuppressive strategy in HCV-positive liver transplant recipients still remains to be defined. However, acute rejection episodes and the need for steroid boli should be avoided as steroid bolus treatment is associated with reduced graft and patient survival and increase HCV infectivity.

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