Mature liver cells may be better than stem cells for liver cell transplantation therapy

Contact: David Eve
celltransplantation@gmail.com

Cell Transplantation Center of Excellence for Aging and Brain Repair

Mature liver cells may be better than stem cells for liver cell transplantation therapy

Tampa, Fla. (June 4, 2012) – After carrying out a study comparing the repopulation efficiency of immature hepatic stem/progenitor cells and mature hepatocytes transplanted into liver-injured rats, a research team from Sapporo, Japan concluded that mature hepatocytes offered better repopulation efficiency than stem/progenitor cells.

Until day 14 post-transplantation, the growth of the stem/progenitor cells was faster than the mature hepatocytes, but after two weeks most of the stem/progenitor cells had died. However, the mature hepatocytes continued to survive and proliferate one year after their implantation.
The study is published in Cell Transplantation (21:1), now freely available on-line at http://www.ingentaconnect.com/content/cog/ct/.

"Cell-based therapies as an alternative to liver transplantation to treat liver disease have shown promise," said study corresponding author Dr. Toshihiro Mitaka of the Cancer Research Institute of the Sapporo Medical University School of Medicine, Sapporo, Japan. "However, the repopulation efficiency of two candidate cell sources - hepatic progenitor/stem cells and mature hepatocytes - had not been comprehensively assessed and questions concerning the efficiency of each needed to be resolved."

The researchers noted that the shortage of cell sources and the difficulties of cryopreservation have limited the clinical application of cell based therapies. Stem or progenitor cells have been considered candidate cells because they can expand in vitro and can be cryopreserved for a long time.
However, after transplantation into liver injured rats, the researchers found that stem/progenitor cells did not survive well and most of the transplanted cells had disappeared within two months. In contrast, the mature hepatocytes gradually repopulated the rat livers and continued doing so past one year.
The researchers noted that the sizes of the hepatocytes were not uniform.

"Unexpectedly, the small hepatocytes repopulated significantly less well than the larger ones," explained Dr. Mitaka. "We also found that serial transplantation did not enhance nor diminish the repopulation capacity of the cells to any significant degree."

The researchers concluded that because the stem/progenitor cells had died much earlier than the mature hepatocytes, most were immediately excluded from the host livers, reducing their potential impact on liver generation.

"Further experiments are required to clarify the mechanism by which this might occur," concluded the authors.

"This study suggests that mature hepatocytes may be a better treatment option than stem cells" said Dr. Stephen Strom of the Karolinska Institute, Sweden and section editor for Cell Transplantation. "However, determining the factors that allow for the survival and continued growth of the stem/progenitor and mature hepatocytes could be relevant for future improvements of hepatocyte transplantation in the clinic".

###

Contact: Toshihiro Mitaka, MD, PhD, Department of Pathophysiology, Cancer Research Institute, Sapporo medical University School of medicine, South-1, West-17, Chou-ku, Sapporo 060-8556, Japan
Tel. +81-11-611-2111 ext. 2390
Fax. +81-11-615-3099
Email tmitaka@sapmed.ac.jp

Citation: Ichinohe, N.; Kon, J.; Sasaki, K.; Nakamura, Y.; Ooe H.; Tanimizu, N.; Mitaka, T. Growth ability and repopulation efficiency of transplanted hepatic stem cells, progenitor cells, and mature hepatocytes in retrorsine-treated rat livers. Cell Transplant. 21(1):11-22; 2012.

The Coeditor-in-chief's for Cell Transplantation are at the Diabetes Research Institute, University of Miami Miller School of Medicine and Center for Neuropsychiatry, China Medical University Hospital, TaiChung, Taiwan. Contact, Camillo Ricordi, MD at ricordi@miami.edu or Shinn-Zong Lin, MD, PhD at shinnzong@yahoo.com.tw or David Eve, PhD at celltransplantation@gmail.com
News release by Florida Science Communications

Former CRO Employee Stole Merck Compounds

Former CRO Employee Stole Merck Compounds

By Ed Silverman // June 4th, 2012 // 11:05 am

Last month, a court in Shanghai convicted a former employee of WuXi PharmaTech, a contract research organization with operations in the US and China, of stealing samples of two different Merck compounds that were being tested in Chinese facilities.......... 

The reports indicate that he stole small quantities of MK-3102, a GLP-1 inhibitor that is being developed to treat diabetes, and MK-5172, which is being devloped to combat hepatitis C, both of which were in Phase II testing as of last fall, according to the Merck pipeline (read here). After the thefts, Xiao offered them for sale on the Internet, which Merck later discovered. The thefts took place last year, although were apparently not disclosed until the recent sentencing.........

Continue Reading @ Pharmalot

Partner? Pretty Please? Gilead-GS-7977 and Bristol's -Daclatasvir

Partner? Pretty Please?
By Brian Orelli, The Motley Fool
Posted 7:42PM 06/01/12 Posted under: Investing

Bristol-Myers Squibb (NYS: BMY) CEO Lamberto Andreotti might call it a difference in opinion about how to proceed, but it's looking a lot more like a difference in pipelines.

Andreotti reportedly told investors at a conference yesterday that Bristol was still interested in continuing the development of its hepatitis C drug, daclatasvir, in combination with Gilead Sciences (NAS: GILD) GS-7977, but that Gilead isn't willing to play ball.

The combination produced beautifully in a phase 2 trial with early cure rates between 91% and 100%, depending on the strain of virus. Some of those patients might relapse, but considering the combination doesn't require Merck's (NYS: MRK) PegIntron or Roche's Pegasys, which have to be injected and carry unpleasant side effects, it's still outstanding data.

Why doesn't Gilead want to continue, then? The biotech has a drug, GS-5885, which is in the same class -- NS5A inhibitor -- as daclatasvir. Given the similarities, Gilead hopes to jump straight into phase 3 trials, testing GS-7977 with GS-5885. (Wonder if they'll call it GS-13862.) Assuming the in-house combo works, Gilead will get to keep all the revenue from the treatment rather than having to share it.

Bristol has a drug, INX-189, which it now calls BMS-986094, in the same class as GS-7977, from the acquisition of Inhibitex. I haven't seen any data combining the two, but Bristol's public announcement of its desire to partner with Gilead makes you think that there might be something wrong with BMS-986094. Of course, Johnson & Johnson (NYS: JNJ) agreed to test its hepatitis C drug TMC435 with BMS-986094, so there's at least one company that thinks it's a viable drug.

At this point it looks like Gilead has the upper hand in negotiations, especially as Bristol hasn't been playing its cards very close to its vest. If Bristol really wants to develop a combination of GS-7977 and daclatasvir, it'll probably have to give up some of the economics on the combination drug. If BMS-986094 turns out to be a $2.5 billion blunder, accepting only 30% to 40% of a joint venture wouldn't be the end of the world.

David Gardner and his team at Rule Breakers aren't counting on alliances to get solid returns from one of their recent health-care picks. Find out what it is and why they like it in the Fool's free report, "Discover the Next Rule-Breaking Multibagger."


At the time this article was published Fool contributor Brian Orelli holds no position in any company mentioned. Check out his holdings and a short bio. The Motley Fool owns shares of Johnson & Johnson. Motley Fool newsletter services have recommended buying shares of Johnson & Johnson and Gilead Sciences and creating a diagonal call position in Johnson & Johnson. The Motley Fool has a disclosure policy. We Fools don't all hold the same opinions, but we all believe that considering a diverse range of insights makes us better investors. Try any of our Foolish newsletter services free for 30 days.
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http://www.dailyfinance.com/2012/06/01/partner-pretty-please/

N.H. among few with no mandate to report hepatitis C

N.H. among few with no mandate to report hepatitis C

By JIM HADDADIN jhaddadin@fosters.com

Sunday, June 3, 2012

EXETER — When he announced last week that an outbreak of hepatitis C at Exeter Hospital is the first of its kind in New Hampshire, the state's top public health official included one noteworthy caveat.

Exeter Hospital was forced to temporarily halt operations at its cardiac catheterization laboratory last month after discovering four cases of hepatitis C with a possible link to the lab.

Discussing the development at a press conference on Thursday, May 31, Public Health Director Dr. Jose Montero said it's impossible to judge with certainty whether the situation at Exeter Hospital is unprecedented in New Hampshire.

That's because unlike a majority of other states, New Hampshire does not require hospitals, labs and medical clinics to report new cases of hepatitis C.

States have autonomy to set their own regulations for disease reporting, and the list of reportable diseases differs across the country, according to the Centers for Disease Control and Prevention.

New Hampshire law specifies about 75 reportable diseases, including tetanus, mumps, rabies and some sexually transmitted diseases.

The virtue of collecting disease data is that it can be used to spot trends, detect unusual clusters and measure the effectiveness of prevention efforts. Notifications also help local health officials identify people at risk of infection.

When the New Hampshire Department of Health and Human Services learns of a new case of measles, for example, staffers interview the family of the patient, contact physicians and reach out to the patient's classmates.

But when it comes to hepatitis C, New Hampshire has among the most lax reporting requirements in the country, according to both Montero and information from the Council of State and Territorial Epidemiologists.

In 2010, CSTE conducted a survey of state epidemiologists to learn how each state handles disease reporting.

The results showed 46 states require all medical clinics, hospitals and laboratories to report acute cases of hepatitis C to local health officials.

Of the remaining four states, California and Alaska exempt only hospitals from the requirement. North Carolina exempts hospitals and laboratories, but requires reporting from clinics.

However, New Hampshire is an outlier. It doesn't require any medical provider to provide information about new hepatitis C cases unless an outbreak is confirmed.

Under state law, any "outbreak, cluster of illness, or unusual occurrence of disease" that poses a public health concern must be reported to the state within 24 hours.

One of the reasons hepatitis C hasn't been categorized as a reportable disease in New Hampshire is the added administrative burden and cost of taking in reports, Montero said. Another is the fact that the effectiveness of hepatitis C monitoring remains in dispute.

Since many people who are infected with the virus develop symptoms only weeks, or years, after contracting the virus, Montero said it can be tricky to pinpoint when or how someone contracted hepatitis C.

However, monitoring individual cases could have benefits. Montero said the state could be missing opportunities to target prevention efforts, like outreach around safe needle use.

In Massachusetts, Maine and Vermont, hepatitis C reporting is already mandatory.

Sheila Pinette, director of the Maine Centers for Disease Control and Prevention, said a dedicated staff member is assigned to investigate new cases of hepatitis and STDs.

When the state receives a report of a diagnosis, state officials make contact with the patient's primary care physician and investigate any potential risk posed by the disease.

That includes interviewing the patient about past sexual partners and recommending for the patient to get tested for HIV, since the condition often coexists with hepatitis C.

Vermont State Epidemiologist Patsy Kelso said hepatitis C is one of the most commonly reported viral diseases in the state, and requires "a good deal of effort" on the part of state health officials.

Vermont does not follow up with each patient diagnosed with hepatitis C, but Kelso said staffers try to identify patients who are younger than 25 or older than 65.

People younger than 25 are more likely to have been infected recently, and can help to identify points from which the disease is being spread, Kelso said.

For the past several months, New Hampshire public health officials have been holding discussions about whether to add hepatitis C and a number of other diseases to the list of reportable diseases as part of a regular review, Montero said.

If the Division of Public Health Services recommends placing hepatitis C on the reportable diseases list, the proposal would also need approval from a committee of lawmakers.

"We are reviewing that specific point over the next several months," Montero said, "and certainly outbreaks like this offer more information on what we are doing and may trigger a different decision."

http://www.fosters.com/apps/pbcs.dll/article?AID=/20120603/GJNEWS_01/706039911/-1/FOSNEWS

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Quality of life factors are reduced in patients with Hepatitis B

Reference: Wang, L., et al., Quality of life and the relevant factors in patients with chronic hepatitis B. Hepatogastroenterology, 2012. 59(116): p. 1036-42.

A little bit different of an article that I am used to publishing on this blog, but I like difference. Here is a study quantifying the quality of life factors for patients with Hepatitis B. I can’t tell you how much fun I had reading this article!

Brief Summary:
Hepatitis B is an infectious inflammatory disease of the liver caused by the Hepatitis B virus. Currently, little is known regarding the health-related quality of life (HRQL) factors which are affected by Hepatitis B. The main objective of this study was to access the HRQL factors for patients with Hepatitis B. The HRQL factors were physical functioning (PF), role physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role emotional (RE) and mental health (MH) from the Chinese version of the medical outcomes study 36-Item Short-Form health survey. A total of 407 patients were accrued into the study, and they were compared to a literature based control group. Secondary objectives were to ascertain the effect of genotype differences in the ACE and DRD4 genes on the HRQL factors, and also to study the effect of anti-viral therapies on some of the HRQL factors. These factors included physiology function (PHD) and psychology function (PSD)

Results:

The HRQL factors were significantly lower for the patients with Hepatitis B compared to the literature-based control group, and they were lower for all 8 previously mentioned factors. Furthermore, the genotype of the ACE and DRD4 genes were found to be associated with HRQL, and the anti-viral therapies were found to improve several HRQL factors which included physiology function and society function. Other therapies (hepatoprotective, jaundice eliminating and supportive treatment ) were not shown to add an improvement.

Implications for Practice:

Patients with Hepatitis B have significantly lower quality of life factor scores. If the Hepatitis B patient has a highly negative physiology function psychology function, then anti-viral therapies can help improve these quality of life factors.

Discussion:

I found it really interesting how genotype can have such a drastic effect on the quality of life factors. I imagine this relationship would hold for other types of Gastroenterology based diseases as well. Just very fascinating.

In the discussion, the authors stated that clinical therapy has a minimal effect on the emotional state of a patient Hepatitis B. Rather, family and community care are more effective than any therapy at increasing the quality of life. All of this is probably true, and I’ve seen some past quality of life studies say the same thing.

Commentary on Statistics and Study Design:

Overall, the statistical analysis was very good. I like how the author’s performed both a uni-variate and multi-variate analysis between the factors and the main response variable which was the HRQL scores. Since the version I read was not in current print, I could not see the figures, but I assume that both the uni- and multi- variate analysis was shown. Also, it was good that the author’s pointed out the limitation with using a literature-based control group. This is a definite limitation. I didn’t see a sample size for the control group, but I’m assuming it was rather large, so this technique should have been fine.

My one major suggestion would be in the interpretation of the coefficients. I am assuming that the multi-variate table (which again, I couldn’t see) included the coefficients from the multi-variate analysis. If it did not, then it needs to be there, and there should be an explicit and detailed explanation of the coefficients. For instance, if the coefficient is -20.0 for one of the factors (let’s say physical functioning), then an explicit interpretive statement needs to be stated such as “this coefficient means that the patients in the Hepatitis B group had a physical functioning quality of life score that was 20 less those patients in the control group, and this coefficient is significantly different than 0.0.” This type of explicit and descriptive statement can really help out your non-statistician tremendously, and remember, your average Joe doctor is not a statistician.

Other than that, everything looks good. I assume the sample size was good enough.

It was good to read a paper way over in China. Thanks!
.   

About the Author

Chad, PhD (Translational Bioinformatics, University of Pittsburgh), combines his love and expertise of statistics, study design and medical research to produce for you “TheGastroenterologyBlog.” Chad hopes that this resource can be helpful for both Gastroenterologists and statisticians alike.

Poor awareness of infection among individuals testing positive for HCV

Poor awareness of infection among individuals testing positive for HCV

A study in the most recent issue of Hepatology examines awareness of infection, knowledge of hepatitis C, and medical follow-up among individuals testing positive for hepatitis C.

Many persons infected with hepatitis C virus (HCV) are unknown to the healthcare system because they may be asymptomatic for years, have not been tested for HCV infection, and only seek medical care when they develop liver-related complications. Dr Maxine Denniston and colleagues from Georgia, USA analyzed data from persons who tested positive for past or current HCV infection during participation in the National Health and Nutrition Examination Survey (NHANES) from 2001 through 2008. A follow-up survey was conducted 6 months after examination to determine how many participants testing positive for HCV infection were aware of their HCV status before being notified by NHANES. 80% indicated they had seen a doctor about their first positive HCV test result Hepatology The researchers investigated what actions participants took after becoming aware of their first positive test, and participants' knowledge about hepatitis C. Of 30,140 participants tested, 1% had evidence of past or current HCV infection, and 43% could be contacted during the follow-up survey and interviewed. Only 50% were aware of their positive HCV infection status before being notified by NHANES, and only 4% of these respondents reported that they had first been tested for HCV because they or their doctor thought they were at risk for infection. The team observed that 85% had heard of hepatitis C. Correct responses to questions about hepatitis C were higher among persons 40-59 years of age, white non-Hispanics, and respondents who saw a physician after their first positive HCV test. The researchers noted that 80% of respondents indicated they had seen a doctor about their first positive HCV test result. Dr Denniston's team commented, "These data indicate that fewer than half of those infected with HCV may be aware of their infection." "The findings suggest that more intensive efforts are needed to identify and test persons at risk for HCV infection." Hepatology 2012: 55(6): 1652–1661 04 June 2012

Future hepatitis cure rates expected to soar

Future hepatitis cure rates expected to soar

After “astonishing” preliminary results from new drugs

EMBARGOED to 0001 AEST Monday, 4 June

4 June, 2012 in Centenary, Media releases

As the burden of Hepatitis C (HCV) associated liver failure and liver cancer rises in our community so hepatitis C therapy is undergoing radical and rapid change, says Centenary’s Prof Geoff McCaughan.

A review has shown how the next generation drugs telaprevir and boceprevir, approved by the TGA in 2011 for use by patients with the most common genotype 1 of the blood-borne viral infection, are significantly improving outcomes for patients living with hepatitis C.

The review, published in the Medical Journal of Australia (MJA) today (Monday, June 4), describes how these drugs, when used in conjunction with existing therapy, boost the percentage of patients who clear the virus from 45% to 70%.

Not only do the new drugs allow more patients to be cured, they also work much faster than conventional therapy. The review indicates that adding the drugs to conventional therapy allowed treatment times to be halved, from 12 months to 6 months, for around half of the patients without impacting on outcomes.

Prof McCaughan, writing in an MJA editorial published in today’s MJA, said progress in the field is astonishing.

There are also even newer kinds of drugs coming down the development pipeline.

“It seems likely that, within five years, we will have short-duration anti-hepatitis C therapy with minimal side-effects and cure rates above 90%,” said Prof McCaughan, who is head of the Liver Injury and Cancer group at the Centenary Institute and a physician based at Sydney’s Royal Prince Alfred Hospital.

“The challenge then will be how we can deliver such therapies to the 200,000 Australians with hepatitis C infection.”

Treatment times could be wound in to three months with further advances, Prof McCaughan said.

He said the long duration, side-effects and uncertain outcomes of conventional hepatitis C therapy see many people go without treatment.

Among patients with chronic infections, it is thought just 2% per year are receiving the antiviral therapy which could stop them from progressing to end-stage liver disease.

“… by moving hepatitis C treatment from hospital clinics into the community these new therapies will potentially reduce stigma and may stimulate increased testing and treatment for hepatitis C infection,” Prof McCaughan said.

“Short treatment duration, high cure rates and low toxicity will mean that all hepatitis C-infected patients should eventually receive curative therapy.”

Professor McCaughan is Assistant Director of the Centenary Institute and head of the Institute’s Liver Injury and Cancer program. He is also Director of the Australian National Liver Transplant Unit at Royal Prince Alfred Hospital.

He is available for media interviews on Sunday 3 and before 0800 and after 1100 on Monday June 4.

For interviews contact:

• Suzie Graham, the Centenary Institute, 0418 683 166, s.graham@centenary.org.au
• Or Niall Byrne, Science in Public for Centenary, 0417 131 977, niall@scienceinpublic.com.au

Paper online at: https://www.mja.com.au/journal/2012/196/10/end-chronic-hepatitis-c-virus-infection-sight (MJA paywall).

Background information

What is hepatitis C?
Hepatitis C is a blood-borne viral disease transmitted mainly by injection with infected needles. While the condition can eventually lead to serious liver disease such as cirrhosis, liver cancer and liver failure, many patients with hepatitis C do not display symptoms until their liver starts to fail, which can be up to 15 years after the virus was first contracted.
Hepatitis C is a serious problem. At present, of about 220,000 Australians thought to be infected by hepatitis C, nearly a quarter are already suffering moderate to severe liver disease. But fewer than one in fifty is treated each year, and about 11,000 new cases are diagnosed annually.
Unlike hepatitis A and B, there is no vaccine for hep C, making any improvements in treatments even more important. At present the disease is overwhelmingly associated with intravenous drug use, but in the past poor infection control during blood transfusions has also been to blame.

What happens if chronic hepatitis C infection is not treated
People with chronic hepatitis C infection who do not receive treatment can progress to liver cirrhosis and, ultimately, liver failure placing them in need of a life-saving liver transplant.
These patients face a long waiting list and a tight supply of livers suitable for transplant. Many do not survive the wait.

Liver cirrhosis is also responsible for 90% of liver cancer cases and ranks #8 overall in causes of death in the world. In Australia, the rate of liver cancer has increased 4-fold in the past 20 years and liver cancer is the 3rd leading cause of cancer deaths in the world. Sadly, this trend is expected to continue.

Conventional treatment for hepatitis C
There is no vaccine for Hepatitis C and existing treatment is expensive, prolonged, has many side effects and is not largely successful. The existing therapy uses two drugs – ribavirin and pegylated interferon.

The hope is to develop new Hepatitis C anti-viral therapies that do not involve interferon, as this accounts for many of the side-effects of conventional treatment. The arrival of new direct-acting agents to target hepatitis C supports this aim

New drugs for hepatitis C
The new drugs, boceprevir and telaprevir, are the first in a new class of direct antiviral agents which target hepatitis C.

The drugs have been approved by Australia’s Therapeutic Goods Administration (TGA) so far for treatment of adults with chronic hepatitis C genotype-1 who are previously untreated or have failed previous treatment.

Patients receive the new drugs for the first 12 weeks of either a 24 or 48 week drug regimen that still includes the current Standard of care drugs Interferon and Ribavarin. Both boceprevir and telaprevir d are awaiting listing on the Pharmaceutical Benefits Scheme.

In the US at present a course of the new treatment costs between $45,000 and $85,000, but that’s a lot less than the estimated $130,000 plus $15,000 a year in therapy for a liver transplant.
Preliminary results in small numbers of patients however indicate that even newer drugs directed against different parts of the hepatitis C can be used without Interferon .These drugs seems to have low side effects , can cure patients in up to 90% of cases and only require 3-6 months of therapy. How they will be used in combination is currently under study in many world-wide clinical trials.

About Professor Geoffrey McCaughan
Professor McCaughan can provide expert comment liver disease, liver cancer and transplantation, gastroenterology and hepatitis. His titles are:
Assistant Director of the Centenary Institute
Head of the Institute’s liver injury and cancer program
Director of the Australian National Liver Transplant Unit at Royal Prince Alfred Hospital

About the Centenary Institute
The Centenary Institute is an independent leader in medical research seeking improved treatments and cures for cancer, cardiovascular, autoimmune, liver, genetic and infectious diseases. We are working to discover new prevention, early diagnosis and treatment options to enable each generation to live longer, healthier lives than the one before. Centenary’s affiliation with the RPA Hospital and the University of Sydney means that our discoveries can be quickly applied to the fight against disease in the clinic. More at: http//www.centenary.org.au

http://www.scienceinpublic.com.au/

The changing therapeutic landscape for hepatitis C

The changing therapeutic landscape for hepatitis C

Gregory J Dore

Med J Aust 2012; 196 (10): 629-632.

doi: 0.5694/mja11.11531

Download PDF
Received 29 Nov 2011, accepted 5 Mar 2012

Summary

• The next decade will be a crucial period in the public health response to hepatitis C virus (HCV) infection.
• The rapid development of direct-acting antiviral therapy for HCV infection has brought considerable optimism to the HCV sector, with the realistic hope that therapeutic intervention will soon be more effective and offer shorter treatment duration.
• The initial phase of combination pegylated interferon, ribavirin and a protease inhibitor will be associated with increased toxicity and complexity of therapeutic management but, over the course of the decade, strategies including interferon-free combination direct-acting antiviral regimens with enhanced tolerability and simplified dosing schedules and monitoring protocols will emerge.

Hepatitis C virus (HCV) infection progresses to chronic HCV in around 75% of cases,1 with the resultant risk of progressive liver fibrosis, cirrhosis and hepatocellular carcinoma. Around 20%–30% of people with chronic HCV will develop cirrhosis, generally following at least 20–30 years of infection.2 The large pool of chronic HCV in Australia (220 000)3 and the “ageing cohort” effect of this population related to high incidence of injecting drug use-acquired infection in the 1980s and 1990s means that the already escalating rates of HCV-related cirrhosis, liver failure and hepatocellular carcinoma are projected to further increase over the next two decades.4

Combined pegylated interferon (PEG-IFN) and ribavirin (RBV) treatment leads to a sustained virological response (SVR, equivalent to cure of infection) in around 50%–60% of people with chronic HCV, but treatment uptake remains low (3500–4000 people per year).5 Several factors contribute to low HCV treatment rates, including toxicity of interferon-based therapy, prolonged course of treatment (24–48 weeks), social marginalisation of many people with chronic HCV infection, lack of treatment infrastructure (particularly in opiate pharmacotherapy, prison, community health, and primary care settings), and lack of awareness of the curative potential of treatment.

Poorer HCV treatment responses in those with advanced liver disease also limit the impact on disease burden.

Fortunately, a revolution in HCV treatment is fast approaching, with the advent of direct-acting antiviral (DAA) therapy and the move towards interferon-free regimens.6 Before the end of this decade, simple (single daily dosing oral regimens), tolerable, short-duration (6–24 weeks) therapy with extremely high efficacy (cure rates above 90%) should be the norm for the HCV-infected population. The broad implementation of such therapeutic regimens has the potential to produce one of the major turnarounds in disease burden seen in public health and clinical medicine.

This review will cover major recent developments in DAA therapy for chronic HCV, present challenges that will be evident in the initial clinical use of HCV protease inhibitors, and provide an opinion on how the many DAA agents currently in development may be used in future therapeutic strategies.

HCV life cycle and DAA therapy classes

As the HCV viral life cycle has been more fully elucidated (Box 1),7 rational drug design has been used to identify small molecule inhibitors of various HCV proteins involved in HCV replication: (i) NS3/4A protease, which is involved in post-translation processing of HCV polyproteins; (ii) NS5B RNA-dependant RNA polymerase that is required for copying the HCV RNA genome and transcribing mRNA; and (iii) NS5A enzyme, which like the two previous target enzymes is involved in HCV viral replication, although its functions are somewhat less clear.

Employing drug development strategies similar to those used for HIV antiretroviral therapy, many inhibitors of these three target enzymes are in Phase 2 and 3 clinical development, and two HCV protease inhibitors have been licensed (Box 2).

Recent DAA developments

Over the past 12 months, several major milestones have been reached in the clinical development of DAA therapy for chronic HCV infection. Findings from Phase 3 trials in treatment-naive and treatment-experienced patient populations with genotype 1 (55% of the chronic HCV population in Australia8) have been published for two HCV protease inhibitors, telaprevir and boceprevir.9-13 In treatment-naive populations, telaprevir or boceprevir, when added to PEG-IFN/RBV (triple therapy), improve SVR (undetectable HCV RNA 24 weeks post-treatment) from 38%–44% to 66%–75%, and enable treatment duration to be shortened from 48 weeks to 24–28 weeks for around half of patients.9,11 In treatment-experienced populations, telaprevir and boceprevir both provided considerably enhanced SVR when combined with PEG-IFN/RBV (from 17%–21% to 64%–66%), although treatment response varied from around 30% for those patients with a prior “null response” (< 2 log decline in HCV RNA with PEG-IFN/RBV through Week 12), to around 55% for those with a prior “partial response” (> 2 log decline HCV RNA at Week 12, but no on-treatment undetectable HCV RNA), to 75%–85% for those with prior relapse (end-of-treatment undetectable HCV RNA with post-treatment viral rebound).10,12 Telaprevir and boceprevir were licensed by the United States Food and Drug Administration in May 2011. However, several concerns regarding these two agents remain, including:

• a problematic dosing schedule of three times per day with a meal (fatty for telaprevir), and a large pill burden (boceprevir, 12 pills per day; telaprevir, six pills per day);
• reduced treatment efficacy in patients with prior PEG-IFN/RBV null response, particularly those with advanced fibrosis (10%–20% SVR);
• high rates of HCV resistance in patients with limited IFN sensitivity — for many patients with prior PEG-IFN/RBV null response, the addition of a single protease inhibitor provides functional monotherapy;
• therapeutic toxicity, including increased incidence of rash (telaprevir) and anaemia (boceprevir and telaprevir) — anaemia is more pronounced with boceprevir, due to the longer duration of protease inhibitor therapy (24–44 weeks, compared with 12 weeks for telaprevir);
• a large number of potential drug–drug interactions, due to the metabolism of HCV protease inhibitors through cytochrome P450 (3A4) pathways;
• complex treatment algorithms, with different strategies for telaprevir (12 weeks of triple therapy followed by 12–36 weeks of PEG-IFN/RBV treatment) and boceprevir (a 4-week PEG-IFN/RBV “lead in”, followed by 24–44 weeks of triple therapy), and different strategies for patients with cirrhosis and non-cirrhosis;
• complex HCV RNA monitoring schedules and stopping rules that differ between telaprevir and boceprevir; and
• the high cost of protease inhibitor agents — in the US, boceprevir is $1100 per week ($26 400–$48 400 for a treatment course) and telaprevir is $49 200 for a 12-week course — which will be added to cost of PEG-IFN/RBV therapy.

Telaprevir and boceprevir also have more limited potency against non-1 HCV genotypes, with particularly poor activity against genotype 3,14,15 and have therefore only been licensed for genotype 1.

Selection of patients for initial DAA therapy

In Australia, telaprevir and boceprevir were registered by the Therapeutic Goods Administration in early 2012, and could potentially receive Pharmaceutical Benefits Advisory Committee (PBAC) listing in late 2012. Early access schemes through Janssen (telaprevir) and Merck Sharp and Dome (boceprevir) are providing preregistration access to patients with chronic HCV genotype 1 infection; however, numbers are limited and restricted to major clinics.

Assuming these two initial HCV protease inhibitors receive PBAC listing, appropriate selection of patients for PEG-IFN/RBV/telaprevir and PEG-IFN/RBV/boceprevir regimens will be crucial. In the HCV-treatment-naive population, many of the pretreatment factors that are predictive of PEG-IFN/RBV response remain predictive for response to protease inhibitor-containing triple therapy, in particular fibrosis stage.9,11 Host genetic polymorphisms in the IL28B region, recently associated with PEG-IFN/RBV response in chronic HCV genotype 1 infection,16-18 also remain predictive of triple therapy response19 albeit less so due to the overall higher response rates.

Factors that are specific to DAA therapy response should also be helpful in patient selection. HCV genotypes 1a and 1b are not associated with PEG-IFN/RBV treatment response, but in protease inhibitor-containing triple therapy, patients with genotype 1a have a higher rate of treatment failure, which is related to the lower genetic barrier to viral resistance compared with genotype 1b.20

Patients with chronic HCV genotype 1 infection who should be targeted for the initial phase of triple therapy include: treatment-naive patients with significant fibrosis (F2–4); and treatment-experienced patients with significant fibrosis (F2–4), particularly those with prior PEG-IFN/RBV post-treatment relapse.

Individualised treatment decision making is crucial, with informative discussion between patients and clinicians, taking into account social, family and clinical factors. The potential advantages and disadvantages of initial DAA-based therapy should be covered. However, it is expected that many patients with early liver disease (F0–1) and those with prior PEG-IFN/RBV null response will be recommended to wait for further developments in DAA therapeutic strategies.

Future strategies for DAA therapy

Triple therapy with PEG-IFN/RBV/protease inhibitor (telaprevir or boceprevir) should be the standard of care for patients with chronic HCV genotype 1 infection for the next 2–3 years. However, the rapid clinical development of numerous DAA agents across several classes provides the opportunity for both improved triple therapy regimens and additional therapeutic strategies. HCV protease inhibitors with preliminary evidence of enhanced efficacy, minimal toxicity, and improved dosing schedules (daily dosing)21,22 are in Phase 3 evaluation in combination with PEG-IFN/RBV (TMC435, BI 201335).

Quadruple therapy, with PEG-IFN/RBV and two DAA agents, is being evaluated in patients with prior PEG-IFN/RBV null and partial response and in those with advanced fibrosis. A small Phase 2 study in genotype 1 patients with prior PEG-IFN/RBV null response using PEG-IFN/RBV combined with BMS-650032 (protease inhibitor) and BMS-790052 (NS5A inhibitor) for 24 weeks produced a 100% (all 10 patients) SVR rate.23

This compares extremely favourably with the SVR of around 30% seen in prior PEG-IFN/RBV null responders treated with triple therapy as described above.

IFN-free HCV therapy was initially evaluated in the INFORM-1 study undertaken in Australia and New Zealand, which demonstrated that mericitabine/danoprevir (nucleoside analogue/protease inhibitor) combination produced potent viral suppression with no viral breakthrough during 14 days of dual dosing.24 Following this proof of concept, a study explored the curative potential of IFN-free dual DAA therapy.

In patients with chronic HCV genotype 1 and prior PEG-IFN/RBV null response, four of 11 treated with BMS-650032 (protease inhibitor) and BMS-790052 (NS5A inhibitor) for 24 weeks achieved an SVR.23 Of particular interest, both genotype 1b patients were cured compared with two of nine genotype 1a patients. A subsequent study involving Japanese chronic HCV genotype 1b-only patients treated with the same regimen provided a 100% SVR rate (all 10 patients).25

Important data have also been presented on IFN-free therapy for chronic HCV genotype 2 and 3a. A Phase 2 study undertaken in New Zealand evaluated the nucleotide analogue PSI-7977 in combination with RBV for 12 weeks, with a 100% SVR rate (all 10 patients).26

The high genetic barrier to resistance, cross-genotype activity, and preliminary evidence of limited toxicity, make PSI-7977 (now known as GS-7977) a very attractive agent for use with other DAA agents and/or RBV. Further patient cohorts are evaluating the GS-7977/RBV regimen for chronic HCV genotype 1. Phase 3 data will be required to confirm preliminary efficacy and, more importantly, to evaluate safety in larger study populations.

Several other interferon-free combination DAA regimens are under clinical evaluation.27 A combination of a nucleos(t)ide analogue with an NS5A inhibitor may be an ideal therapeutic strategy as both classes have cross-genotype activity and lack the CYP3A4 interactions seen with the HCV protease inhibitor class.

Although time lines for future HCV therapeutic strategies are not completely clear, initial Phase 3 studies of IFN-free therapy will commence in 2012. Thus, it is possible that the period of triple therapy with PEG-IFN/RBV and protease inhibitor therapy will be relatively short-lived, to be replaced by IFN-free therapy for the vast majority of patients with HCV (Box 3).

Initial concerns with telaprevir- and boceprevir-containing triple therapy, as outlined above, will increase the overall complexity of HCV clinical management. However, the likely switch to IFN-free regimens with markedly reduced toxicity, shortened treatment durations, and simplified dosing and monitoring schedules should lead to a rapid decline in complexity (Box 3). Clearly, significant toxicity or suboptimal efficacy revealed in Phase 3 evaluation with various IFN-free regimens will delay this relatively optimistic time line. Broad availability within the Australian context will also be dependent on the PBAC approval process.

Laying the foundation

The initial phase of DAA-based therapy will provide enhanced efficacy, but challenges to their clinical utility will be evident. There are several priorities for the next 3–5 years as we move towards IFN-free simplified combination DAA regimens. Chronic HCV should continue to be treated primarily as a chronic liver disease with enhanced capacity for staging of fibrosis.

Non-invasive methods of liver disease staging, in particular hepatic elastography (Fibroscan), will be central to this strategy. The recent development of portable Fibroscan technology should further improve access to disease staging in non-tertiary clinic settings.

Those patients with at least moderate fibrosis (estimated 54 000)3 should be targeted for therapeutic intervention, given their significant risk of progression to advanced liver disease complications. Once the era of IFN-free combination DAA therapy arrives, the overall strategy should switch to treatment of HCV as predominantly an infectious disease involving therapeutic intervention for all stages of disease (including acute HCV).

Patients with advanced liver disease will continue to require specific liver disease management, while the utility of IFN-free therapy in the setting of HCV-related liver failure (including potential hepatic function restorative capacity) remains unknown. A major increase in HCV treatment uptake will require expanded access through community-based and primary care practices, opiate pharmacotherapy clinics, and prisons. Furthermore, enhanced public HCV awareness and targeted screening campaigns will be required. The potential for HCV treatment as a prevention tool, a remote possibility in the IFN-based therapy era, may also become a feasible public health strategy.

Box 2 – Hepatitis C virus direct-acting antiviral therapy agents in clinical development

Agent	Phase 2	Phase 3	Licensed
NS3/NS4A protease inhibitors	Danoprevir/r* (RG7227); ACH-1625; GS-9256; GS-9451; ABT-450/r*; MK-5172; GSK2336805	Simeprevir (TMC435); BI 201335; asunaprevir (BMS-650032)	Boceprevir; telaprevir
NS5B polymerase inhibitors
Nucleos(t)ide analogues	Mericitabine (RG7128); IDX184; INX-189	GS-7977
Non-nucleos(t)ide analogues	VX-222; tegobuvir (GS-9190); BMS-791325; ABT-333; ABT-072; ANA598; BI 207127; filibuvir; IDX375; VCH-916
NS5A inhibitors	ABT-267; GS-5885	Daclatasvir (BMS-790052)
* Ritonavir boosted.

Provenance:

Commissioned; externally peer reviewed.

Received 29 Nov 2011,   accepted 5 Mar 2012

https://www.mja.com.au/journal/2012/196/10/changing-therapeutic-landscape-hepatitis-c