A risk for hepatocellular carcinoma still persists long-term after sustained virological response in patients with hepatitis C associated liver cirrhosis

Clin Infect Dis. (2013) doi: 10.1093/cid/cit234 First published online: April 24, 2013

Soo Aleman1,2, Nogol Rahbin1, Ola Weiland2, Loa Davidsdottir1, Magnus Hedenstierna2, Nina Rose1, Hans Verbaan3, Per Stål1, Tony Carlsson2, Hans Norrgren4, Anders Ekbom5, Fredrik Granath5, and Rolf Hultcrantz1

+ Author Affiliations

Correspondence to: Soo Aleman, Department of Gastroenterology and Hepatology, and Infectious Diseases, Karolinska University Hospital, at Karolinska Institute, 171 76 Stockholm, Sweden, Phone: +46 8 517 72741, Fax: +46 8 517 700 00, E-mail: soo.aleman@ki.se

Alternate corresponding author: Rolf Hultcrantz, Department of Gastroenterology and Hepatology, Karolinska University Hospital, 171 76 Stockholm, Sweden, Phone: +46 8 517 00 00, E-mail: rolf.hultcrantz@ki.se

Abstract

Background. The long-term effect of sustained virological response (SVR) to antiviral therapy on the risk to develop hepatocellular cancer (HCC), liver complications, liver-related deaths and overall death in hepatitis C (HCV) infected patients with liver cirrhosis is not fully known.

Methods. These risks were evaluated during long-term follow-up in in 351 patients with HCV related cirrhosis. 110 with SVR, 193 with non-SVR and 48 untreated patients were included in a multi-center cohort which was initiated 2001 and prospectively followed-up for a mean 5.3 ±SD 2.8 years. Complementary follow-up data from national registries were used to minimize the loss of patients during follow-up.

Results. Six patients with SVR developed HCC at 0.04, 0.64, 2.4, 7.4, 7.4 and 7.6 years after achieving SVR. The incidence of HCC, any liver complication, liver-related and overall death per 100 person-years was significantly lower in SVR time with 1.0, 0.9, 0.7, 1.9, compared to 2.3, 3.2, 3.0, 4.1 and 4.0, 4.9, 4.5, 5.1 in non-SVR and untreated time, respectively. The long-term consequences did not decline significantly after more than 3-year versus during the first 3-year of follow-up.

Conclusions. The risk for HCC, liver decompensation, and death in patients with liver cirrhosis related to HCV was markedly reduced after SVR, but a long-term risk to develop HCC remains for up to 8 years. Cirrhotic patients with HCV who achieve SVR should therefore maintain long-term surveillance for HCC. Future studies aimed to better identify those with remaining long-term risk for HCC are needed.

Received October 28, 2012. Accepted February 11, 2013.

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AbbVie's Investigational HCV Regimen Receives Breakthrough Therapy Designation from the U.S. Food and Drug Administration

- Interferon-free, direct-acting antiviral combination therapy currently in Phase 3 development

May 6, 2013

NORTH CHICAGO, Ill., May 6, 2013 /PRNewswire/ -- AbbVie (NYSE: ABBV) today announced that its investigational direct-acting antiviral (DAA) combination with and without ribavirin for the treatment of genotype 1 (GT1) hepatitis C virus (HCV) infection has been designated as a Breakthrough Therapy by the U.S. Food and Drug Administration (FDA).

The designation is based, in part, on positive data from AbbVie's clinical development program, including the Phase 2b clinical trial M11-652, known as "Aviator." The Aviator study was conducted in 571 patients infected with HCV GT1. Results from the treatment arms evaluating ABT-450/r + ABT-267 + ABT-333 with and without ribavirin demonstrated that the regimen provided high sustained viral response rates (SVR) with 12 weeks of therapy in patients who had not been previously treated (treatment naive) and in those who had failed prior therapy with pegylated interferon and ribavirin (null responders), regardless of sex, HCV subtype, stage of fibrosis, viral load or IL28B genotype.

According to the FDA, Breakthrough Therapy designation is intended to expedite the development and review of drugs for serious or life-threatening conditions. The criteria for Breakthrough Therapy designation includes preliminary clinical evidence demonstrating a drug may have substantial improvement on at least one clinically significant endpoint compared to available therapy. A Breakthrough Therapy designation conveys all of the fast track program features, as well as more intensive FDA guidance on an efficient drug development program.⁽¹⁾

"AbbVie is pleased that the FDA has granted Breakthrough Therapy designation to our 3-DAA combination with and without ribavirin. We feel it reflects the potential of this regimen to be important in the treatment of HCV," said John M. Leonard, M.D., senior vice president and chief scientific officer, AbbVie. "Our HCV program is one part of our advancing pipeline which is focused on delivering innovative therapies to address pressing areas of unmet clinical need."

New results from Aviator were recently presented at the 2013 International Liver Congress® in Amsterdam. These results continued to demonstrate high SVR rates against GT1 HCV with the 12-week, triple-DAA regimen with ribavirin, across patient types. Specifically,

• 99 percent of treatment-naive patients (n=79) achieved SVR₁₂, 96 percent achieved SVR₂₄ in an intent-to-treat analysis
• 93 percent of prior null responders (n=45) achieved SVR₁₂ and SVR₂₄
• A single relapse with this regimen occurred at post-treatment week two
• Of the 247 patients treated for 12 and 24 weeks with triple DAA with ribavirin, four patients (1.6 percent) discontinued the study because of drug-related adverse events. Serious adverse events were noted in four patients (1.6 percent), with one (arthralgia) considered possibly drug-related. Other events reported in more than 10 percent of patients included headache, fatigue, nausea, insomnia, and diarrhea. Grade 3-4 laboratory abnormalities in total bilirubin (six patients) and ALT (one patient) were noted; all resolved with continued dosing.

AbbVie's all-oral, triple-DAA combination is currently being studied in Phase 3 clinical trials. The Phase 3 program includes more than 2,000 patients with HCV genotype 1, with trial sites in 29 countries. The DAAs in the studies include ABT-450/r (protease inhibitor and ritonavir), ABT-267 (NS5A inhibitor) and ABT-333 (non-nucleoside polymerase inhibitor). Treatment durations under investigation are 12 weeks in non-cirrhotic patients, and 12 or 24 weeks in cirrhotic patients. All patients will be followed for 48 weeks post-treatment. Co-formulated tablets of ABT-450/r and ABT-267 are being used in the Phase 3 trials.

About the Hepatitis C Virus

Across the world, about 160 million people are chronically infected with hepatitis C.⁽²⁾ Hepatitis C is an inflammation of the liver caused by an infection with the hepatitis C virus (HCV).⁽³⁾ HCV is transmitted when an infected person's blood enters the bloodstream of another person.⁽⁴⁾

For the hepatitis C virus, there are six major HCV genotypes (GT1-6).⁽⁵⁾ Presently, there is no vaccine for the hepatitis C virus (HCV) infection.⁽⁵⁾ Decision to treat is dependent on a number of factors such as the amount of liver damage present, other conditions the patient may have, amount of virus in the body, and viral genotype.⁽⁵⁾ If treatment is needed, a hepatitis C infection is typically treated with a combination of antivirals.⁽⁵⁾

About AbbVie's HCV Development Programs

AbbVie's HCV portfolio includes investigational medicines with three different mechanisms of action, including protease (ABT-450/r), polymerase (ABT-333) and NS5A (ABT-267) inhibitors, currently being studied in clinical trials. ABT-450 is being developed with low dose ritonavir which enhances the pharmacokinetic properties of ABT-450. The use of ritonavir 100mg with ABT-450 for the treatment of HCV is investigational.

ABT-450 was discovered during the course of a collaboration between AbbVie and Enanta Pharmaceuticals for HCV protease inhibitors and regimens that include protease inhibitors. ABT-450 is being developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of HCV. AbbVie is well-positioned to explore combinations and co-formulations of these medicines.

Ritonavir Use in the Treatment of HIV

Ritonavir is in a class of medicines called the HIV protease inhibitors. Ritonavir is used in combination with other anti-HIV medicines to treat people with human immunodeficiency virus (HIV) infection. Ritonavir is for adults and for children greater than 1 month in age and older.

Ritonavir does not cure HIV infection or AIDS and does not reduce the risk of passing HIV to others. People taking ritonavir may still get opportunistic infections or other conditions that happen with HIV infection. Some of these conditions are pneumonia, herpes virus infections, and Mycobacterium avium complex (MAC) infections.

Ritonavir Safety in Treatment of HIV

Patients should not take ritonavir with certain medicines, as these can cause serious or life-threatening problems such as irregular heartbeat, breathing difficulties, or excessive sleepiness. Patients should not take ritonavir if they have had a serious allergic reaction to any of its ingredients. Some patients taking ritonavir may develop liver and pancreas problems, which can cause death.

Patients may develop large increases in triglycerides and cholesterol, diabetes, high blood sugar, changes in body fat, increased bleeding in people with hemophilia, allergic reactions, and/or changes in heart rhythm. Patients may develop signs and symptoms of infections that they already have after starting anti-HIV medicines.

For more information, please see Important Safety Information and Full Prescribing Information.

About AbbVie

AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott. The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. In 2013, AbbVie employs approximately 21,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com. Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.

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1.U.S. Food and Drug Administration. Frequently Asked Questions: Breakthrough Therapies. 2013. http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FDASIA/ucm341027.htm. Accessed April 19, 2013.

2.Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect. 2011; 17(2):107-15.

3.World Health Organization. Global Alert and Response (GAR): Hepatitis C. 2003. http://www.who.int/csr/disease/hepatitis/whocdscsrlyo2003/en/index1.html. Accessed April 9, 2013.

4.World Health Organization. Hepatitis C Fact Sheet 2012. http://www.who.int/mediacentre/factsheets/fs164/en/ Accessed April 9, 2013.

5.European Association for the Study of the Liver. Clinical Practice Guidelines: Management of hepatitis C virus infection. Journal of Hepatology. 2011; 55: 245-264.

SOURCE AbbVie

For further information: Media, Tracy Sorrentino, +1 (847) 937-8712, or Roseanne Durril, +1 (847) 938-6114, or Investors, Larry Peepo, +1(847) 935-6722, or Liz Shea, +1 (847) 935-2211

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Some liver transplants 'avoidable'

4 May 2013 Last updated at 19:08 ET

Some patients with severely damaged livers may not need a transplant as their own organ is actually regrowing, say doctors at a hospital in London.

They made the discovery by looking at a rare group of patients given a transplant while their own damaged liver is left in the body.

Sometimes the original liver recovers.

A study, in the American Journal of Transplantation, suggests doctors can predict which patients do not need a transplant as their liver is healing.

King's College Hospital has a leading liver transplant centre and is one of few places to perform "auxiliary transplants".

They are performed in sudden cases of liver failure caused by overdoses or viral infections, rather than the long-term damage caused by alcohol abuse.

Normally in organ transplants one organ comes out and a new one goes in. However, in this complex operation the transplant is put in beside the old liver.

After any transplant a patient needs to take a lifetime of drugs to suppress the immune system in order to avoid rejection. The drugs leave the body vulnerable to infection.

However, if the patient's liver does eventually recover then they can come off the immunosuppressant drugs and their body will get rid of the transplant.

The transplant is used to get the patient past the critical stage of the illness.

But the recovery happens only in some patients. In the study, the transplant was no longer needed in seven out of 11 patients.

So doctors analysed the detailed chemistry inside the liver cells of patients and looked for differences between those who recovered and those who did not.

Dr Varuna Aluvihare told the BBC: "There was a big difference right from the point of transplantation in the expression of some very small molecules between the group that would, three years down the line, regrow their liver versus the group that never did."

Those molecules regulated the way cells in the liver grow.

"Some of them were already starting to regrow. So what we may be able to do is come up with a better set of tests to allow us to identify those patients who are already regrowing and may not need transplantation.

"So we may be able to remove a group from the transplant list."

The liver does have a phenomenal ability to regenerate. In healthy people it will recover in the space of months even if a large amount is taken away.

People who need a transplant because of acute liver failure are seriously ill. Even if doctors could tell which patients' livers were already on the path to recovery, they would still need to keep those patients alive long enough for the liver to return to form.

Dr Aluvihare argued this would be possible as a small amount of restored liver function would be enough for patients to leave hospital.

He said there are cases at King's of patients recovering while they were on the waiting list.

"I would say five to 10 patients a year we seriously consider for emergency transplantation and then they start recovering.

"That tells us there probably is a pool there and there is probably quite a lot of mileage in identifying people would would recover."

Whether this would work is still uncertain. The team have received funding to look for those chemical differences in the blood of patients.

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New antiviral treatment could significantly reduce global burden of hepatitis C

Press release issued 6 May 2013

Scientists show potential impact of therapy in reducing transmission in UK, Canada and Australia

Around 150 million people globally are chronically infected with the hepatitis C virus (HCV) – a major cause of liver disease and the fastest growing cause of liver transplantation and liver cancer.¹ New prevention strategies are urgently required as people are continuing to be infected with HCV. Findings, published in Hepatology, reveal the impact of a new antiviral treatment that could potentially reduce HCV rates in some cities affected by chronic HCV prevalence by half over 15 years.

In Europe, the US and other developed countries the majority of HCV infections occur among people who inject drugs (PWID). Although current prevention strategies, which are based on needle and syringe programmes and opiate substitution therapy, can avert HCV infections and have reduced its prevalence in some cities from the very high levels that occurred in the 1980s, these interventions are unlikely alone to achieve further substantial reductions.

HCV treatment as prevention has been proposed as a possible solution. However, while current HCV antiviral treatment of pegylated-interferon and ribavirin can cure approximately 60 per cent of people treated, they are poorly tolerated, long in duration (five to 11 months), and have a low take-up among PWID.

Several new interferon free direct-active antivirals (DAAs) treatment are emerging with very promising results in trials suggesting that treatment is shorter (12 weeks) with fewer complications and side effects, and around a 90 per cent cure rate.

Using a mathematical model, researchers at the University of Bristol and London School of Hygiene and Tropical Medicine in collaboration with researchers and clinicians in the UK, Australia and Canada projected the potential impact of these new DAAs treatment among PWID in three cities with similar PWID prevalence (~1 per cent among adults) but very different levels of chronic HCV prevalence among PWID. The cities were Edinburgh, UK (25 per cent chronic HCV), Melbourne, Australia (50 per cent chronic HCV) and Vancouver, Canada (65 per cent chronic HCV).

In Melbourne and Vancouver, where current annual HCV treatment take-up rates and other interventions are around one per cent of PWID with chronic HCV, the findings show that switching to the new DAA treatment is likely to have very little impact on reducing HCV prevalence over the next 15 years. But in Edinburgh where chronic HCV prevalence is lower and current treatment rates already at three per cent of PWID with chronic HCV, then once the new DAA become available HCV prevalence is projected to reduce by 25 per cent over the next 15 years.

The researchers predict that chronic HCV prevalence among PWID could be halved in 15 years by doubling HCV treatment in Edinburgh to six per cent among PWID with chronic HCV and increasing HCV treatment by 13 to 15 fold in Melbourne and Vancouver respectively.

The findings strengthen the evidence that achievable levels of HCV antiviral treatment for PWID, particularly with the new emerging DAAs treatment, can substantially reduce prevalence across a range of global settings.

Clinicians, patient groups and policy-makers will be able to plan for large-scale population reductions in HCV and chronic liver disease. However, an important consideration will be how to make HCV treatment scale-up affordable — especially for lower and middle income settings but possibly also for developed countries that require very high treatment rates to achieve population goals.

The researchers estimate that if the cost of the new DAAs are equivalent to other new HCV antiviral drugs then treatment rates would require an annual treatment budget of US $3.2 million in Edinburgh and approximately $50 million in Melbourne and Vancouver.

Matthew Hickman, Professor in Public Health and Epidemiology at the University of Bristol's School of Social and Community Medicine and lead author of the study, said: “Scaling up HCV treatment is critical to the prevention of HCV in the population to support and enhance traditional harm reduction measures — opiate substitution treatment and needle exchange. The new direct-active antivirals treatment offer many sites the opportunity to achieve substantial reductions in HCV and future liver disease in the population, and the chance to demonstrate empirically that our model projections are right.”

Professor David Goldberg, lead of the team implementing Scotland’s hepatitis C Action Plan (2008-2011), said: “This study demonstrates that, in a country like Scotland which has a Government seriously committed to the improvement of hepatitis C services, increasing patient access to antiviral therapy could potentially have a major impact in the prevention of transmission of infection.”

Professor Greg Dore, Head of the Viral Hepatitis Clinical Research Program, Kirby Institute for infection and immunity in society at the University of New South Wales Australia, said: "The development of highly effective simplified new HCV treatments has the potential to greatly enhance existing HCV prevention strategies. Access to affordable HCV direct acting antiviral regimens for people who inject drugs should be a major focus to harness this potential prevention capacity."

Professor Margaret Hellard from the Burnet Institute in Australia added: “This research suggests that with the advent of new direct-active antivirals treatment there is a real opportunity to achieve substantial reductions in HCV and future liver disease in the population. Although the cost of these treatments appear to be expensive, economic models by Martin et al in the UK and Burnet researchers in Australia suggests that scaling up HCV treatment in people who inject drugs is highly cost effective. It is also important that the scale up of HCV treatment occurs in combination with traditional harm reduction measures — opiate substitution treatment and needle exchange which have previously also been shown to be highly cost effective.”

Further information:

1. World Health Organisation: http://www.who.int/mediacentre/factsheets/fs164/en/

2. About hepatitis C

Hepatitis C is a blood-borne virus that predominantly infects the cells of the liver. This can result in inflammation and significant damage to the liver. It can also affect the liver’s ability to perform its essential functions. Although it has always been regarded as a liver disease - ‘hepatitis’ means ‘inflammation of the liver’ - recent research has shown that the hepatitis C virus (HCV) affects a number of other areas of the body. These can include the digestive system, the lymphatic system, the immune system and the brain. Source: The Hepatitis Trust - http://www.hepctrust.org.uk/Hepatitis_C_Info/About+Hepatitis+C/About+Hepatitis+C

3. Paper

‘Hepatitis C Virus Treatment for Prevention Among People Who Inject Drugs: Modeling Treatment Scale-Up in the Age of Direct-Acting Antivirals’ by Natasha K Martin, Peter Vickerman, Jason Grebely, Margaret hellard, Sharon J Hutchinson, Viviane D Lima, Graham R Foster, John F Dillon, David J Goldberg, Gregory J Dore and Matthew Hickman is published in Hepatology.

The draft online paper (ahead of print) available to download from the below URL: http://onlinelibrary.wiley.com/doi/10.1002/hep.26431/pdf

4. Funders

UK: Scottish HCV Action plan; NIHR postdoctoral research training fellowship; MRC New Investigator Award G0801627; NIHR SPHR; MRC Addiction Cluster; UKCRC DeCipher

Australia: NHMRC Career Development Fellowship, Project Grant & Practitioner Research Fellowship.

US: National Institute on Drug Abuse Michael Smith Foundation for Health Research Scholar Award.

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