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In this bulletin we focus on recent treatment news, including research presented at the 64th Annual Meeting of the American Association for the Study of the Liver in Washington D.C, along with other stories relevant to the treatment of viral hepatitis. It is pleasing to see the number of new treatments and the success rates generated however it is hoped that the larger numbers can lead to increased competition and hence lower prices and that research results are replicated in real world use. A rise in all-drug resistance may also be a longer term issue.
Bristol-Myers Squibb seek Japanese approval for Daclatasvir in all oral combo
Bristol-Myers Squibb have become the first drug company to seek approval for a Hepatitis C treatment which doesn't include older standard of care drugs Interferon or Ribavirin. This follows phase 3 trials in Japan of Daclatasvir along with the protease inhibitor Asunaprevir. The overall cure rate of the trial was 84.7%
BMS has made Japan the focus of it's all oral efforts at tackling Hepatitis C. Around 1.2million people in Japan suffer from Hepatitis C, with an older patient demographic compared with other developed countries and around 70% of cases being the difficult to treat Genotype 1b.
Sofusbuvir and Simeprevir near US approval
The US FDA is on the verge of approval for Gilead's Sofusbuvir and Janssen's Simprevir for treatment of Hepatitis C. The panel voted 15-0 that both drugs were approved for use in the US.
Sofusbuvir has been recommended for treatment of genotypes 2 and 3 along with Ribavirin. It is also recommended for genotypes 1 and 4 along with ribavirin and interferon in patients who have not previously been treated. The addition of Sofusbuvir has shown clearance rates above 90% in clinical trials.
Janssen's Simeprevir (a protease inhibitor) has been recommended for treatment of Hepatitis C genotype 1 patients with compensated liver disease. Simeprevir along with standard of care therapy has shown clearance rates of around 80%.
European Medicines Agency approves 'compassionate use' for Sofusbuvir
An EMA panel has approved 'compassionate use' of Sofusbuvir in patients with chronic Hepatitis C who are waiting for a liver transplant or who have already received one. The 'compassionate use' designation has only been issued twice before, and allows clinicians to treat people with life threatening, chronic or severely disabling illness before the drug has been approved for wider use.
Sofusbuvir taken before or after liver transplant reduces Hepatitis C recurrence
The decision by the EMA is good news for those in need of liver transplantation due to Hepatitis C infection according to further studies presented at the The Liver Meeting 2013. Results showed that administering Sofusbuvir plus Ribavirin before transplantation prevented Hep C recurrence in two thirds of patients and early viral clearance in 75% of those treated after transplantation.
Hep C patients who need liver transplants are often in desperate need of treatment but are unable to tolerate interferon based therapy. Left untreated, Hep C almost always reinfects the new liver and can lead to cirrhosis, organ rejection and death.
Sofosbuvir and ledipasvir have good result, daclatasvir and asunaprevir looking good, Abbvie has similar outcomes, Merck's all oral hits the spot as inteferon may be phased out.
Liver 2013 saw the release of numerous Phase II and III trials reporting excellent results for all oral combinations of various compounds, with and without ribavirin. At least 95% of newly treated people with genotype 1 hepatitis C and prior non-responders achieved sustained virological response using a fixed-dose combination of sofosbuvir plus ledipasvir, with or without ribavirin. While response rates were high overall, the two relapsers in the trial were not taking ribavirin.
An interferon- and ribavirin-free oral regimen of daclatasvir plus asunaprevir taken for 24 weeks led to sustained virological response in 85% of Japanese patients with hepatitis C virus subtype 1b, interestingly, people with cirrhosis did at least as well as non-cirrhotics (91% and 84%, respectively) and patients age 65 and older fared slightly better than younger participants (90% vs 81%).
While these are good results for people with HCV 1b, studies have shown that the dual regimen of daclatasvir/asunaprevir is not as effective against subtype 1a. (Asunaprevir is also not active against HCV genotypes 2 or 3.)However, as also reported at the Liver Meeting, adding a third agent, a non-nucleoside NS5B polymerase inhibitor, raised sustained response rates to 91% for people with HCV 1a and 100% for 1b.
Merck also reported on its all oral combination with and without ribavirin which across a 65 patient cohort achieved high rates of SVR amongst genotype 1a (with RBV) and 1b (with or without RBV).
(sources include hivand hepatitis.com)
A study of US veterans published online in the Journal of American Medicine Association (JAMA) has shown that achieving an undetectable viral load was associated with decreased liver-related morbidity and mortality. The study analysed data from the Department of Veterans Affairs Clinical Registry.
HCV infection was found to increase the risk of death by 37%. Previous research had shown that patients with undetectable viral load or who achieve SVR through treatment are at significantly lower risk of late-stage liver events and deaths. In this study, patients who achieved undetectable viral loads reduced their risk of death by 45% and reduce their risk of composite end point of liver-related events by 27% relative to patients whose viral load was detectable over the entire period following diagnosis. Very few patients achieved an undetectable viral load without treatment - 39 out of 97,485 untreated patients.
Treatment numbers low
The study noted potentially worrying figures that only 1 in 4 patients with HCV and a detectable viral load were willing to start treatment. It cited fears of adverse side effects and poor clearance rates with standard of care therapy (this study group were 80% genotype 1 infected). It acknowledges that while protease inhibitors have seen significant increases in SVR rates compared with standard therapy, they also increased the frequency and severity of adverse side effects.
The study points out that new therapeutic options offer significant benefits to patients, with increase likelihood of achieving SVR and significantly reduced side effects. The study authors conclude that natural history data and an understanding of the challenges and expectations of patients from patients are essential to help providers and patients make informed decisions about when to initiate antiviral therapy and motivate patient adherence.
Arrowhead Pharmaceuticals has presented new data on it's Hepatitis B treatment candidate ARC-520 at the Liver Meeting 2013. The treatment was given to a chimpanzee chronically infected with HBV and resulted in substantial and sustained reductions in HBV DNA, HBeAg, and HBsAg, which did not return to baseline until study day 43, 43, and 71 respectively.
They also observed an increase in ALT levels after 4 weeks at the same time as the lowest point of circulating HBsAG. This is suggestive of a therapeutic immunological flare, which is thought to be part of a cascade that under chronic therapy may lead to HBsAg seroconversion and functional cure.
Arrowhead will shortly be submitting documents to Hong Kong regulatory authorities to enable a Phase 2a study in patients with chronic HBV infection.
Read more here.
A Hepatitis B vaccination programme in China has been successful in vastly reducing the number of children under 5 infected with the virus, from nearly 10% of children in 1992 to under 1% in 2005 - representing 80 million children protected by vaccination.
However, according to findings to be published in the Journal of Virology, these gains are in danger of being eroded as the virus develops surface mutations. Indeed 'breakout' mutations of the virus, which could enable it to elude the vaccine, have more than doubled.
Tao Bian, part of the team of researchers, said that although the vaccine remains quite effective, public health officials must track the rise in escape mutants in order to know when it becomes time to consider new vaccination strategies. This could include the use of a next generation HBV vaccine which contains a second antigen in addition to the virus surface antigen which makes it more difficult for the virus to elude the vaccine.
Hepatitis B mutation seen only in men and increased risk for liver cancer
Research from South Korea, due to be published in the Journal of Clinical Microbiology in December, have identified a novel mutation in the Hepatitis B virus which affects only men. The discovery could help explain why men with chronic Hepatitis B are 5 times more likely than women to develop liver cancer.
An article recently published in the Journal of Gastroenterology looks at non liver related (extra hepatic) conditions linked to Hepatitis C virus infection. It stresses that clinicians must have a high index of suspicion and a knowledge of these extra hepatic manifestations of Hepatitis C, not only to treat the manifestation but also to begin timely therapies for the underlying Hepatitis C infection.
A poster presentation at the Liver 2013 conference illustrated a study looking at the likely real world manufacturing costs of the new medications versus the many tens of thousands they are likely to cost when introduced to market.
The analysis concluded that large-scale production of direct acting antivirals may be possible for as little as $100 to $200 for 12 weeks of treatment. The estimate cited HIV drugs, which initially cost tens of thousands of dollar per patient but have since dropped significantly in price, as a framework.
These low prices could make widespread access to HCV treatment in low and middle income countries, and potentially even HCV eradication, a realistic goal.
This report is relevant to a recent Global Commission on Drug Policy report that suggested "Governments, international bodies and civil society organisations should seek to replicate the successful reduction in HIV treatment costs around the world, including the use of patent law flexibilities, to make them more accessible".
(partly sourced from pharmalot.com)
This study published in Liver International, and available on Medscape, aimed to evaluate the association between Hepatitis B/C infection and metabolic syndrome.
Aside from affecting the liver, Hepatitis C is also known to cause early stage diabetic problems such as steatosis and insulin resistance (metabolic syndrome). Obesity can worsen these problems and is another example of a 'classic' metabolic syndrome. These metabolic conditions can negatively impact on responses to Hepatitis C treatment. The link between Hepatitis B and metabolic syndrome is not as well studied.
The study speaks of a pressing need to identify strategies to improve/resolving metabolic problems in order to improve SVR rates in patients infected with Hepatitis C and potentially Hepatitis B. This comes against a backdrop of increasing metabolic disorders such as obesity and diabetes in Scotland, issues which have been covered in previous Hepatitis Scotland e-Bulletins.
HCV/HIV coinfected people with poor prognostic indicators such as higher Hepatitis C viral load, lower CD4 cell counts and older age and unfavourable IL28B indicators may not respond well to interferon based treatments and may be more likely to achieve Rapid or Sustained Viral Response to HCV treatment with the addition of a Direct Acting Antiviral (protease inhibitors), according to new research.
The researchers say that because of the increased likelihood of side effects and the risk of drug interactions with HIV antiretrovirals, understanding who is likely to respond to HCV treatment can help optimise therapy.
This article, published in Medscape, reviews the virology, natural history and treatment of Hepatitis C genotype 3. It explains that previously HCV genotypes 2 and 3 were viewed as easier to treat with higher rates of SVR than the more problematic genotype 1. However, due to an intense research focus genotype 1 will soon have among the highest clearance rates.
Recent randomised trials have shown that Genotype 2 is highly interferon sensitive, with continued high response rates to treatment. Genotype 3 HCV patients have far less successful response rates, effectively making it the most difficult to treat genotype.
The article concludes that with new direct acting antivirals moving rapidly into clinical trials this means that new focus can be given to genotype 3 and it is anticipated that with this renewed targeting of genotype 3 we should soon be able to see the same 90% response rates as with other Hepatitis C genotypes.
Treating HCV Genotypes 2 and 3 in HIV co-infected patients
People co-infected with HIV and HCV, mostly with Hepatitis C genotype 3 responded almost as well as HIV negative people to interferon based therapy after taking into account other factors associated with poor treatment response, according to an Italian study.
Results from a randomised trial published in the Journal of Gastroenterology have shown that reduction of ribavirin dosage may be the primary approach for management of anemia in Hepatitis C patients on Boceprevir triple therapy.