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Welcome to the second of 2 September e-Bulletins. This bulletin focuses on recent treatment updates and other clinical research relating to viral hepatitis.
Medivir has announced that the US FDA has granted Priority Review designation to the supplemental New Drug Application for use of the once daily Olyssio (simeprevir) pill in combination with Sovaldi (sofosbuvir) for 12 weeks in treatment of adult patients with Hepatitis C genotype 1.
The European Medicines Agency Committee for Medicinal Products for Human Use has recommended Bristol Myers Squibb’s new Hepatitis C therapy Daklinza, an NS5A complex inhibitor, for use in combination with other medicinal products. This is the first drug in its’ class to be recommended for approval by the EMA having demonstrated potential benefits in clinical trials of over 5,000 patients.
Daklinza (daclatasvir) approved for use alongside Sunvepra (asunaprevir) in Japan
The Japanese Ministry of Health, Labor and Welfare has approved Daklinza (daclatasvir), an NS5A complex inhibitor, for use alongside Sunvepra (asunaprevir), an NS3/4a protease inhibitor, for treatment in Hepatitis C genotype 1 patients. The treatment is the first all oral, interferon and ribavirin free treatment for Hepatitis C in Japan and is also suitable for those with compensated cirrhosis.
In a real world study by a US insurance provider, discontinuation rates were approximately four times greater than the rates observed in clinical trials although the highest rate still included interferon.
Sovaldi + pegIFN+RBV (10.2% of patients discontinued) Sovaldi + Olysio (4.2%) and Sovaldi + RBV (9.0%)
A recent study has shown that diabetes is an independent indicator for various liver related outcomes in Hepatitis C patients with cirrhosis, including ascites, renal dysfunction, bacterial infection and hepatocellular carcinoma. The researchers posited that improved diabetes control may improve the outcome of cirrhosis .
A risk model, published in PLOS one, has shown that Hepatitis C infection was an increased risk for developing end stage renal disease (ESRD) among patients with chronic kidney disease. Chronic kidney disease and Hepatitis C are closely linked but the association between Hep C and developing ESRD had not been analysed with the competing risk model.
New research highlights that Hepatitis C infection among adults was associated with a higher prevalence of low muscle mass, an early sign of malnutrition, even in the absence of advanced liver disease. Researchers said, ‘Importantly, low muscle mass is a modifiable risk factor that leads to worse health outcomes, and clinicians should consider evaluating the nutritional status of their chronic HCV-infected patients routinely to identify those at-risk.
In a cross sectional study, Dr. Charitha Gowda and colleagues of the University of Pennsylvania, analysed data from 18,513 patients enrolled in the National Health and Nutrition Examination Study (1999-2010). The cohort included 303 patients with chronic Hepatitis C.
According to findings in a new study led by King’s College London and the University of Barcelona. Transplant patients can develop tolerance to a new liver even if they have Hepatitis C, with the virus having been shown to affect the immune system in a way which actually helps the body to accept the new organ.
When a Hepatitis C patient receives a new liver it will become infected with the virus. A new liver is normally less likely to be rejected by the body than other organs, with patients able to develop ‘operational tolerance’ to the new liver. Normally after transplantation a patient will receive immunosuppressant drugs to decrease the likelihood of rejection of the organ. Because the liver is less susceptible to rejection anyway, clinical trials in non Hepatitis C infected patients had previously been carried out to investigate whether these immunosuppressant drugs could be withdrawn.
This would be particularly important with Hepatitis C patients because immunosuppressant drugs weaken the immune system, causing Hepatitis C to flourish after transplantation and aggressively attack and damage the new liver.
However, in trying to evade the immune system, ‘rewiring’ immune cells to reduce their function, the Hepatitis C virus itself performs a similar function to immunosuppressant drugs – thereby helping the body to accept the new liver.
"This is exciting research that shows the hepatitis virus changes the immune system in such a way to protect these liver transplants from being rejected by the body," said Dr. Gregory Pappas, medical director of Hepatitis Foundation International.
However, Dr. Thomas Schiano, medical director of liver transplant for Mount Sinai Health System said this may prove a moot point anyway with the advent of new Hepatitis C treatments.
A recent study and associated commentary in the respected medical journal Gut have highlighted how Vitamin D may have a key role to play in decreasing the rate of liver fibrosis. The increased scientific examination of Vitamin D's impact on liver health is welcomed as the Vitamin is potentially a very cost effective way to impact on liver health, as highlighted in previous Hepatitis Scotland bulletins.
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This study and commentary put forward a clinical model that can help identify those patients with advanced liver disease who are most at risk of medical complications. It will thus help to better identify patients who require urgent therapy with direct-antiviral agents .
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A committee of the European Medicines Agency has recommended extending use of entecavir (Baraclude) to children. The decision by the Committe for Medicinal Products for Human Use (CHMP) applies to nucleoside-naive children 2-17 years old with compensated liver disease, with the same qualifications listed for adults.
A recent study found that patients with Hepatitis B treated with Entecavir monotherapy still remained at risk of developing Hepatocellular carcinoma. The study concludes culmulative incidence of HCC was low in people treated with Entecavir but it does not eliminate the risk of HCC.
744 patients were recruited from 11 European centres in the Vigilance Against Viral Resistance network. All patients were chronically infected and had been treated with Entecavir for at least 3 months between 2005 and May 2013. 42% were Caucasian and 29% were Asian.
14 developed HCC, including 9 with cirrhosis at baseline, during a median follow up of 167 weeks. Patients with cirrhosis had a greater cumulative 5 year incidence rate of HCC compared with non cirrhotics. The HCC incidence rate was also greater in older patients.
Greater HCC risk scores were associated with developing HCC at baseline when age, sex, cirrhosis and albumin, bilirubin and HBV DNA levels were included, though predicted risk for HCC based on those scores decreased during therapy.
Arrowhead have completed dosing of their Phase 2a cohorts and have said the initial data suggests the magnitude of HBsAg reduction seen is similar to that seen in earlier research on primates.
An Indiana University biochemist’s discovery of a class of anti-viral small molecules that target the function of a virus DNA hidden in the infected livers of hepatitis B patients may lead to a cure for this viral infection that kills more than 600,000 people annually.
Adam Zlotnik, a professor of molecular and cellular biochemistry at Indiana University, has discovered a class of anti-viral small molecules that target the function of a virus DNA hidden in the infected livers of Hepatitis B patients. He and some colleagues formed a company called Assembly Pharmaceuticals in 2012 to develop new anti viral drugs based on his discoveries.
New compounds based on his discoveries, Core Protein Allosteric Modulators, are capable of altering the activities of a core Hepatitis B protein that is essential for the virus’ continued survival, according to an Indiana University press release.
New research has shown that patients with chronic Hepatitis B infection with a liver stiffness value of 8kPa or greater were at increased risk for experiencing a liver related event after achieving virologic response with anti viral therapy.
The 12-week stopping rule for pegylated interferon was the most cost-effective treatment for patients with chronic hepatitis B virus who were positive for hepatitis B e antigen, according to data from a recent study.
Researchers compared the following treatments: Peg interferon with 12 week stopping rule, conventional 48 week course of peg interferon, entecavir monotherapy, tenofovir monotherapy, telbivudine monotherapy, telbivudine roadmap with tenofovir switch treatment and no treatment.
Stopping treatment after 12 weeks was the best option for patients with HBeAg because it had the lowest cost effectiveness ratio of $9,501 per quality life adjusted year. Entecavir had the lowest cost effectiveness ratio, with a lifetime treatment cost of $70,028, if peg interferon wasn’t available.
People who are negative for HBeAg need lifetime antiviral treatment and Entecavir was found to be most cost effective for this group.
Co-infection with HIV and Hepatitis C is associated with increased risk of low bone mineral density and fracture, investigators have reported in the online edition of AIDS. 15 separate studies showed that those living with co-infection had a moderately higher risk of osteoporosis than those who were HIV mono-infected and that incidence of fracture was moderately higher among co-infected than those HIV mono-infected, but substantially higher than in healthy controls.
Study authors believe their findings show the importance of monitoring bone mineral density in all older people who are co-infected.
Factors independently associated with increased risk of osteoporosis were HIV/HCV co-infection, older age, lower BMI (body mass index), post-menopausal status and longer duration of treatment with an HIV protease inhibitor. Smoking, low physical activity and methadone use were identified as risk factors in some studies.
Risk factors for fracture included co-infection, older age, smoking, white ethnicity, alcohol and substance abuse, low BMI and diabetes. Some studies also found that injecting drug use, opioid therapy, hormone replacement therapy, oral contraception, kidney function, menopause and peripheral neuropathy were also risk factors.
Three patients co-infected with HIV and Hepatitis C spontaneously became negative for Hepatitis C RNA while undergoing HIV antiretroviral therapy, in a recent study. All had the IL28B CC genotype. The researchers said, “We argue that HIV/HCV coinfected patients probably should commence ART prior to HCV treatment, in particular if they have the IL28B CC gene, since it might occasionally induce spontaneous HCV clearance of a chronic HCV infection.
“HCV RNA testing should be recommended immediately before initiation of HCV treatment, to find the subset of HIV/HCV coinfected patients with IL28B CC that may have cleared their chronic infection spontaneously.”
Swedish researchers selected the patients from an HIV/HCV infected cohort of 466. All 3 cases were in the IL28B CC genotype tested group of 64 who underwent anti-viral therapy. After testing negative for Hepatitis C RNA for the first time, all 3 remained negative for 3 additional tests.