Cardiovascular disease and hepatitis C

People with hepatitis C are at higher risk of dying from cardiovascular disease, suffering a stroke or developing cardiovascular problems than people with similar risk factors for heart disease who do not have hepatitis C, a meta-analysis of published studies has shown.

The findings, published in the January 2016 edition of Gastroenterology, come from a meta-analysis of 22 epidemiological studies. The meta-analysis found that, when compared to the general population, the risk of dying from a cardiovascular cause was increased by 65% for people with hepatitis C. The risk of coronary artery disease was two-and-a-half times higher, and the risk of suffering a stroke or other coronary event was 30% higher. Even after allowing for the well-established risk factors for heart disease – diabetes, high blood pressure and smoking – the risk of death, cardiovascular disease and carotid artery disease was still elevated in people with hepatitis C.

Parkinson’s disease

People with hepatitis C virus (HCV) infection may be more likely to develop Parkinson’s disease, especially when combined with other risk factors, although the reason for the association is not fully understood, according to a pair of recently published studies from Taiwan.

While hepatitis C is primarily a disease of the liver, chronic HCV infection has also been linked to manifestations throughout the body. Numerous studies have found associations between HCV infection and various neuropsychological and cognitive symptoms.

Parkinson’s disease is a progressive neurodegenerative disorder – the second most common after Alzheimer’s disease – leading to movement disorders including tremors, muscular rigidity and gait impairment.

A national cohort study of approximately 50,000 people found that, over an average follow-up period of 12 years, people with hepatitis C were more than twice as likely to develop Parkinson’s disease. A second study, of 62,276 people in Taiwan, found a similarly increased risk of Parkinson’s disease in people diagnosed with hepatitis C. The study also found that HCV damages the brain cells which produce dopamine. Loss of dopamine-producing nerve cells in one area of the brain leads to Parkinson’s disease. If other studies confirm this mechanism, earlier curative treatment for hepatitis C, especially in older people, has the potential to reduce the risk of Parkinson’s disease for those with hepatitis C.

Australia hepatitis C treatment funding

The Australian government has announced that it will provide funding for treatment for anyone diagnosed with hepatitis C from 1 April 2016. Patients will be charged a small co-payment for medication. The funding will cover the prescription of sofosbuvir (Sovaldi), sofosbuvir and ledipasvir (Harvoni), daclatasvir (Daklinza) and ribavirin. (See Hepatitis Australia’s website for further details).

“The Turnbull Government is to be congratulated for showing leadership and investing in these game-changing therapies which represent the greatest innovation in the treatment of the hepatitis C virus in a generation,” said Helen Tyrrell, Hepatitis Australia CEO.

“If we can combine access to new treatments with improved access to needle and syringe programs across the country and in all populations, we have a real chance of preventing deaths and eliminating hepatitis C as a public health concern within a generation.”

Around 230,000 people are estimated to be infected with hepatitis C in Australia. The Australian Government has promised AUS$1 billion over 5 years to pay for hepatitis C treatment (approximately US$700 million), but has not disclosed how much it will be paying for the direct-acting antivirals covered by the scheme.

Hepatitis testing contest

Crowd Wisdom in Sexual Health, in collaboration with the WHO Global Hepatitis Programme, is organising an innovation contest on hepatitis B and C testing.

The purpose of this contest is to identify innovative examples of delivering hepatitis B and C testing that will be highlighted within the 2016 WHO Hepatitis Testing Guidelines.

The innovation could be delivery to a new population, in a new setting (e.g. prisons), or a new messaging approach to encourage testing uptake (e.g. social media). The goal is to identify interventions aiming to increase testing, providing real-world examples to be used alongside the WHO Hepatitis Testing Guidelines. 

Your submission, in the form of a 300-500 word description of your innovation and its impact, must be submitted by 1 March 2016. Submissions in English are encouraged, however entries will be accepted in Arabic, Chinese, French, Russian, and Spanish.

New Merck combination Zepatier approved for hepatitis C treatment in the United States

Merck has received a US license for its direct-acting antiviral combination of grazoprevir and elbasvir, to be marketed as Zepatier. The combination of grazoprevir (an HCV protease inhibitor) and elbasvir (an NS5A inhibitor) is dosed once daily for 12 weeks or 16 weeks with or without ribavirin.

The combination has been approved for the treatment of genotypes 1 and 4. Approval is based on results of studies in previously untreated and treatment-experienced patients. It has not been approved for use in people with moderate or severe hepatic impairment (Child Pugh B or C stages).

A 12-week treatment course is recommended for all patients apart from those with genotype 4 who have previous experience of pegylated interferon and ribavirin, or people with genotype 1a and baseline NS5A mutations indicating possible resistance to NS5A inhibitors. These groups of patients should receive a 16-week course of treatment.

Use in combination with ribavirin is recommended for the following groups of people:

  • Genotype 1a: previously untreated people and people previously treated with pegylated interferon and ribavirin if they have baseline NS5A mutations indicating possible resistance to NS5A inhibitors

  • Genotype 1a and 1b: people previously treated with pegylated interferon, ribavirin and a protease inhibitor (boceprevir, simeprevir or telaprevir)

  • Genotype 4: people previously treated with pegylated interferon and ribavirin.

Testing for NS5A resistance-associated polymorphisms (positions 28, 30, 31 or 93) is recommended for GT1a-infected patients prior to starting treatment.

Merck has priced its regimen at a list price of $54,600, significantly below the list price established for its chief competitor product, Gilead’s Harvoni (sofosbuvir/ledipasvir). Merck’s price compares with a list price of $94,500 for Harvoni in the United States, although Gilead is believed to have agreed discounts of up to 30% with many insurers.

The European Medicines Agency is reviewing a licensing application for the combination and a decision is expected in 2016.

Merck is also developing a three-drug pangenotypic regimen. Results of the C-CREST trial, presented at The Liver Meeting in November 2015, showed that an 8-week treatment course with a combination of grazoprevir, the NS5A inhibitors elbasvir or MK8404, and the experimental nucleotide polymerase inhibitor MK-3682, taken for 8 weeks, cured more than 90% of hepatitis C patients without cirrhosis with genotypes 1, 2 or 3. Based on the results from this initial trial, Merck indicated in a press release that it has initiated a further study of grazoprevir (100mg), MK-3682 (450mg), and MK-8408 (60mg) in Part B of the C-CREST phase 2 clinical development programme.

New hepatitis C drugs in development

AbbVie has announced the beginning of enrolment for six phase 3 studies for a once-daily pan-genotypic hepatitis C regimen. The regimen consists of ABT-493, an HCV NS3/4A protease inhibitor active against all genotypes of hepatitis C, and ABT-530, an NS5A inhibitor also active against all genotypes of HCV.

In the SURVEYOR 1 and SURVEYOR 2 phase 2 studies, the new AbbVie combination achieved very high cure rates in genotypes 1, 2 and 3. The phase 3 studies will test the regimen in 8- and 12-week treatment courses in people with genotype 1 without cirrhosis, in genotypes 2 -6 and in genotype 3 in comparison to sofosbuvir and daclatasvir. Two studies will test the combination in people with compensated cirrhosis or severe kidney disease.

Gilead’s pangenotypic combination of sofosbuvir (NS5B polymerase inhibitor) and velpatasvir (NS5A inhibitor) is being reviewed by the US Food and Drug Administration (FDA) and the European Medicines Agency. US approval is expected by the end of June 2016.

Hepatitis B treatment

Gilead Sciences has announced positive results from two phase 3 trials of a new formulation of tenofovir in people with hepatitis B. Tenofovir is recommended for treatment of hepatitis B. The new formulation of tenofovir, known as TAF, concentrates at higher levels in cells and has been shown to cause fewer bone and kidney side-effects when used as an HIV treatment. The two clinical trials compared TAF with the existing formulation of tenofovir (TDF) in the treatment of people with HBeAg negative or positive hepatitis B. The studies showed no difference in the proportion of participants with HBV DNA levels below 29 IU/mL at 48 weeks of therapy, and fewer negative effects on kidney function or bone mineral density in people who received TAF. Gilead Sciences is seeking a US licence for the use of TAF in hepatitis B treatment.

Future treatments for hepatitis B are still at an early experimental stage. One agent, NVR 3-778, which targets the core protein of hepatitis B, has been shown to reduce virus levels in a laboratory study. Another agent, REP 2139, is designed to interfere with assembly and release of HBV subviral particles, thereby lowering HBsAg levels in the blood. It is also active against hepatitis delta, for which there are only limited treatment options at present. A small phase 2 study presented at the Liver Meeting in November 2015 showed that it reduced levels of both hepatitis B and hepatitis delta virus in the blood when used in combination with pegylated interferon.

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