The European Commission has granted marketing approval to a new interferon-free combination for treatment of hepatitis C virus (HCV), developed by AbbVie. The combination consists of a fixed-dose tablet containing the HCV protease inhibitor paritaprevir boosted by ritonavir and the NS5A inhibitor ombitasvir, dosed once daily (to be marketed as Viekirax), accompanied by the NS5B non-nucleoside polymerase inhibitor dasabuvir, dosed twice daily (to be marketed as Exviera).

In the European Union, Viekirax and Exviera have been licensed for treatment of genotype 1 infection, with or without ribavirin, and for treatment of genotype 4 in combination with ribavirin. The regimen has also been approved for treatment of hepatitis C in people with HIV co-infection. The regimen is taken for 12 weeks in all patients apart from those with genotype 1a infection who have cirrhosis, who should take the regimen for 24 weeks. The combination may be dosed with or without ribavirin.

In clinical trials the regimen has produced very high cure rates (above 95%) in all groups of patients with hepatitis C; 92% of patients with hepatitis C and HIV co-infection were cured in a clinical trial.

In the United States (US), the three drugs will be co-packaged and marketed under the brand name Viekira Pak. The US Food and Drug Administration approved the combination for treatment of genotype 1 infection in December 2014. The US label recommends administration with ribavirin in all patients with genotype 1a infection who have cirrhosis. AbbVie has announced a US list price of $83,319 for a 12-week treatment course, approximately 10% lower than the price of Harvoni (sofosbuvir/ledipasvir), marketed by Gilead. European prices have not been announced yet.

Gilead’s interferon-free combination of sofosbuvir/ledipasvir (Harvoni) received US approval in October 2014 and European Union marketing approval in November 2014.

In the case of both drugs, national availability will depend on the result of reimbursement negotiations.

The US approval of Viekira Pak has sparked strong competition between AbbVie and Gilead to sign exclusive prescribing deals with a number of large payers. This means that people with hepatitis C who obtain prescription drugs through a number of large insurance and pharmacy benefits schemes will automatically receive either Viekira Pak or Harvoni, depending on which pharmaceutical company has offered the better price to the insurer or pharmacy benefit scheme. For example, CVS Health has made Harvoni its preferred option for all patients, while Express Scripts has made Viekira Pak its preferred option.

Exclusive or restricted deals have been criticised for restricting patient choice and ignoring the additional costs of ribavirin and management of side-effects.

Cost containment measures by health insurers in the US are likely to become more aggressive as the number of people needing treatment for hepatitis C grows. A study presented at the Liver Meeting in Boston in November 2014 estimated that just over 800,000 Americans are already ‘high’ or ‘highest’ priority for treatment based on staging of their liver disease.

An associated study found that a high proportion of people in these categories could be expected to progress to liver decompensation (failure), liver cancer or death. During an average follow-up period of five years, the cohort study of 2839 people receiving care for hepatitis C in four US states found that 29% of people with cirrhosis suffered decompensation and 11% developed liver cancer. Twelve per cent of patients with F3 fibrosis suffered decompensation during the same period. These findings suggest that health systems have limited scope for deferring treatment among people with cirrhosis or advanced fibrosis.

Plans to make sofosbuvir (Sovaldi) available for prescription in England and Wales have been pushed back by four months due to the high estimated cost of treating all who need the drug. This is despite a recommendation by the National Institute for Health and Care Excellence (NICE) that sofosbuvir is cost-effective. Introduction of the drug has been delayed from April 2015 to the end of July 2015. Scotland has a separate budget for medicines from the rest of the United Kingdom and gave approval for the use of sofosbuvir in June 2014.

Meanwhile, Janssen has agreed that the National Health Service in England and Wales will only pay for a course of treatment with simeprevir (Olysio) where a patient is cured. A similar agreement is already in place in Scotland.

The India Patent Office has rejected an application for a patent on sofosbuvir, saying that the patent lacks sufficient inventiveness compared to a previous formulation.

The decision will allow Indian manufacturers to make generic versions of sofosbuvir for sale in India. Generic production could bring the cost of a treatment course of sofosbuvir down to $100 where pegylated interferon is not needed, according to one estimate. Countries without patents for sofosbuvir may be able to buy any generic versions of sofosbuvir manufactured in India, but the number of companies able to manufacture sofosbuvir in India may be restricted by a previous licensing deal that permits export of licensed generic versions by Indian companies to 91 low-income countries. This deal excludes middle-income countries. Separate licensing deals are being negotiated in higher-burden countries such as India, Turkey and Brazil. Gilead’s pricing policy and measures to prevent diversion of lower-cost versions of sofosbuvir to higher-value markets have been strongly criticised. Critics say that the measures – and licensing deals – are designed to extract as much money as possible from new markets in the near future, while delaying the point at which Gilead will be forced to drop its price substantially. These measures will make it more difficult to eliminate hepatitis C because they ensure that only the sickest patients will be treated. Asymptomatic and undiagnosed people who are more likely to transmit the infection to others will not be tested or treated because the short-term cost of treatment acts as a major disincentive to expansion of diagnosis and treatment, one critic argues.

Parvez Mantry speaking at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting. Photo by Liz Highleyman, hivandhepatitis.com.

If hepatitis C infection leads to decompensation, a liver transplant will be necessary. People with hepatitis C who receive a liver transplant will almost always experience recurrence of hepatitis C and a rapid progression of liver disease. Curing hepatitis C after a liver transplant has been difficult until now because transplant recipients respond less well to interferon.

Two studies presented at the Liver Meeting showed that new interferon-free combinations proved highly successful in curing hepatitis C in transplant recipients.

A study of 223 liver transplant recipients treated with sofosbuvir/ledipasvir (Harvoni), of whom 61 had either grade B or C cirrhosis. The study found that whereas cure rates were very high for patients with fibrosis or grade A cirrhosis (96-98% according to treatment duration), cure rates were lower for patients with grade B cirrhosis (83-85% and grade C cirrhosis (60-67%). A study of the AbbVie interferon-free combination Viekirax and Exviera in 34 transplant patients without cirrhosis found a 97% cure rate.

These findings suggest that the chances of cure are very good in transplant patients with hepatitis C before the onset of advanced cirrhosis, and that careful monitoring of liver disease progression is necessary to ensure that transplant patients have the best chance of clearing hepatitis C.

Stephen Pianko, speaking at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting. Photo by Liz Highleyman, hivandhepatitis.com.

Gilead has a pipeline of hepatitis C drugs in development. Its first interferon-free combination for genotype 1, sofosbuvir and ledipasvir (Harvoni), was approved in Europe and the United States in late 2014. Gilead is now working to develop an interferon-free combination that is ‘pan-genotypic’, or active against multiple genotypes. Unlike ledipasvir – which is only active against HCV genotype 1 – Gilead’s next-generation NS5A inhibitor GS-5816 is pan-genotypic. In addition to more effectively treating people known to have HCV genotypes other than 1 or 2, a pan-genotypic regimen could help increase access by eliminating the need for genotypic testing prior to treatment.

Studies in treatment-experienced and previously untreated patients presented at the Liver Meeting in November 2014 show that, whereas the new combination may cure the vast majority of patients with genotypes 1 and 2 in eight weeks, a 12-week treatment course will be necessary for treatment-experienced patients. Phase III studies will compare a sofosbuvir/GS-5816 coformulation without ribavirin for 12 weeks versus the currently approved regimen of sofosbuvir/ribavirin for 12 weeks for genotype 2 or 24 weeks for genotype 3.

We have recently published a new factsheet on daclatasvir (Daklinza), an addition to the four other hepatitis C treatment factsheets.

Each factsheet focuses on one direct-acting antiviral drug and gives an overview of how it works, who can use it, how it is taken, what trial results tell us about how effective it is, known side-effects and drug interactions.

The factsheets are available to read online, and are also designed to be printed and shared.

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