Over one million people treated for hepatitis C in low- and middle-income countries

Over one million people in low- and middle-income countries have been treated for hepatitis C with direct-acting antivirals in the past two years, the World Health Organization (WHO) said this week in its Global Report on Access to Hepatitis C Treatment. Around two-thirds of those treated are in Egypt.

Argentina, Brazil, Georgia, Indonesia, Morocco, Nigeria, Pakistan, the Philippines, Romania, Rwanda, Thailand and Ukraine have also made important progress towards providing wider access to hepatitis C treatment, the WHO report shows.

The report also shows that the price of hepatitis C treatment has fallen most sharply in countries where generic competition is possible. The report outlines the options available to countries to improve access to hepatitis C treatment including:

  • price negotiations, price controls and price transparency
  • competitive tendering
  • patent oppositions
  • voluntary licensing
  • compulsory licensing.

FDA hepatitis B reactivation warning, and hepatitis B testing for people taking hepatitis C treatment

People considering direct-acting antiviral (DAA) therapy for hepatitis C should first be tested for hepatitis B virus (HBV) and monitored throughout therapy, as elimination of hepatitis C virus (HCV) can lead to HBV reactivation and worsening of liver disease, according to recent updates to American and European hepatitis C treatment guidelines.

On 4 October the US Food and Drug Administration (FDA) issued a new safety warning about the risk of HBV reactivation in people treated with DAAs, which in a few cases has led to serious liver problems or death.

An FDA review identified 24 confirmed cases of HBV reactivation – either reported to the agency or described in published literature – in people with HBV/HCV co-infection treated with DAAs between November 2013 and July 2016. HBV reactivation usually occurred within 4 to 8 weeks (average 52 days) after starting DAA therapy, and was seen in people with both detectable and undetectable HBV DNA at baseline.

Updated American and European guidelines now recommend testing for HBV with HBsAg, anti-HBs and anti-HBc, and those who are antigen or anti-HBc antibody positive should also have an HBV DNA viral load test to see if the virus is actively replicating.

Panels from the American Association for the Study of Liver Diseases (AASLD)/Infectious Diseases Society of America (IDSA) and the European Association for the Study of the Liver (EASL) both recommend that people who meet criteria for treatment of active HBV infection should start nucleoside/nucleotide antivirals such as entecavir (Baraclude) or tenofovir (Viread) at the same time as – or before – initiating hepatitis C DAA therapy.

People with low or undetectable HBV DNA levels should be monitored at regular intervals during hepatitis C treatment and post-treatment follow-up to check for HBV reactivation, and started on hepatitis B antivirals if they meet treatment criteria.

Hepatitis B elimination

Hepatitis B virus (HBV) could be eliminated as a global health threat with a scale-up of vaccination coverage, enhanced efforts to prevent vertical (mother-to-child) transmission and expansion of testing and treatment, according to a modelling study published in The Lancet Infectious Diseases. With these interventions, incidence of new chronic infections could be reduced by 90% and mortality rates by two-thirds between 2015 and 2030. HBV-related mortality could be eliminated in Western Europe as soon as 2017 but it would take until 2090 to achieve this goal in sub-Saharan Africa. The total cost of the strategy would be approximately $88 billion, but this would fall if a cure were developed.

"Maintenance of a business as usual approach will not end the epidemic and will lead to 17 million avoidable deaths over the next 15 years," comment the authors. "A comprehensive and ambitious package of interventions that tackle prevention and treatment could lead to a 90% reduction in incidence of new chronic infections and a 65% reduction in worldwide mortality by 2030."

European action plan for the health sector response to viral hepatitis

Image credit: Image by ECDC, European Centre for Disease Prevention and Control.

States in the European Region adopted a World Health Organization (WHO) action plan for the health sector response to viral hepatitis in September 2016.

The plan sets the ambitious goal of eliminating viral hepatitis as a public health threat in the Region by 2030. This is to be achieved by reducing new infections and deaths from viral hepatitis and its complications, and ensuring equitable access to recommended preventive, testing, care and treatment services for all. It proposes priority actions for Member States, accompanied by supporting actions for WHO, in five strategic directions: information for focused action, interventions for impact, delivering for equity, financing for sustainability and innovation for acceleration. 

Commenting on the goals set out in the action plan, the European Centre for Disease Prevention and Control (ECDC) emphasises the importance of national testing and screening programmes to identify people with the infection and improve estimates of prevalence. Making testing available to populations at higher risk of viral hepatitis, especially people who inject drugs and migrants from countries with a high burden of viral hepatitis, will be especially important.

Larger-scale treatment access is also essential, not just to reduce the burden of disease and death but also to limit transmission. Public Health England (which is not responsible for providing treatment) notes that although deaths due to hepatitis C-related end-stage liver disease or liver cancer fell by 11% in 2015 in England and Wales, probably due to targeting treatment at those with advanced liver disease, treatment needs to be much more widely available to reduce transmission.

Reinfection risk

Reinfection with the hepatitis C virus (HCV) after successful treatment has been raised as a concern regarding treatment of people who inject drugs and men who have sex with men. A recent European study found that a quarter of men who have sex with men cured with a 12-week regimen of pegylated interferon and ribavirin were subsequently reinfected at least once.

Findings presented at the 5th International Symposium on Hepatitis Care in Substance Users (INHSU 2016) in September showed that approximately 4% of people who took part in the C-EDGE CO-STAR study were reinfected with HCV within 24 weeks of achieving an undetectable viral load on treatment. The C-EDGE CO-STAR study recruited people who had a history of injecting drugs and who were currently receiving opioid substitution therapy. People were not excluded from the study if drug testing showed evidence of illicit drug use during the trial. Participants received a 12-week course of treatment with grazoprevir/elbasvir (Zepatier) either immediately or after a 12-week delay.

Six reinfections were detected. These were distinguished from viral rebound by checking whether the rebounding virus was genetically different from the virus present before treatment. In three cases reinfection was cleared spontaneously, without treatment. The researchers calculated that the reinfection rate was 4.6 per 100 person-years of follow-up, and the rate of chronic reinfection requiring treatment was 3%.

The rate seen in this study was fairly similar to rates seen in previous studies.

Dr Håvard Midgard of Akershus University, Oslo, stressed to the conference the importance of acknowledging the occurrence of HCV reinfection without stigma and discrimination, which could drive people away from care. Education and counselling about the possibility of reinfection are needed, as are ongoing post-treatment surveillance and harm reduction efforts.

Mortality risk after SVR in Scotland

Direct-acting antiviral therapy or interferon-based therapy eliminates hepatitis C infection and has been shown to reduce liver-related and all-cause mortality. A new study raises the question whether successful treatment also reduces the risk of death in older people with advanced liver disease or people with heavy drug/alcohol use.

A study of a large population of people in Scotland who received treatment with interferon-based therapy and who achieved sustained virologic response (SVR) between 1996 and 2011 has shown that factors unconnected with the liver damage caused by hepatitis C infection may be the most important causes of death after treatment.

Hepatitis C infection is strongly associated with a history of injecting drug use in Scotland. Alcohol consumption is a major cause of liver disease in Scotland regardless of hepatitis C virus infection.

The study of 1824 people found that the risk of death remained approximately twice as high in those cured as in the general population during the post-treatment follow-up period. Although liver cancer accounted for approximately a quarter of all deaths, drugs contributed to death in 42% of people, and were even more likely to be the cause of death in under-50s.

Having cirrhosis and being older before starting treatment predicted an increased risk of death after being cured, but so did a history of drug use, heavy alcohol use or hospitalisation for drug or alcohol intoxication. The study authors say that their findings suggest the need for greater attention to risk factors such as alcohol consumption, drug use and resumption of injecting drug use in people at the time of hepatitis C treatment, and in post-treatment follow-up. Better linkages between specialist care and primary care in order to support people after being cured of hepatitis C may be necessary to avoid drug and alcohol-related harm.

Shortening treatment

Direct-acting antiviral therapy that combines drugs targeting different steps of the hepatitis C virus (HCV) lifecycle – usually taken for 12 weeks – is highly effective, but researchers continue to explore new combinations that can be used for a shorter duration, thereby improving convenience and reducing cost.

Two studies of shorter-duration treatment regimens were presented last month at the New Perspectives in Hepatitis C Virus Infection – The Roadmap for Cure conference in Paris.

A triple regimen containing two experimental hepatitis C drugs – AL-335 and odalasvir – plus simeprevir taken for either 6 or 8 weeks cured all participants with previously untreated genotype 1 hepatitis C who did not have cirrhosis in a small study, while a dual regimen without simeprevir cured 90%.

A larger phase 2b trial (NCT02765490) evaluating 800mg AL-335 + 25mg odalasvir + 75mg simeprevir, all once-daily for 6 or 8 weeks, is expected to begin enrolment this autumn for treatment-naive and treatment-experienced people without cirrhosis who have HCV genotypes 1, 2, 4, 5 and 6.

The combination is being developed by Janssen in partnership with Achillion.

AbbVie presented results of a study of a shortened treatment duration for people with genotype 1b using its '3D' regimen. The 3D regimen (marketed as Viekirax/Exviera in Europe and Viekira Pak or Viekira XR in the US) consists of the HCV protease inhibitor paritaprevir boosted with ritonavir, the NS5A inhibitor ombitasvir and the NS5B polymerase inhibitor dasabuvir. The approved indication in the EU and US is 12 weeks of the 3D combination alone for people with HCV genotype 1b with or without liver cirrhosis, 12 weeks of 3D plus ribavirin for people with harder-to-treat genotype 1a without cirrhosis and 24 weeks of 3D plus ribavirin for people with genotype 1a and compensated cirrhosis.

AbbVie’s paritaprevir-based 3D regimen taken for just 8 weeks without ribavirin led to sustained virological response in 98% of easier-to-treat people with HCV genotype 1b who did not have cirrhosis, according to findings from the GARNET study.

Based on these findings, the hepatitis C treatment recommendations newly released by the European Association for the Study of the Liver (EASL) now say that previously untreated people with genotype 1b and without cirrhosis can be treated with the 3D regimen for either 8 or 12 weeks.

Access to treatment

A Canadian study of access to hepatitis C treatment shows that 85% of provinces and territories apply restrictions on who can obtain hepatitis C treatment, with almost all limiting access to those with F2 fibrosis or above, and denial of access to sofosbuvir in Quebec province. The regional variations are due to the lack of national strategy on hepatitis C control, say researchers from the Canadian Network on Hepatitis C.

In the United States access to hepatitis C is partly determined by whether an individual has private or public insurance coverage. Yet, even for people with insurance coverage, co-payment charges can pose a huge financial barrier to treatment. A study by one clinic in New York state has found that patients were required by their insurer to pay an average of $320 from their own pocket as co-payment for a course of hepatitis C treatment. The study found huge variation between insurers in co-payments and patients experienced long delays attempting to negotiate assistance from pharmaceutical companies or reductions in co-payments.

In England and Wales the Hepatitis C Trust has decided to end a legal challenge to the restriction on the number of people who will receive hepatitis C treatment. NHS England is providing treatment for 10,000 people in the 2016/17 financial year with a monthly limit on the number of patients each regional network of hospitals can treat.

The decision follows the rejection of a judicial review request by Hepatitis C Trust. In his ruling Justice Blake said that the monthly limit was lawful and represented a rational means of ensuring that treatment was available for people with the highest unmet clinical need.

Next month: news coverage of The Liver Meeting 2016

Next month, infohep will be providing news coverage from The Liver Meeting 2016, organised by the American Association for the Study of Liver Diseases (AASLD). The conference is taking place in Boston, USA from 11-15 November.

We will be publishing news online and the November infohep bulletin will be dedicated to news from the conference.

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