US guidelines for the treatment of hepatitis C developed by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America have been updated to recommend direct-acting antiviral treatment for everyone with hepatitis C, regardless of disease stage.

The guideline panel says that when the new medications first became available, the goal was to treat people in most urgent need – and to avoid doing harm. Now that more experience has accumulated as a result of early trials, and patients in especially high need of treatment have in theory been prioritised for treatment, the guidelines panel says that the weight of evidence regarding reduced mortality and illness means that everyone should be treated.

However, the guidelines also acknowledge that funding may not be available to treat everyone, and that clinicians should be particularly aware of the need for treatment in people with:

• Advanced liver disease
• Rapidly progressing fibrosis
• Post-transplantation recurrence of hepatitis C
• Extrahepatic manifestations of hepatitis C.

The guidelines implicitly acknowledge that one of the biggest barriers to treatment in the United States – aside from lack of insurance coverage – is the tight restrictions imposed by many insurers on who is eligible for hepatitis C treatment.

However, insurers are rationing treatment because the high prices of hepatitis C drugs threaten to overwhelm budgets, in both the private and the public insurance systems. In New York state, for example, spending on hepatitis C drugs for over-65s accounted for 9% of the entire national fund (Medicare) that subsidises prescription drug costs for the elderly. California seniors took a similar chunk of the fund to pay for hepatitis C drugs.

Recently published US research tends to support the prioritisation of treatment for people with more advanced liver disease. For patients with hepatitis C virus (HCV) monoinfection, baseline fibrosis stage is strongly predictive of the medium-term risk of serious liver disease and death, investigators from the United States reported in the online edition of Clinical Infectious Diseases. After five years of follow-up, over a third of patients with F4 stage liver fibrosis at baseline had developed hepatic decompensation or liver cancer. This compared to a progression rate of just 2% among patients with F0/F1 stage disease at baseline.

The US Food and Drug Administration (FDA) has issued a warning that two drug combinations for hepatitis C, Viekira Pak and Technivie, may be associated with an increased risk of serious liver injury in people with advanced cirrhosis.

Viekira Pak contains the HCV direct-acting antivirals dasabuvir, ombitasvir, paritaprevir, and ritonavir. It is marketed in the European Union as Viekirax.

Technivie contains ombitasvir, paritaprevir, and ritonavir. It is marketed in the European Union as Viekiraz (note the different spelling).

Both combinations are manufactured by AbbVie.

Both combinations are already contraindicated for people with Child-Pugh C stage cirrhosis (decompensated cirrhosis). The new warning adds a contraindication to the product label for use in people with Child-Pugh B cirrhosis.

The US FDA said: “Our review of adverse events reported to the FDA Adverse Event Reporting System (FAERS) database and to the manufacturer of these medicines, AbbVie, identified cases of hepatic decompensation and liver failure in patients with underlying liver cirrhosis who were taking these medicines. Some of these events resulted in liver transplantation or death.”

Some of the cases occurred in people who should not have been prescribed either Viekira Pak or Technivie because of advanced cirrhosis.

“Of the 26 assessable cases in which causality to components of Viekira Pak or Technivie was attributed to be possible or probable, 10 patients experienced hepatic failure resulting in transplantation or death, and 16 patients experienced various degrees of liver dysfunction.

“The post-marketing cases of hepatic decompensation and liver failure are difficult to interpret because they occurred mostly in patients with underlying advanced chronic liver disease. However, temporal association from starting Viekira Pak or Technivie and resolution of symptoms in some patients after the medicine was stopped suggest a potential causal association.”

AbbVie chairman Barry Bernstein said in an interview with MD Magazine, “The information is limited and it is impossible to establish a causal relationship.”

New recommendations on hepatitis C treatment and care for people who inject drugs encourage physicians to offer treatment to all people who inject drugs diagnosed with HCV, and to offer a comprehensive package of social support and harm reduction to enable people to adhere to treatment.

The recommendations are published this month in the International Journal of Drug Policy.

The publication of the recommendations coincided with an international meeting in Sydney, Australia, the 4th International Symposium on Hepatitis in Substance Users (view presentations here), which focused on the management of hepatitis among substance users.

The conference featured an analysis of the phase ION studies of sofosbuvir/ledipasvir, looking only at study participants who were receiving opioid substitution therapy (OST). The overall SVR12 rate (sustained virological response 12 weeks after the end of treatment – considered a cure) for people on OST was 94% – comparable to the 97% for other participants; ribavirin offered no added benefit. Similarly, people on OST were about equally likely to maintain at least 80% adherence (94% vs 96%, respectively). The conference also heard data on a study of HCV treatment responses in people receiving opioid substitution therapy in New York: 80% of people receiving sofosbuvir/ribavirin achieved a cure. Injecting drug use during the study did not affect the chances of a cure. There was a decline in treatment adherence in people treated for more than 12 weeks, indicating the importance of short hepatitis C treatment courses for people who inject drugs.

A second meeting, the 24th International Harm Reduction Conference, heard that achieving a preventive benefit of hepatitis C treatment among people who inject drugs will require a substantial reduction in barriers to treatment. While epidemiologists and public health experts are excited by the potential of new hepatitis C drugs to limit onward transmission of the virus among people who inject drugs, the strategies ignore profound barriers to drug users engaging with healthcare and their broader needs. For ‘treatment as prevention’ to be ethical and acceptable to people who inject drugs, enabling treatment and policy environments need to be created, advocates said.

Public health rhetoric advocating the targeting, testing and treatment of specific populations can raise fears in an already alienated and marginalised population, Magdalena Harris of the London School of Hygiene and Tropical Medicine suggested. The language used is often stigmatising (for example calling for a focus on “the core transmitters of incident HCV infections”).

She noted the many barriers which discourage people who use drugs from receiving hepatitis C treatment. These barriers include those to do with the individual (for example, mistrust of healthcare professionals, limited knowledge and concern about treatment side-effects) and barriers at the level of the healthcare provider (for example, perceptions of the patients’ readiness or eligibility for treatment or concerns about ongoing substance use). The availability of interferon-free hepatitis C treatments can help remove some of these barriers, and others can be worked on, she suggested.

However, the social and structural barriers are deeply entrenched and are rarely mentioned by proponents of hepatitis C treatment as prevention. These barriers include homelessness, poverty, stigma, marginalisation, criminalisation, limited social support, problems with health insurance or coverage, and alienating and confusing health care systems.

Magdalena Harris said that an enabling treatment environment would be needed. Her numerous qualitative studies with people who inject drugs suggested the potential of bringing hepatitis C treatment into community settings, with peer support as part of a holistic package. Services need to be trusted, familiar, accessible and convenient.

The conference also heard that opioid substitution therapy significantly reduces the risk of hepatitis C infection. A pooled analysis of 25 studies showed for the first time good evidence that methadone and other forms of opioid substitution therapy substantially reduce new hepatitis C infections. Previously, this had been clearly demonstrated for HIV, but not hepatitis C.

While an independent effect of needle and syringe exchange on hepatitis C was not demonstrated, programmes which combined opioid substitution therapy with needle and syringe exchange were more effective. Lucy Platt of the London School of Hygiene and Tropical Medicine presented the results to the 24th International Harm Reduction Conference.

The European Association for the Study of Liver Disease (EASL) and HIV in Europe have issued a consensus definition of late presentation of viral hepatitis in Europe, ahead of European HIV-Hepatitis Testing Week (20-27 November).

The consensus expert definition will contribute to improving surveillance of viral hepatitis as well as testing policies and strategies.

In 2011, a consensus definition for late presentation for HIV was presented and has since been widely implemented in Europe. It has contributed to shedding light on the number of people diagnosed late for HIV and has been used to evaluate current testing policies and strategies.

A consensus definition on late presentation for viral hepatitis is essential in order for public health authorities in Europe and elsewhere to be able to understand and respond to the issues around late presentation of viral hepatitis.

• Definition 1: Advanced HBV, HCV or HDV associated liver disease is clinically defined by presence of hepatocellular carcinoma or decompensated cirrhosis (jaundice, hepatic encephalopathy, clinically detectable ascites, variceal bleeding).

• Definition 2: Late presentation of HBV or HCV associated liver disease is defined as a patient with chronic hepatitis B or C and significant fibrosis (≥F3 assessed by APRI score >1.5, FIB-4 >3.25, Fibrotest > 0.59 or alternatively a FibroScan >9.5 kPa) with no previous antiviral treatment.

Hepatic encephalopathy is a brain dysfunction and complication of liver cirrhosis that is estimated to affect up to 200,000 people in Europe. Hepatic encephalopathy remains underdiagnosed and under-treated, resulting in poor quality of life for patients and a high burden on those who care for them.

The European Liver Patients Association (ELPA) has issued a report calling for a greater focus on hepatic encephalopathy, with training and information on how to recognise the condition for doctors and patients and greater access to treatments to improve quality of life for those with the condition.

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