Victor Virlogeux and Bart Rijnders at CROI 2017. Photo by Liz Highleyman, hivandhepatitis.com

A little more than a year after the Netherlands instituted a policy allowing unrestricted access to direct-acting antivirals (DAAs) for the treatment of hepatitis C, researchers have already seen a dramatic decline in acute hepatitis C virus (HCV) infections among one at-risk population, HIV-positive men who have sex with men.

These findings were reported at the Conference on Retroviruses and Opportunistic Infections (CROI 2017) in Seattle in February.

As of November 2015, DAAs can be prescribed to all people with co-infection regardless of liver fibrosis stage in the Netherlands. Researchers looked first at the responses to DAA treatment in a large national cohort of people living with HIV. The cohort included 1420 people with HIV/HCV co-infection.

As of January 2017, 82% had started DAA treatment and 70% were either cured or still on therapy. Among people treated with DAAs, the sustained virologic response rate was very high, at 98%.

The researchers then looked at changes in acute HCV infections among HIV-positive men who have sex with men since the DAA roll-out, comparing HCV incidence in 2014 and 2016 – the first full year of unrestricted DAA availability.

Annual HCV incidence fell from 1.1% to 0.5% per year – a highly significant 51% reduction. Annual incidence also declined further during 2016, from about 0.7% during the first half of the year to 0.4% during the second half.

Presenting the findings, Bart Rijnders noted that there was an "astonishing" 41% increase in new syphilis cases among HIV-positive men who have sex with men during this period, so he was confident the reduced HCV incidence was not attributable to changes in sexual risk behaviour.

Another study carried out in the Netherlands provides less good news about  HCV infections, in HIV-negative men who have sex with men. HCV prevalence is higher than expected among HIV-negative men who have sex with men taking part in a study of pre-exposure prophylaxis (PrEP) in Amsterdam. PrEP is the use of two anti-HIV drugs by HIV-negative people to prevent infection with HIV.

Historically, the risk of HCV infection via sex in HIV-negative people has been seen as low. US guidelines still state that the risk of infection even in people with multiple partners or with a partner with HCV is ‘low’ and that screening or regular testing is not recommended.

However, the AmPrEP study found a prevalence of 4.8% among men joining the study. The rate of new infections is not known yet, but the baseline prevalence is much higher than seen in any previous study in HIV-negative men. Genetic testing shows that many of the infections are linked, either to other men receiving PrEP, or to men with HIV/HCV co-infection in the Amsterdam Clinic cohort.

Hepatitis C is much more common in HIV-positive gay men than in HIV-negative men. A number of studies from Europe and North America have found that in the region of 6.5% of HIV-positive gay men have chronic hepatitis C at any one time and that gay men with HIV are 7.5 times more likely to have hepatitis C than men without HIV. Infection rates have been rising in HIV-positive gay men over time.

Investigator Maria Prins said that hepatitis C screening and regular testing should become the norm among gay men seeking and taking PrEP.

Australia may be able to eliminate hepatitis C infection by 2026 if current rates of treatment continue, a report from the Kirby Institute of the University of New South Wales predicts.

The report estimates that between 30,000 and 33,000 people started direct-acting antiviral (DAA) treatment in 2016. After an early spike in the number of people treated, new treatment initiations have settled down below 2500 a month.

Australia has been able to scale up hepatitis C treatment rapidly as a result of a price deal between the federal government and pharmaceutical companies. The Australian government has committed to spend AUS$1 billion over 5 years on DAAs from 2016. In return, pharmaceutical companies have agreed that if expenditure exceeds a certain limit in any year, any extra medication will be supplied at a very steep discount. This creates an incentive to diagnose and treat as many people as possible. In November 2016 the Kirby Institute estimated that two-thirds of people with cirrhosis as a result of hepatitis C had already started DAA treatment in Australia.

Other countries and cities are also working towards hepatitis C elimination, although without the agreement on drug pricing that has encouraged such rapid treatment expansion in Australia.

In San Francisco the End Hep C SF programme aims to make San Francisco the first hepatitis C-free city in the United States. A citywide alliance of healthcare professionals and community organisations is committed to:

• Citywide community-based hepatitis C virus (HCV) testing for highly impacted populations paired with augmented HCV surveillance infrastructure to track the HCV epidemic and progress towards elimination.
• Linkage to care and treatment access for all people living with HCV.
• Prevention of new HCV infections and reinfection in those cured of HCV.

The programme includes provision of harm reduction and opioid substitution therapy, as well as methadone-based directly observed therapy, and reinfection prevention counselling.

Testing and diagnosis of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection is the gateway for access to both prevention and treatment services, and is a crucial component of an effective response to the hepatitis epidemic. Early identification of people with chronic HBV or HCV infection enables them to receive the necessary care and treatment to prevent or delay progression of liver disease. Testing also provides an opportunity to link people to interventions to reduce transmission, through counselling on risk behaviours and provision of prevention commodities (such as sterile needles and syringes) and hepatitis B vaccination.

The World Health Organization (WHO) has issued new guidelines on testing for chronic HBV and HCV infection to complement its guidance on the prevention, care and treatment of chronic hepatitis C and hepatitis B infection. The guidelines outline the public health approach to strengthening and expanding current testing practices for HBV and HCV, and are intended for use across age groups and populations.

These guidelines also provide a framework for country decision-making and planning in two key areas:

• how to organise hepatitis laboratory testing services
• how to plan the best strategic mix of different testing approaches.

WHO has also produced a useful policy brief summarising the guidelines. The policy brief includes algorithms for diagnosis, treatment and monitoring of hepatitis B and C infection.

As well as causing liver damage, hepatitis C infection can lead to extrahepatic disease, including cryoglobulinemia, chronic kidney disease and renal failure, diabetes and B-cell non-Hodgkin lymphoma. Hepatitis C has also been implicated in the development of cardiovascular disease.

Curing hepatitis C infection has been shown to reduce the risk of diabetes, kidney failure and cardiovascular disease in people with mono-infection, but the extrahepatic effects of curing hepatitis C have not been established in people with HIV and hepatitis C virus (HCV) co-infection.

Curing hepatitis C infection substantially reduces the risk of developing type 2 diabetes in people with HIV/HCV co-infection, but does not reduce the risk of cardiovascular disease, cancers or other non-AIDS events, a study of people with co-infection treated in Spain between 2000 and 2008 has shown. The findings are published online ahead of print in the journal Hepatology.

Heiner Wedemeyer, presenting at AASLD 2016. Photo by Liz Highleyman, hivandhepatitis.com

Hepatitis delta is a small, defective virus that can only replicate in the presence of hepatitis B virus (HBV). Over years or decades chronic HBV infection can lead to advanced liver disease including cirrhosis and liver cancer. HBV/hepatitis delta virus (HDV) co-infection is associated with more rapid and severe liver disease progression, and people who carry both viruses are more likely to develop cirrhosis and hepatocellular carcinoma than those with HBV alone.

Antiviral therapy using nucleoside/nucleotide analogues (NUCs) such as tenofovir DF (disoproxil fumarate) or tenofovir AF (alafenamide) (Viread or Vemlidy) can suppress HBV replication during treatment but usually does not lead to a cure, so long-term treatment is generally needed. NUCs, however, are ineffective against the delta virus.

There is no standard treatment for hepatitis delta, although pegylated interferon has been shown to suppress HDV replication at least temporarily. Across studies, about one quarter of individuals are still HDV RNA negative 6 months after pegylated interferon treatment. However, even this sustained response is often not durable. Late relapses of HDV RNA have been observed in many of these people, even several years after completing treatment.

Lonafarnib is being tested as an inhibitor of hepatitis delta replication. Results from a phase II study presented at the AASLD Liver Meeting in November 2016 show that lonafarnib reduces hepatitis delta levels in the blood and liver enzyme levels. Boosting of blood levels of lonafarnib with another drug, ritonavir, led to higher blood levels, but only a third of people were able to tolerate the highest dose for a full treatment course. The study did not report whether the highest blood levels and highest dose were correlated with the best responses to treatment.

Besides lonafarnib, clinical studies are also investigating other agents such as the entry inhibitor myrcludex B and nucleic acid polymers (most recently REP 2139-Mg and REP 2165-Mg) against hepatitis B and delta.

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