The World Health Organization (WHO) has issued its first guidelines on the prevention, treatment and care of hepatitis B virus (HBV). WHO estimates that 650,000 people die each year from liver cancer or cirrhosis as a consequence of hepatitis B infection, predominantly in lower- and middle-income countries. Approximately 240 million people are estimated to be infected with hepatitis B worldwide; between 20% and 30% of people who become infected with hepatitis B will go on to develop cirrhosis or liver cancer.

The guidelines recommend a simplified approach to hepatitis B monitoring and treatment in order to encourage the expansion of hepatitis B treatment in lower- and middle-income settings. In their quest to simplify hepatitis B treatment, WHO is following the successful example of the scale up of antiretroviral treatment for HIV. The guidelines are based on expert recommendations, following a rigorous review of the published evidence.

For people diagnosed with chronic hepatitis B, WHO recommends the use of a non-invasive test, the AST-to-platelet ratio (APRI) to assess the presence of cirrhosis where Fibroscan or Fibrotest is not available. Anyone with indications of cirrhosis by these tests should be treated, regardless of ALT levels, HBeAg status or HBV DNA levels. Treatment is also recommended in persons aged over 30 years without evidence of cirrhosis if they have persistently elevated ALT levels and high-level HBV DNA (>20,000 IU/ml). If HBV DNA testing is not available, treatment should be considered in cases of persistently elevated ALT levels even if cirrhosis is absent. People who do not meet these criteria at present should be monitored annually for signs of disease progression. In people with fluctuating ALT and HBV DNA levels more frequent monitoring may be indicated.

The preferred first-line therapy for chronic hepatitis B is either tenofovir or entecavir due to their high barriers to resistance. Lamivudine, adefovir or telbivudine are not recommended due to the higher risk of resistance to these drugs. Tenofovir is recommended as the preferred second-line treatment in people who have previously received other antiviral drugs.

Treatment should be lifelong in people with cirrhosis. Treatment discontinuation should be considered only in people without cirrhosis who show evidence of HBeAg loss and seroconversion to anti-HBe, and who have persistently normal ALT levels and undetectable HBV DNA. Treatment should be resumed if reactivation of hepatitis B replication occurs, and all people who stop treatment should be monitored for reactivation.

All people on treatment with cirrhosis should be monitored every six months for liver cancer, as should people with chronic hepatitis B with a family history of liver cancer. Regular monitoring for liver cancer is also indicated for people aged 40 and over with HBV DNA above 2000 IU/ml, in the absence of cirrhosis.

In people with HIV and hepatitis B co-infection, antiretroviral treatment containing tenofovir should be initiated in all those with evidence of severe chronic liver disease and in those with CD4 cell counts below 500, regardless of liver disease.

The guidelines also include recommendations on how to scale up treatment and monitoring, and special considerations for populations including people with decompensated cirrhosis and pregnant women.

People with HIV and hepatitis C co-infection who delay hepatitis C treatment remain at risk for liver failure, hepatocellular carcinoma and liver-related death even after being cured – with outcomes worsening the longer it is delayed – indicating that treatment should not be deferred until advanced disease, according to a presentation at the Conference on Retroviruses and Opportunistic Infections (CROI 2015) last month in Seattle, USA. Treating only after progression to cirrhosis increased the risk of liver-related death by more than five-fold and the duration of infectiousness by four-fold.

Debates over when to treat hepatitis C have been dominated by the question of rationing treatment due to its high cost. National recommendations prioritise people with cirrhosis because they are at high risk of progression to decompensated cirrhosis and liver cancer, and also people with F3 fibrosis.

The study used historical data on the occurrence of liver disease and liver-related death from the Swiss HIV Cohort Study to simulate rates of disease progression and clinical events such as decompensated cirrhosis and liver cancer. They compared a scenario of disease progression rates in the period before the introduction of direct-acting antivirals to treatment with direct-acting antivirals that cured at least 90% of people, and compared the effects of starting treatment at different stages of liver damage.

Another study presented at the conference showed that almost half of the ‘baby boomer’ generation of Americans with hepatitis C born between 1945 and 1965 are likely to have already progressed to severe fibrosis or cirrhosis. This means that they are a high priority for treatment.

The study found little evidence that expanded screening within this birth cohort, which the CDC has recommended since 2012, has led to people being diagnosed with hepatitis C at less-advanced stages of disease. This is likely due to the fact that the hepatitis C infection remained undetected and therefore untreated for several decades in most of these patients. The results underline the urgency to continue expanded screening, as time is running out for many patients at risk.

Studies of two interferon-free regimens have shown that people with HIV and hepatitis C co-infection can achieve the same very high hepatitis C cure rates as people who are monoinfected. Studies of sofosbuvir combined with ledipasvir (Harvoni) and sofosbuvir combined with daclatasvir (Sovaldi plus Daklinza) showed cure rates above 95%. In both studies, treatment lasted for 12 weeks. The regimen containing daclatasvir was studied in people with genotypes 1-6, both treatment-experienced and previously untreated. Both regimens were well-tolerated.

It is unlikely that sofosbuvir will be used with daclatasvir in higher-income countries owing to the cost, but this regimen could prove to be of value in lower-income settings where intellectual property laws permit generic drug manufacturers to combine the two agents, and where the pan-genotypic activity of this combination makes pre-treatment genotyping unnecessary.

People receiving interferon-based treatment for hepatitis C value clinicians who give information and clinical feedback that is personalised to their individual needs and lifestyle, and cite this as an important facilitator of good adherence. Furthermore, clinicians should better understand and acknowledge their patients’ motivations for persevering with an often difficult course of treatment. These insights come from two recently published qualitative studies from Australia and the United States, each interviewing around 20 current or former hepatitis C patients.

Feedback on progress during interferon-based treatment was critical for many patients. People also wanted personalised advice based on their health, lifestyle, social, and employment situation, rather than one-size-fits-all information provision.

People stuck to a course of treatment despite difficult side-effects for a number of reasons, most of them not directly related to health. The eradication of a stigmatised infection and treatment as part of a process of personal rehabilitation from drug use were frequent themes when people were asked about their motivations for completing a course of treatment.

With the arrival of new antivirals with better tolerability, side-effects may have a lesser impact on patient adherence than interferon-based treatment. However, these new drugs are still not available in many resource-limited settings.  

A Bangladeshi company, Incepta, has begun manufacturing a generic version of sofosbuvir that will sell for US$900 for a 12-week course of treatment. Incepta is not one of the 11 Indian companies licensed to produce generic versions of sofosbuvir, but will seek World Health Organization prequalification of its product.

Prequalification is a procedure in which generic manufacturers submit data on quality and bioequivalence of their generic versions of branded products to the World Health Organization. Prequalification covers drugs used in the treatment of HIV, tuberculosis, malaria, neglected tropical diseases and influenza. Hepatitis C was added to this list in 2014. If products meet stringent standards, they are prequalified, which speeds up registration in countries with limited regulatory capacity. Prequalification also permits products to be bought by international donors, in the case of antiretroviral drugs for treatment of HIV. The World Health Organization also prequalifies tests used for screening or diagnosis.

UNITAID, the medicines finance fund for HIV, tuberculosis and malaria, has begun an investigation of ways in which it can support work to reduce the cost of hepatitis C drugs. UNITAID works with generic manufacturers, diagnostic companies, donors and governments to identify ways to reduce prices and expand access to lifesaving medicines. For example, UNITAID funded work with manufacturers to find ways to reduce manufacturing costs for antiretroviral drugs. It also works on forecasts of demand for drugs.

UNITAID has issued a Hepatitis C Medicines Technology and Market Landscape report which describes agents available for hepatitis C treatment and the barriers to affordable treatment. Although the report acknowledges that high prices of branded products are an enormous barrier, it also demonstrates that in order to achieve price reductions, numerous policy changes are needed. A number of mutually reinforcing barriers also need to be overcome. These include:

• Generic manufacturers will need predictable large-volume orders before they can reduce prices substantially. This happened for HIV drugs when the Global Fund and the US Government committed funds to support treatment.
• Donor support and national commitment for hepatitis C treatment in lower-income countries are lacking due to perception of high price, lack of demand, lack of advocacy infrastructure and lack of epidemiological surveillance.
• Widespread patenting of originator products and exclusion of middle-income countries from voluntary licensing keeps prices high in many countries with large numbers of people in need of treatment, adding to the perception that national treatment programmes would be unaffordable.

Delays in regulatory approval and in the updating of treatment guidelines also create barriers to access.

The National Institute for Health and Care Excellence (NICE), the health technology assessment body for England, has recommended that sofosbuvir/ledipasvir (Harvoni) should be made available through the National Health Service for treatment of genotype 1 and 4 hepatitis C.

In patients with genotype 1 infection, Harvoni is recommended in England for all previously untreated patients and for treatment-experienced patients without cirrhosis. A 24-week course of treatment in treatment-experienced patients with cirrhosis was not found to be cost-effective when compared to sofosbuvir plus pegylated interferon and ribavirin, and so it is not recommended. The same is true for treatment-experienced patients who do not have cirrhosis.

However, NICE says that there is not enough evidence that use of Harvoni in combination with ribavirin for treatment of genotype 3 would be cost effective, despite the fact that the European Medicines Agency has granted a European Union license for this use.

This guidance is still draft guidance, and could change after public consultation.

Final NICE guidance documents on the use of sofosbuvir (Sovaldi) and simeprevir (Olysio) were also issued in February.

The 24th International Harm Reduction Conference will take place in Kuala Lumpur, Malaysia, in October 2015.

The online process for submitting papers is now open, and will remain open until 27th March 2015.

We have recently published a new factsheet on Harvoni, an addition to the five 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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