Experimental treatments for hepatitis B

Andrew Vaillant, presenting at AASLD 2016. Photo by Liz Highleyman, hivandhepatitis.com

Today there is no cure for hepatitis B infection. Current treatment consists of prolonged antiviral treatment, preferably using either tenofovir or entecavir, to control viral replication. Owing to the integration of hepatitis B virus (HBV) DNA into the cellular nucleus in a form called cccDNA, it is not possible to eradicate the virus with antiviral drugs available today. New drugs are needed that will either interrupt the production of new cccDNA in the liver, or target other steps in the viral lifecycle, leading to loss of HBsAg. Ultimately the aim of experimental treatment for HBV is either to eradicate the virus entirely, or to achieve a 'functional' cure, meaning that the immune system is able to control any residual HBV infection without ongoing damage to the liver and without further antiviral treatment.

One approach to targeting a new step in the HBV lifecycle is to block the release of HBV viral subparticles from infected hepatocytes. Montreal-based Replicor, Inc. is developing nucleic acid polymers (NAPs) that interfere with the assembly and block the release of these particles. At the 2016 Liver Meeting, organised by the American Association for the Study of Liver Diseases (AASLD), the company presented promising preliminary results of a study of two nucleic acid polymers – REP 2139 and REP 2165 – used in combination with tenofovir disoproxil fumarate and pegylated interferon for the treatment of hepatitis B 'e' antigen (HBeAg)-negative chronic hepatitis. The study found that all people who received REP 2139 and six of the nine who received REP 2165 experienced a reduction of 90% or more in HBsAg levels after 12 weeks of treatment.  People in the study also experienced large increases in ALT (alanine transaminase) levels during treatment; this may be a sign of immune restoration but will need careful observation in future studies to ensure patient safety. This study will continue, and will test whether people who receive the experimental drugs are able to control HBV replication after stopping all treatment for at least six months. Larger studies will be needed to determine whether this form of treatment can deliver a functional cure.

Improving the immune system’s ability to control HBV and recognise HBV-infected cells might also assist in controlling the infection, even if it cannot be eradicated. Therapeutic vaccines are one means of improving immune responses to a viral infection. By presenting an inactive sequence of the virus in the form of a vaccination, researchers try to stimulate improved immune responses that will lead to better control of HBV.

At the AASLD Liver Meeting Gilead Sciences reported the results of a phase II study of a therapeutic vaccine, GS-4774, designed to improve HBV-specific immune responses. The vaccine was tested in a randomised study of 195 people taking tenofovir as antiviral treatment. The study found no significant difference in HBsAg levels between those receiving the vaccine and those receiving tenofovir alone after 24 weeks. The study investigators say that this is not the end of HBV therapeutic vaccine research; the study findings will inform how future therapeutic vaccines will be designed, and in particular, which immune responses need to be improved in order to control HBV.

8-week sofosbuvir/ledipasvir treatment course

Large real-world studies have confirmed that for people without cirrhosis, an 8-week course of sofosbuvir/ledipasvir (Harvoni) is just as likely to cure genotype 1 infection as a 12-week course of treatment.

The European Association for the Study of the Liver (EASL) treatment recommendations state that treatment with sofosbuvir/ledipasvir for 8 weeks can be considered in people with viral load below 6 million IU/ml – but for anyone treatment-experienced, a 12-week course of treatment is recommended. The guidelines also say that for people with F3 fibrosis, an 8-week course of treatment should be approached with caution.

However, some physicians still prefer to treat for 12 weeks to be on the safe side, and some patients are concerned that an 8-week course of treatment is suboptimal and is being prescribed to save money.

Reviews of three treatment cohorts presented at the AASLD Liver Meeting showed no difference in the rates of cure according to whether people were treated for 8 weeks or 12 weeks.

Considering only previously untreated people with viral load under 6 million IU/ml, a cohort study of approximately 850 people found a 98.5% cure rate in those treated for 8 weeks. A German study found no difference in cure rate between 8-week and 12-week treatment courses – 98% in each group. And, in a smaller cohort of people with HIV/HCV co-infection (59 people), there was no difference in cure rate between those treated for 8 weeks or 12 weeks.

These findings suggest that an 8-week treatment course is just as effective as a 12-week treatment course for those without very high viral load.

DAA treatment in HIV/HCV co-infection

Juan Gonzalez-García of Hospital La Paz, Madrid. Photo by Liz Highleyman, hivandhepatitis.com

Several large real-life cohort studies also confirmed that for people with HIV/HCV co-infection, direct-acting antiviral (DAA) treatment is just as effective in real life as in clinical trials.

A study of 2030 people with co-infection treated in Madrid found a 92% cure rate, with very little variance in the cure rate between genotypes 1a, 1b, 3 and 4. The predominant regimen used was sofosbuvir/ledipasvir (63%). Almost half the cohort had cirrhosis. People with compensated cirrhosis were just as likely to be cured as those without. Decompensated cirrhosis or the use of regimens such as sofosbuvir/ribavirin or simeprevir/daclatasvir were the only predictors of treatment failure.

A review of approximately 700 people treated with sofosbuvir/ledipasvir in the United States and Portugal found that cure rates across all sub-groups – including black people, women, treatment-experienced people and people with cirrhosis – were very similar to those seen in clinical trials. Between 92 and 97% of people with co-infection were cured.


Research carried out by Mount Sinai Medical Center, New York, found that non-adherence was the strongest risk factor for treatment failure in people taking sofosbuvir/ledipasvir (Harvoni). The main reasons cited for non-adherence were failing to take medication as prescribed and hospitalisation.

The study looked at reasons for virological failure in people attending the clinic, and found that among the small number who experienced virological failure, non-adherence was the main reason. Not understanding the need to continue taking medication after viral load became undetectable on treatment may have been one reason, but the study also found that hospitalisation affected ability to take medication. In older people with hepatitis C virus (HCV) other health conditions may lead to emergency hospitalisation.

The researchers concluded that their findings “underscore the need for providers to clearly communicate dosing information and to ensure that patients have access to an uninterrupted supply of medication.” They suggested that pre-treatment adherence counselling and a pill bottle monitoring system may also improve sustained virological response rates.

The content of pre-treatment counselling needs to be tailored to patient characteristics and pre-existing beliefs about treatment, as well as addressing lifestyle factors that might affect adherence.

The Psychosocial Readiness Evaluation and Preparation for Hepatitis C Treatment (PREP-C) tool has been designed to allow healthcare providers to conduct a psychosocial evaluation of readiness to take hepatitis C treatment, and to identify areas of psychosocial functioning that can be improved before an individual begins HCV treatment to ensure that treatment will be successful.

People can also assess their own readiness for treatment by using the HepCure app, developed by the Mount Sinai hepatitis C team. The app can also be used to set adherence reminders and to communicate with healthcare providers on treatment adherence, side-effects and lab test results.

Use of generic drugs for treatment of hepatitis C

Dr James Freeman presenting at ILC 2016. Photo by Liz Highleyman, hivandhepatitis.com

Mylan, a generic pharmaceutical manufacturer in India, has agreed a licence with the Medicines Patent Pool to produce a generic version of daclatasvir for sale in 112 lower-income countries. The licence allows Mylan to develop fixed-dose combinations that offer the potential to treat all of the six major genotypes of hepatitis C virus.

Availability of fixed-dose combinations that contain daclatasvir would encourage optimal use of generics. Owing to the low daily dose of the drug (60mg), its manufacturing cost is low. Analysis of the cost of raw materials needed to make daclatasvir led researchers to estimate in 2015 that it might be possible to reduce the cost of daclatasvir to $22 for a 12-week course of treatment. A 12-week course of daclatasvir and sofosbuvir could be manufactured for $200, they estimated.

A study presented at the AASLD Liver Meeting showed that suboptimal use of generic direct-acting antivirals was leading to disappointing cure rates in Qatar. Physicians reported on the use of generics or branded products in approximately 250 people, two-thirds of whom were using generic drugs. The cure rate was significantly higher in people receiving branded drugs, but the researchers point out that many of those taking generics were treated with sofosbuvir and ribavirin only, most likely for reasons of cost. In April 2016, interim results of a different study presented at the International Liver Congress had suggested that generics were just as effective as branded products.

Prequalified hepatitis C rapid test

A 20-minute rapid test for hepatitis C antibodies has been approved by the World Health Organization (WHO) prequalification scheme for medicines and diagnostics. The test is designed to be used by healthcare workers to speed up diagnosis of hepatitis C virus (HCV) in lower-income settings. The SD Bioline HCV test can be performed without electricity. The SD Bioline HCV test is the first rapid test for HCV to meet stringent quality standards. The WHO prequalification gives regulatory agencies and funders confidence that the test can be approved rapidly and purchased, and wider availability of a rapid diagnostic test will improve screening and diagnosis efforts for hepatitis C.

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