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Combination therapies show promise against hepatitis D

Liz Highleyman
16 December 2019
Heiner Wedemeyer presenting results of a phase 2b study of bulevertide at the AASLD LIver Meeting, 2019. Photo by Liz Highleyman.

Combination regimens using lonafarnib or bulevirtide reduced levels of hepatitis delta virus (HDV) in a majority of people with HDV and hepatitis B virus (HBV) co-infection, researchers reported at the AASLD Liver Meeting last month in Boston.

HDV is a small, defective virus that can only replicate in the presence of HBV. Worldwide, as many as 20 million people are thought to carry HDV, according to Dr Christopher Koh of the US National Institute of Diabetes and Digestive and Kidney Diseases.

Over years or decades chronic hepatitis B can lead to advanced liver disease including cirrhosis and liver cancer. HBV/HDV co-infection is associated with more rapid and severe disease progression than hepatitis B alone, and up to 80% of people with co-infection may develop cirrhosis within five to ten years, Koh said.



A non-invasive test, used instead of a biopsy, to measure the stiffness or elasticity of the liver using an ultrasound probe.

Antivirals such as tenofovir disoproxil fumarate (TDF or Viread), tenofovir alafenamide (TAF or Vemlidy) and entecavir (Baraclude) can suppress HBV replication indefinitely during treatment, but they seldom lead to a cure. There is currently no approved treatment for HDV, though studies have shown that pegylated interferon can suppress HDV replication at least temporarily.


Koh presented findings from a phase II study of the prenylation inhibitor lonafarnib (brand name Sarasar) in combination with pegylated interferon lambda. Lonafarnib blocks the action of farnesyl transferase, an enzyme that modifies proteins through a process known as prenylation. This interferes with the assembly and packaging of new HDV virus particles. Pegylated interferon lambda (previously studied but never approved for hepatitis C) stimulates immune activity against viral hepatitis with fewer side effects than pegylated interferon alfa.

Previous research showed that lonafarnib reduced HDV RNA levels in a dose-dependent manner in short-term studies, but higher doses led to gastrointestinal side effects. As reported at the 2017 Liver Meeting, administration of lonafarnib with ritonavir allowed more people to take effective doses with acceptable side effects.

The LIFT-HDV trial included 26 participants. A majority (60%) were men and the median age was 40 years. At baseline the median HDV RNA level was 4.74 log10 IU/ml and the mean ALT level was 64 IU/ml. They had a median Ishak fibrosis score of 3, indicating moderate liver damage, and the median FibroScan liver stiffness score was 11.8 kPA (18 kPa is the usual cut-off for cirrhosis in people with hepatitis B).

All participants in this open-label study were treated with 50mg lonafarnib boosted with 100mg ritonavir administered orally twice daily, along with 180mcg pegylated interferon lambda administered by subcutaneous injection once weekly for 24 weeks.

Among participants treated for 24 weeks, HDV viral load fell by a mean of 3.18 log10 IU/ml, a significant decline from the baseline level. Among the 19 people who completed treatment, all but one (95%) had more than a 2 log10 IU/ml decline in HDV RNA and 10 (53%) achieved an undetectable level. Lower HDV viral load at baseline appeared to be a predictor of response, Koh said.

Treatment was generally safe, though side effects were common. The most frequent adverse events were diarrhoea (100%), nausea (63%), bloating (63%), gastroesophageal reflux (63%), loss of appetite (47%) and weight loss (37%). However, these side effects were usually mild and diminished after four weeks on treatment. About 20% had elevated bilirubin, a known side effect of interferon lambda. Three people reduced their drug doses and four stopped treatment.

"These interim results support continued exploration of this therapeutic combination in HDV," the researchers concluded.

A phase III study of ritonavir-boosted lonafarnib with or without pegylated interferon-alfa 2a is currently underway (NCT03719313).


Prof Heiner Wedemeyer of Essen University Hospital in Germany presented the latest results from a phase IIb study of another combination therapy for people with HBV/HDV co-infection, bulevirtide with either pegylated interferon alfa or TDF.

Bulevirtide, formerly known as Myrcludex B, is an experimental entry inhibitor that binds to the receptor HBV uses to enter liver cells, interfering with the lifecycle of HBV and thereby also preventing HDV replication.

The main MYR203 trial enrolled 60 people who were randomly assigned to receive 2mg or 5mg bulevirtide by subcutaneous injection once daily plus 180mcg pegylated interferon alfa injected once weekly, 2mg bulevirtide alone or pegylated interferon alone for 48 weeks.

As Wedemeyer reported at this year's EASL International Liver Congress, 50% of participants in the two combination arms had undetectable HDV RNA at week 48, compared with 13% in the two monotherapy groups. At week 72 – six months after completing treatment – 40% still had an undetectable level and 40% experienced ALT normalisation. In addition, 27% achieved hepatitis B surface antigen (HBsAg) loss and 20% experienced HBs antibody seroconversion, considered a functional cure. No one in the monotherapy arms experienced a sustained response.

At the AASLD meeting, Wedemeyer presented interim findings from an extension phase of the study that evaluated 10mg daily bulevirtide plus weekly pegylated interferon alfa or 5mg twice-daily bulevirtide plus daily TDF for 48 weeks.

These two groups included 15 patients each, all in Russia. About three-quarters were men and the mean age was approximately 37 years. The median HDV RNA level at baseline was 6.26 log10 IU/ml and the median FibroScan score was nearly 11.

At the end of treatment, 87% of those taking 10mg daily bulevirtide plus pegylated interferon had undetectable HDV viral load. The 48-week response rate in the 5mg twice-daily bulevirtide plus TDF group was 40%. ALT normalisation rates at week 48 were 27% and 40%, respectively.

However, only one person taking the 10mg daily bulevirtide plus pegylated interferon regimen and no one taking the TDF combination achieved HBsAg loss, failing to replicate the promising functional cure rate seen in the main study. Seventy-two week follow-up results are pending.

Treatment was generally safe and well tolerated. Most adverse events were attributable to pegylated interferon. No bulevirtide-related serious adverse events or treatment discontinuations were reported. Injection site reactions were uncommon. Almost everyone saw an asymptomatic increase in bile salts, a known side effect of bulevirtide. In the main study, levels returned to normal soon after stopping therapy.

Wedemeyer and colleagues concluded that 10mg bulevirtide per day "is a safe and promising strategy for maintenance therapy of chronic hepatitis D," and adding pegylated interferon alfa shows "a strong synergism."

Two phase III trials of bulevirtide, alone and in combination with pegylated interferon alfa, are currently underway (NCT03852719 and NCT03852433).


Koh C et al. A phase 2 study of lonafarnib, ritonavir and peginterferon lambda for 24 weeks: interim end-of-treatment results from the LIFT HDV study. AASLD Liver Meeting, Boston, abstract LO8, 2019.

Wedemeyer H et al. Safety and efficacy of 10mg (high-dose) bulevirtide (Myrcludex B) in combination with peg-interferon alpha 2a or tenofovir in patients with chronic HBV/ HDV co-infection: week 24 interim results of the MYR203 extension study. AASLD Liver Meeting, Boston, abstract 85, 2019.