Bulevirtide for hepatitis D proves effective in real-world studies

The entry inhibitor bulevirtide (Hepcludex) led to a reduction in hepatitis delta virus (HDV) viral load and improved liver enzyme levels in real-world studies in France and Austria, according to findings presented at the American Association for the Study of Liver Diseases (AASLD) 2021 Liver Meeting. Several other studies shed more light on the prevalence and outcomes of hepatitis D.

Hepatitis delta is a defective virus that can only replicate in the presence of hepatitis B virus (HBV). It is estimated that around 15 million people worldwide have HDV. Accurate data are lacking in part because HDV testing is inadequate. The European Association for the Study of the Liver (EASL) recommends that everyone with active hepatitis B (HBsAg positive) be tested for HDV, while AASLD recommends testing for HBsAg positive people with risk factors, but these guidelines are not always followed.

At the Liver Meeting, Dr Robert Gish of the Hepatitis B Foundation and colleagues reported an HDV prevalence of 11% among people diagnosed with HBV in a large US database. Another analysis, by Dr Carla Osiowy of the Public Health Agency of Canada, showed that nearly 5% of Canadians with active hepatitis B (HBsAg positive) had HCV. Dr Ilona Argirion of the US National Cancer Institute and colleagues looked at HDV prevalence among participants in the US Women’s Interagency HIV Study, nearly three-quarters of whom were HIV positive, finding an HDV co-infection rate of 22% among women who were HBsAg positive.

Over years or decades, chronic hepatitis B can lead to severe liver disease, and people with HBV/HDV co-infection typically experience more aggressive liver disease progression than those with HBV alone. Studies presented at the conference showed that people who carry both viruses were more likely to progress to decompensated cirrhosis, develop liver cancer or need a liver transplant.

Bulevirtide (formerly known as Myrcludex) blocks surface receptors that HBV uses to enter liver cells. This interferes with the hepatitis B lifecycle and thereby also prevents HDV replication. In July 2020, the European Medicines Agency (EMA) granted conditional approval of bulevirtide as the first ever treatment for hepatitis D. Gilead Sciences submitted an application for approval to the US Food and Drug Administration in October 2021.

At the 2021 EASL International Liver Congress, Prof. Heiner Wedemeyer of Hannover Medical Hospital in Germany presented the first interim results from the phase III MYR301 trial (ClinicalTrials.gov NCT03852719), in which 150 adults with chronic hepatitis D, nearly half of whom already had cirrhosis, were randomly assigned to receive either immediate treatment with 2mg (the EMA approved dose) or 10mg injections of bulevirtide once daily or delayed treatment.

After 24 weeks, 55% of people in the 2mg bulevirtide arm and 68% in the 10mg arm either reached an undetectable plasma HDV viral load or experienced at least a 2-log decrease in HDV RNA from baseline, compared with just 4% in the delayed treatment arm. The likelihood of reaching a combined endpoint of virological and biochemical response (ALT normalisation) was 37% in the 2mg arm and 28% in the 10mg arm, but no one in the delayed treatment group did so.

Bulevirtide was safe and well tolerated. No serious adverse events were reported and no one discontinued treatment due to adverse events. Bulevirtide blocks a bile salt transporter, and asymptomatic bile salt increases were common, but no one experienced symptomatic elevation. 

At the Liver Meeting, Dr Lena Allweiss of University Medical Centre-Hamburg Eppendorf and colleagues reported that after 48 weeks of treatment, intrahepatic HDV RNA levels strongly declined in a subgroup of 66 people who underwent paired liver biopsies; 33% in the 2mg bulevirtide arm and 52% in the 10mg arm reached undetectable levels. HDV antigen levels and the number of HDV antigen positive liver cells also declined. In addition, patients in both groups had a similar decline in expression of inflammatory genes.

“Changes in host genome expression correlated with HDV infection levels,” the researchers concluded. “This indicates that therapeutic reduction of HDV infection also diminishes liver inflammation.”

What’s more, Prof. Maria Buti of Hospital Universitario Valle Hebron in Barcelona and colleagues reported that MYR301 study participants treated with bulevirtide reported greater improvement in health-related quality of life than the delayed treatment group, including general health, bodily pain, vitality, mental health, social functioning and hepatitis-specific limitations and health distress.

These promising clinical trial findings were borne out in the first real-world studies of bulevirtide since EMA approval.

Prof. Victor De Ledinghen of Bordeaux University Hospital in France and colleagues looked at outcomes from the French early access programme. The analysis included 145 patients with chronic HBV/HDV co-infection who either had advanced fibrosis or compensated cirrhosis or moderate fibrosis and elevated ALT levels.

More than two-thirds were men, and the average age was 41 years. About 15% also had HIV co-infection. They were treated with 2mg bulevirtide once daily, either alone (77 patients) or with pegylated interferon (68 patients), for at least one year. Nearly 80% were also using nucleoside analogues to treat hepatitis B, and about two-thirds had undetectable HBV DNA.

Among patients treated with bulevirtide alone, mean serum HDV RNA viral load declined by -3.64 log IU/ml at 12 months. Among those treated with bulevirtide plus pegylated interferon, the corresponding reduction was -5.56 log IU/ml. People treated with bulevirtide monotherapy were much less likely to reach an undetectable HDV viral load at 12 months than those who added pegylated interferon (39% vs 85%, respectively). However, those on monotherapy were more likely to achieve a normal ALT level (49% vs 36%, respectively). Looking at a combined endpoint of undetectable HDV viral load or at least a 2-log decline in HDV RNA plus ALT normalisation, 39% on bulevirtide alone and 30% on bulevirtide and pegylated interferon met both metrics.

As in the MYR301 trial, bulevirtide was generally well tolerated. In the monotherapy group, 19 people modified and seven discontinued treatment for various reasons. In the bulevirtide plus pegylated interferon group, five modified and 12 stopped treatment. Two and three patients, respectively, discontinued due to adverse events. All but one person experienced the expected bile acid elevations.

“In this real-life study, [bulevirtide] 2mg shows favourable HDV RNA and ALT normalisation,” the researchers concluded. “HDV RNA levels continued to decline throughout 12-month treatment.”

In another analysis, Teresa Binter of the Medical University of Vienna and colleagues assessed 17 patients who received bulevirtide, first through a compassionate use programme and then through the Austrian health insurance system. Eleven were women, the average age was 50 years and 65% had compensated cirrhosis. Fifteen received 2mg bulevirtide once daily, but two used a 10mg dose. Most were concurrently taking nucleoside analogues for hepatitis B and had been unsuccessfully treated with pegylated interferon.

About 80% of patients saw at least a 2-log reduction in HDV RNA and about 90% experienced ALT normalisation at 48 weeks. Four people achieved viral load suppression for at least six months while on treatment. One person without cirrhosis who started on a 10mg dose maintained an undetectable viral load for 20 weeks after stopping treatment. Another received a 2mg dose of bulevirtide for 63 weeks and maintained an undetectable viral load for six months, experienced viral rebound four weeks after stopping treatment and restarted bulevirtide. A third responder elected to stay on bulevirtide despite having viral suppression for more than six months. Four non-responders added pegylated interferon, which led to steep drops in HDV RNA, and they are still on treatment.

“To eradicate HDV, long-term treatment is needed. A response-guided approach is recommended,” the investigators concluded, noting that an individualized approach is needed.

They suggest starting with 2mg bulevirtide and measuring viral load at 24 weeks. Those with at least a 2-log drop in HDV RNA should continue as long as viral load continues to decline. Once HDV RNA is undetectable for at least six months, they can stop treatment. Those with a less than a 2-log decline should continue treatment for another 12 to 24 weeks and measure viral load again. Those who still do not see a 2-log decline can add pegylated interferon. If they still do not respond, the researchers advise stopping treatment due to futility.