Hepatitis D: Recent Advances in Virology, Immunology and Treatment

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Forty years after the emergence of HDV, the first anti-HDV therapeutic has been approved by the EMA, indicating the dawn of a new era for this difficult to treat disease

Forty years after the emergence of hepatitis D virus (HDV), the first anti-HDV therapeutic has been approved by the European Medicines Agency (EMA), indicating the dawn of a new era for this difficult to treat disease. These findings are based on a literature review published in Gut.  

It is estimated that at least 12 million individuals infected with hepatitis B virus (HBV) are coinfected with HDV. Simultaneous infection with HBV and HDV in adults typically results in clearance of both viruses. Conversely, super-infection of an HBV-infected individual with HDV typically results in persistence of HBV/HDV. The persistence of HBV/HDV may lead to liver cirrhosis, liver failure, and eventually hepatocellular carcinoma (HCC) within a short period of time. 

Prior to 2020, no approved antiviral treatment was available for patients with HDV. Although not Food and Drug Administration (FDA) or EMA approved, pegylated interferon-α (pegIFNα) has been used for treating patients with HDV over the last 30 years. According to investigators, 48-weeks of weekly subcutaneous injections of pegIFNα suppresses HDV replication in approximately 20% to 30% of patients, 24 weeks off therapy. This treatment is reported to have significant side effects.

The researchers note that the identification of sodium taurocholate cotransporting polypeptide (NTCP) as a cell entry receptor for both HBV and HDV allows for a more detailed study of HDV and contributes to the development of novel treatment strategies. NTCP-expression is sufficient to permit HDV entry and the onset of replication. However, assembly and secretion of viral particles cannot be achieved because there are not enough HBV envelope proteins needed for virus release. This can be solved via cell lines that express both the NTCP receptor and the HBV envelope proteins.

Aside from the spreading of enveloped HDV by an NTCP-receptor dependent de novo infection pathway, another approach to HDV RNA dissemination has recently been described. This mode of dissemination has been characterized by the direct transfer of replication competent HDV RNA between cells during mitosis. In the absence of hepatitis B surface antigen (HBsAg), this process can proceed. To what extent it contributes to HDV persistence in the liver of infected patients remains unknown and further investigation is needed.

The entry inhibitor bulevirtide (BLV), formerly known as myrcludex-B, was approved by the EMA in 2020. FDA approval for this treatment is pending. BLV can be used either in combination with pegIFNα without formal approval from the EMA, or as monotherapy. BLV monotherapy may be a promising ‘suppressive’ strategy for many patients with HDV who cannot be treated with pegIFNα.

The prenylation inhibitor lonafarnib (LNF) is orally administered and blocks the prenylation of large hepatitis D antigen (L-HDAg), showing an intracellular accumulation of ribonucleoproteins and a dose-dependent reduction of serum HDV RNA. LNF has displayed encouraging response rates and is currently under investigation in phase 3 clinical trials.

The nucleic acid polymer REP2139Ca has also displayed encouraging response rates. In the phase 2 REP301 study, 12 treatment-naïve, noncirrhotic patients with chronic HBV/HDV coinfection received 500mg of REP2139Ca intravenously, once per week, for 15 weeks. This was followed by 15 weeks of 250mg REP2139Ca+pegIFNα, then by 33 weeks of pegIFNα monotherapy. At the 24-week off-treatment follow-up, the investigators found that 5 (42%) patients were HBsAg negative, 5 (42%) patients were anti-HBs positive, 7 (58%) patients had HBV DNA levels <10 IU/mL, and 7 (58%) patients had negative HDV RNA by Robogene assay. All patients experienced at least one adverse event, due mostly to pegIFNα.

These recent advances in HDV virology, immunology, and treatment are vital steps to mitigating the challenges of treating HDV. Despite these recent advances, many questions about HDV treatment remain unsolved. Any new therapeutics that lead to a cure for HBV monoinfection may be useful in the treatment of HBV/HDV coinfection.  

Disclosure: Some study authors declared affiliations with the industry. Please see the original reference for a full list of authors’ disclosures.

Disclosure: This research was supported by multiple sources. Please see the original reference for a full list of disclosures.


Urban S, Neumann-Haefelin C, Lampertico P. Hepatitis D virus in 2021: virology, immunology and new treatment approaches for a difficult-to-treat disease. Gut. 2021;70(9):1782-1794. doi:10.1136/gutjnl-2020-323888