Understanding the Science: How does Hepcludex work?

October 7, 2025 •

3 min read

Hepatitis D is the most severe form of viral hepatitis, and for decades, treatment options were severely limited. However, the approval of Hepcludex has introduced a new class of medication, known as an entry inhibitor, that effectively blocks both the hepatitis B and delta viruses from infecting healthy liver cells.

Quick Summary

Hepcludex (bulevirtide) functions as an entry inhibitor by targeting and blocking the NTCP receptor on liver cells. This prevents both hepatitis B and hepatitis D viruses from gaining entry, halting new infections and reducing viral load. It treats chronic hepatitis D in coinfected patients.

Key Points

Entry Inhibition: Hepcludex is a first-in-class entry inhibitor that blocks hepatitis B and D viruses from entering healthy liver cells.
NTCP Target: Its mechanism relies on binding to and blocking the sodium taurocholate co-transporting polypeptide (NTCP) receptor on hepatocytes, which both HBV and HDV use for entry.
Broken Key Analogy: The active substance, bulevirtide, mimics a viral surface protein to plug the NTCP receptor, preventing the virus from infecting new cells.
Dual Action: By blocking NTCP, Hepcludex effectively targets both the hepatitis D virus and its helper virus, hepatitis B.
Reduced Viral Spread: Preventing new infections halts the spread of the virus within the liver, leading to a reduction in viral load and liver inflammation.
Combination Therapy: It can be used in combination with other antivirals to provide a more comprehensive treatment strategy against chronic HBV/HDV coinfection.
Common Side Effects: Due to its effect on the NTCP receptor, common side effects include elevated bile salts in the blood, injection site reactions, and headache.

The Antiviral Mechanism of Action

Hepcludex, containing bulevirtide, is a novel antiviral that targets the initial step of viral infection: entry into the host cell. It is used for chronic hepatitis delta virus (HDV) infection, which only occurs alongside hepatitis B virus (HBV) infection.

Targeting the NTCP Receptor

Hepcludex works by interacting with the sodium taurocholate co-transporting polypeptide (NTCP) on liver cells. While NTCP normally transports bile salts, HBV and HDV exploit it to enter the liver cell. The active ingredient, bulevirtide, is a synthetic peptide mimicking a part of the HBV surface protein. This allows bulevirtide to bind to and block the NTCP receptor, acting like a 'broken key' that prevents the virus from entering.

The Impact on Hepatitis B and Hepatitis D

Hepcludex is effective against both HBV and HDV, which is crucial as HDV requires HBV components to infect cells. By blocking the NTCP receptor, a shared entry point, Hepcludex prevents the spread of both viruses. This halt in new infections helps the body clear existing infected cells, reducing viral load and liver inflammation, thereby improving liver function.

Key Stages of Action

Blockade: Bulevirtide binds specifically to NTCP receptors on healthy liver cells.
Inhibition: This prevents HBV and HDV from using NTCP to enter cells.
Prevention: New infections are stopped, halting the spread within the liver.
Viral Clearance: As infected cells are removed, viral load decreases.
Reduced Inflammation: Less viral activity leads to reduced liver inflammation.

Comparative Overview of Hepatitis D Treatments


Feature	Hepcludex (Bulevirtide)	Pegylated Interferon Alpha	Nucleoside/Nucleotide Analogues (e.g., Tenofovir)
Mechanism	Entry inhibitor; blocks NTCP receptor to prevent viral entry.	Immune system modulator; stimulates the body's own immune response.	Replication inhibitor; stops the hepatitis B virus from replicating its genetic material.
Primary Target	Both Hepatitis B and Hepatitis D viruses.	Both HBV and HDV (indirectly, via immune system).	Primarily Hepatitis B virus.
Effect on HDV	Directly and potently prevents HDV entry.	Limited efficacy; remission in a small percentage of patients.	No direct effect on HDV replication; manages underlying HBV.
Administration	Subcutaneous injection, daily.	Subcutaneous injection, weekly.	Oral tablets, daily.
Adverse Effects	Elevated bile salts, injection site reactions, headache.	Flu-like symptoms, depression, fatigue, weight loss.	Generally well-tolerated, can have renal or bone-related side effects.

Synergistic Treatment Approaches

Hepcludex is often used with other anti-HBV drugs like tenofovir. This combination prevents new infections while suppressing existing HBV replication, leading to significant reductions in HDV viral load and improved liver function in trials.

Safety and Tolerability

Hepcludex is generally well-tolerated in patients with compensated liver disease. Common side effects include increased blood bile salts due to NTCP blockade, injection site reactions, headache, and itching. Stopping treatment can cause liver inflammation rebound, requiring medical supervision.

Conclusion

Hepcludex (bulevirtide) is a significant advance for chronic hepatitis D and B coinfection. Its entry-blocking mechanism targeting the NTCP receptor effectively prevents viral spread, reduces viral load and inflammation, and improves patient outcomes. It can be combined with other antivirals for a comprehensive treatment strategy against this severe disease. Further information on Hepcludex's approval and studies can be found on the European Medicines Agency website.

Frequently Asked Questions

The active substance in Hepcludex is bulevirtide, a synthetic peptide that works as an entry inhibitor for the hepatitis B and D viruses.

Hepcludex primarily targets and blocks the entry of both the hepatitis B virus (HBV) and the hepatitis delta virus (HDV) into liver cells.

It binds to the NTCP receptor on the surface of liver cells, a protein that HBV and HDV use to enter the cell. By blocking this receptor, Hepcludex prevents the virus from gaining entry.

While Hepcludex is effective against hepatitis B entry, it is approved for treating chronic hepatitis delta infection in patients who are also infected with hepatitis B. For HBV monoinfection, other established treatments exist.

The most common side effects include elevated bile salt levels in the blood, injection site reactions, headache, and itching.

There is a risk of a flare-up of liver inflammation after discontinuing Hepcludex, so patients should not stop treatment without consulting their doctor.

Hepcludex is administered as a daily injection under the skin (subcutaneous injection).

Unlike other antivirals for HBV, which do not directly impact HDV replication, Hepcludex specifically prevents HDV from spreading by blocking the shared entry receptor, providing a more effective treatment for the severe coinfection.