HDV
Translational Science
Globally, over 40 million people are infected with the Hepatitis Delta virus (HDV). In the US, there is an alarming trend in the rise of infections. Hepatitis D remains a serious challenge for three reasons. First, there is no FDA approved therapy, and the current treatment with interferon-alpha has a very low success rate, twenty five percent. It is the most aggressive form of viral hepatitis and results in accelerated liver-related deaths and hepatocellular carcinoma (a common form of liver cancer). Lastly, there are limited cell-culture and animal models to study the virus in order to test new antivirals.HDV research is still in the beginning stages and the viral dynamics are unique. It is a “satellite” virus and is only infectious in the presence of the hepatitis B virus (HBV). Infection can occur in two ways: coinfection with both HDV and HBV at the same time or the HDV superinfection of an already HBV-infected individual. It is not known why HDV superinfection (compared to co-infection) leads to a higher risk of chronic HDV infection and hepatitis. There is no vaccine for HDV, but it can be theoretically controlled as a result of the success of global HBV vaccinations.Dahari Lab works across disciplines with computational modelers, virologists, clinicians, mouse-model experts and pharmaceutical companies on advancements in treatment. Our focus is on the discovery of HDV treatment response dynamics, the optimization of HDV therapy, and the evaluation of anti-HDV mode of actions of new drugs. Research can be divided across the study of human patients, mouse models and cell cultures. Data collected from all three types of research contribute to the foundational knowledge that is essential in understanding and treating HDV. Clinical (patient) data increases our understanding of the host/virus interplay, especially with new treatments. Mouse models offer the opportunity to study acute HDV because the moment of infection can be controlled (clinical data is mostly from chronic infections.) At the cellular level, these models allow for research within the liver cells directly.Access to data from all three sources, clinical (human), mouse model, and molecular (cellular), offer richer data to develop more sophisticated multicompartmental models. The ability to isolate the virus dynamics and describe in detail the interplay at the host (human), organ (liver) and cellular level is the key to unlocking effective treatments and eventual cure.
Research Topics
Interferon-alpha (IFN-α): Effect of Interferon-alpha Monotherapy on Hepatitis D Virus (HDV)
There's currently no FDA-approved treatment for hepatitis delta virus (HDV); interferon-alpha remains the standard of care, though relapse is common even after years of consistent treatment. While monotherapies tend to be less effective than combination regimens, they offer valuable building blocks for foundational understanding—and IFN-α, despite its limitations, has served as the backbone of ongoing research in this area.
Our work has used mathematical modeling to study HDV viral kinetics during interferon therapy, building on approaches that previously proved useful for optimizing treatment in hepatitis C. This research has helped characterize how HDV behaves in patients undergoing pegylated interferon treatment, shedding light on HDV-host dynamics and on interferon's mode of action and effectiveness—contributing to the broader basic science of viral dynamics as well as HDV specifically.
More recently, we've extended this work using data from a large Phase 3 clinical trial to further study HDV and HBsAg kinetics during interferon monotherapy over an extended treatment period. This ongoing line of research aims to refine our understanding of HDV-host interactions and to provide the kind of detailed parameters needed to improve mathematical models and guide the design of more effective combination treatment strategies.
Related articles:
Mathematical modeling of patient data suggests that the entry-inhibitor bulevirtide (BLV) may have a more complex effect on HDV than previously understood. While BLV's known mode of action predicts a straightforward decline in circulating virus, modeling revealed a second, unexpected effect: in some patients, HDV levels actually increased transiently before declining. This pattern suggests BLV may also interfere with the liver's ability to clear the virus from circulation, beyond simply blocking new infection. This transient increase was independently observed in a separate analysis presented at a 2022 international HBV research meeting, which modeled data from a published BLV monotherapy study—lending further support to the finding.
Related articles:
Bulevertide
Mathematical modeling of early hepatitis D virus kinetics in transgenic mice
In research conducted in partnership with Ploss Lab at Princeton University, we characterized the early kinetics of HDV and provided insights into early HDV-host dynamics using mathematical modeling. The study involved data from three groups of mice (immunocompetent, immunodeficient, and transgenic*) inoculated with HDV simulating single infection and reinfection. Ongoing research is currently underway to better understand all the dynamics contributing to viral clearance rates.
*Transgenically expressing human NTCP (NRG-hNTCP) the receptor for HBV/HDV entry.