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 (<25%). 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,...

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 (<25%). 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. 

Research Topics

Interferon-alpha (IFN-α): Effect of Interferon-alpha Monotherapy on Hepatitis D Virus (HDV)


Currently there are no FDA approved treatments and the prevalent treatment using Interferon-alpha, however patients often relapse even after years of consistent treatment. Monotherapies are often not as effective as multi-therapy treatments, but they provide useful building blocks for foundational knowledge. IFN-α is an example of a less than optimal treatment that has formed the spine of ongoing research. In the spirit of developing a better understanding of the viral kinetics of HDV, we used mathematical modeling ( Hepatology), which was successful in developing optimal treatment strategies for patients with hepatitis C virus. This study provided the first detailed kinetic analysis of HDV during pegylated IFN-α therapy and provides new information about HDV infection including the HDV-host dynamics. IFN’s mode of action and effectiveness were also evaluated and contribute to basic science in viral dynamics in general and HDV specifically.




INF-Lambda (IFN- λ): Characterization of HDV, HBsAg and ALT kinetics under Peginterferon-Lambda Monotherapy


IFN- λ is another monotherapy used in clinical trials treating patients for HDV. Unlike Interferon-alpha (IFN-α), it does not trigger a broad immune response, but effects specific cell types including liver cells. Because of this, it is better tolerated by patients and provides an alternative treatment therapy. A proof-of-concept clinical trial of 33 patients (in collaboration with Dr. Ohad Etzion) yielded a better understanding of the viral kinetic patterns under IFN- λ treatment as well as potential differences from IFN-α mode of action in viral suppression ( AASLD 2019, Summary).The new data and insights are valuable for building increasingly sophisticated mathematical models which is an ongoing focus at Dahari Lab. IFN- λ is an example of translational (basic) science impacting other virus research. It has recently been used in the search for treatments for Covid-19 ( Lancet Respir Med) and has been shown to accelerate viral decline.




Lonafarnib (LNF): Oral prenylation inhibition with lonafarnib in chronic hepatitis D (HDV) infection


This first-in-man, proof-of-concept study aimed to assess the effect of the prenylation inhibitor lonafarnib (LNF) on hepatitis D (HDV) RNA, safety, and tolerability in patients with chronic HDV. Prenylation inhibition disrupts the interaction between aspects of HDV and hepatitis B (HBV) that allow for HDV to be secreted from infected cells. Clinical research (Lancet Infectious Diseases) with a small sample of patients, in collaboration with Theo Heller and Christopher Koh (NIH, USA), Jeffrey Glen (Stanford) and Eiger Biopharmaceuticals, yielded results strong enough to warrant further research in this area. The use of LNF reduced the viral load significantly faster than monotherapies using interferon-based treatments. For the first time, we were able to estimate LNF high efficacy in blocking HDV production and estimate the half-life of HDV in the blood through mathematical modeling of patient data. LNF was effective in all the patients in the small sample, whereas interferon-based therapies often have a percentage of patients that do not see results.A significant research benefit of LNF is that it targets only HDV, while interferon-based therapies are more general, targeting both HDV and HBV. This is a unique opportunity to better understand the interplay of HDV and HBV as well as map the mode of action. In modeling additional data sets from the research with Koh et al. from patients chronically infected with HDV, it was possible to predict that a LNF monotherapy dose of 610 mg bid would achieve 99% efficacy (Hepatology Communications). While this research did not include clinical trials involving ritonavir, it posed the question that led to actual research on the topic.




Modelling hepatitis D virus (HDV) RNA and HBsAg (surface antigen) dynamics during nucleic acid polymer (NAP) monotherapy suggest rapid turnover of HBsAg


We partnered with Replicor to model the results of NAPs as a monotherapy which is shown to reduce HDV RNA and HBsAG in clinical trials. We analyzed/characterized the HDV, HBV and liver function (i.e. transaminase ALT) kinetics for data to develop a mathematical model. This model was used to estimate viral and host parameters and gain a better understanding of the mode of action and efficacy of NAPs in patients coinfected with HBV and HDV ( Scientific Reports). For the first time we could show monotherapy with NAP effective in treating not only HDV infection, but also blocking the HBV antigen required to produce HDV. NAP treatment works by blocking HBV surface antigen (HBsAg). This antigen is required for assembly and release of the HDV virus in the patient. It is important to note that without suppression of surface antigen, a functional cure is difficult to achieve. NAP treatment results in a rapid decline of both the virus itself as well as HBsAg. The mathematical model reproduced the HDV and surface antigen kinetics from the patient data, allowing us to estimate unknown viral and host parameters. New insights into the half-life of the surface antigen in the blood and rate of removal of HDV-infected cells will help develop more realistic modeling to capture the interplay among HDV, HBV and the patient’s immune responses.




Modeling Hepatitis Delta Virus (HDV) Dynamics During Ritonavir (RTV) Boosted Lonafarnib (LNF) Treatment–The LOWR HDV-3 Study


In further study of treatment with Lonafarnib combined with Ritonavir, data collected from a clinical trial was used to investigate viral kinetics and provide insights into HDV-HBsAg-host dynamics during LNF+RTV treatment. The data model initially predicted that a LNF monotherapy dose of 610 mg bid would achieve 99% efficacy (Hepatology Communication). Given the maximum LNF tolerated dose was 200 mg bid, the clinical trial would need to be adapted to patient-real-world experience. The addition of RTV allows for slower metabolization of the LNF, resulting in lower dosage and higher efficacy. In the LOWR HDV-3 study (Hepatology) combining LNF 100 mg bid with RTV was investigated and exceeded the predicted 99% efficacy concentration. It was associated with dramatic HDV viral load declines and better tolerability than higher doses of LNF monotherapy. The model was also able to reproduce the observed viral, HBsAg and ALT kinetics in each patient and provide insights into viral-host-drug dynamics. The benefit to patients was real-time modeling of viral kinetics which can be used to individualize duration of therapy. In general, this type of modeling can empower patients to participate in shared decision-making regarding length of treatment.




Multi-Therapy LIFT hepatitis (HDV) Study: A Phase 2 Study of Lonafarnib, Ritonavir and Peginterferon Lambda


Based on the successful indications from two previous monotherapy studies using LNF-RTV and Interferon Lambda, this multi-therapy this multi-therapy study was developed for a first-in-humans clinical trial for patients with chronic HDV. This combination of monotherapies into one treatment regimen confirmed the treatment was safe and tolerable for up to 6 months. Not only was it well-tolerated, but there was a sustained ant-HDV response recorded. The research ends with a question as to whether an increased duration of therapy might lead to increased response rates. Our research is ongoing to characterize and analyze the kinetics through mathematical modeling to better understand the viral-host dynamics.

This Multi-Therapy LIFT hepatitis (HDV) study illustrates the direct benefits and impact of research where the outcome is new data or insights which is useful for developing new studies that could lead to new basic science information or a treatment/solution.




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.