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.
Interferon-alpha (IFN-α): Effect of Interferon-alpha Monotherapy on Hepatitis D Virus (HDV)
INF-Lambda (IFN- λ): Characterization of HDV, HBsAg and ALT kinetics under Peginterferon-Lambda Monotherapy
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
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.