A Phase 2 open label study of ledipasvir/sofosbuvir for 12 weeks in subjects with hepatitis B virus infection

Price, Angie; Nelson, Amy; Ghosh, Alip; Kottilil, Shyamasundaran; Chua, Joel V

doi:10.1002/jmv.28105

Cited by 3 publications

(2 citation statements)

References 9 publications

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“…Sofosbuvir has been indicated for chronic HCV infection (genotype 1, 2, 3, or 4) in adults as part of combination therapy and in children older than 3 years with genotype for chronic HCV infections with ribavirin. Many Clinical trials are ongoing for evaluating sofosbuvir in different populations and dosing regimens in combination with other drugs against HCV [42 – 46]. Sofosbuvir also exhibited inhibitory activity against Dengue, Chikungunya, Yellow fever virus, Hepatitis E virus, and SARS-CoV2 [47 –51].…”

Section: Discussionmentioning

confidence: 99%

Sofosbuvir and its tri-phosphate metabolite inhibit the RNA-dependent RNA polymerase activity of non-Structural protein 5 from the Kyasanur forest disease virus

Malik

Vijayan

Jagannath

et al. 2022

Preprint

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Kyasanur forest disease is a neglected zoonotic disease caused by a single stranded RNA based flavivirus, the incidence of which, was first recorded in 1957, in the Southern part of India. Kyasanur forest disease virus is transmitted to monkeys and humans, through the infected tick bite of Haemophysalis spinigera. Kyasanur forest disease is a febrile illness, which in severe cases, results in neurological manifestations leading to mortality. The current treatment regimens are symptomatic and supportive in nature. There are no targeted therapies available for this disease. In this study, we evaluated the ability of the FDA approved drug, Sofosbuvir to inhibit the RNA dependent RNA polymerase activity of NS5 protein from Kyasanur forest disease virus. NS5 protein containing the N-terminal methyl transferase domain and C-terminal RNA dependent RNA polymerase domain was expressed in Escherichia coli and RNA dependent RNA polymerase activity, demonstrated with the purified protein. The RNA dependent RNA polymerase assay conditions were optimized, followed by determination of apparent Km,ATP. IC50 of Sofosbuvir against RNA dependent RNA polymerase activity was determined under the optimized conditions with the purified NS5 protein. Drug repurposing strategies can accelerate the development of targeted therapies for Kyasanur forest disease. This is the first demonstration of inhibition of RNA dependent RNA polymerase activity of Kyasanur forest disease virus with a small molecule inhibitor.

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Section: Discussionmentioning

confidence: 99%

Sofosbuvir and its tri-phosphate metabolite inhibit the RNA-dependent RNA polymerase activity of non-Structural protein 5 from the Kyasanur forest disease virus

Malik

Vijayan

Jagannath

et al. 2022

Preprint

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show abstract

“…The highest HBeAg seroconversion, a sign of decreased infectivity of HBV, was obtained with 45 mg of pradefovir with a percentage of 12. In a recent open-label phase II study [ 49 ], ledipasvir/sofosbuvir, effective drugs for HCV infection, were applied to HBV infection. Sofosbuvir at 400 mg and ledipasvir at 90 mg for 12 weeks led to an HBsAg decline of 0.4 log 10 IU/mL in virally suppressed HBV patients and 0.399 log 10 IU/mL in inactive chronic HBV patients.…”

Section: Hbv Therapymentioning

confidence: 99%

Hepatitis B: Model Systems and Therapeutic Approaches

Yu,

Gao,

Zhang

et al. 2024

Journal of Immunology Research

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Hepatitis B virus (HBV) infection is a major global health issue and ranks among the top causes of liver cirrhosis and hepatocellular carcinoma. Although current antiviral medications, including nucleot(s)ide analogs and interferons, could inhibit the replication of HBV and alleviate the disease, HBV cannot be fully eradicated. The development of cellular and animal models for HBV infection plays an important role in exploring effective anti-HBV medicine. During the past decades, advancements in several cell culture systems, such as HepG2.2.15, HepAD38, HepaRG, hepatocyte-like cells, and primary human hepatocytes, have propelled the research in inhibiting HBV replication and expression and thus enriched our comprehension of the viral life cycle and enhancing antiviral drug evaluation efficacy. Mouse models, in particular, have emerged as the most extensively studied HBV animal models. Additionally, the present landscape of HBV therapeutics research now encompasses a comprehensive assessment of the virus’s life cycle, targeting numerous facets and employing a variety of immunomodulatory approaches, including entry inhibitors, strategies aimed at cccDNA, RNA interference technologies, toll-like receptor agonists, and, notably, traditional Chinese medicine (TCM). This review describes the attributes and limitations of existing HBV model systems and surveys novel advancements in HBV treatment modalities, which will offer deeper insights toward discovering potentially efficacious pharmaceutical interventions.

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A Phase 2 open label study of ledipasvir/sofosbuvir for 12 weeks in subjects with hepatitis B virus infection

Price

Nelson

Ghosh

et al. 2022

Journal of Medical Virology

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Retrospective data showed that when we administered ledipasvir/sofosbuvir (LDV/SOF) to patients with hepatitis B and C coinfection, there was a modest reduction in hepatitis B surface antigen (HBsAg). Therefore, we hypothesize that similar HBsAg reduction can be seen in hepatitis B virus (HBV) monoinfected subjects. Primary and secondary efficacy endpoints are the decline in HBsAg and HBV DNA at Week 12 from baseline, respectively. We conducted an open‐label Phase 2 pilot study to evaluate the safety, tolerability, and antiviral activity of LDV and/or SOF for HBV. Eligible subjects were either suppressed on antivirals (Group B) or inactive chronic HBV (Group A, C, D). Group A and B received LDV/SOF. Group C and D received SOF 400 mg and LDV 90 mg, respectively. All subjects completed the study, and all related adverse events (AEs) were mild. No discontinuations due to AEs or hepatitis flare occurred. At Week 12, HBsAg decline (log10 IU/ml) was similar between Group A (0.399) and B (0.400), less in Group C (0.207), and none in Group D, and there was HBV DNA decline in the inactive chronic HBV groups. LDV and SOF are safe and well tolerated when given to chronic hepatitis B subjects and have modest antiviral activity, particularly when given in combination.

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A Phase 2 open label study of ledipasvir/sofosbuvir for 12 weeks in subjects with hepatitis B virus infection

Cited by 3 publications

References 9 publications

Sofosbuvir and its tri-phosphate metabolite inhibit the RNA-dependent RNA polymerase activity of non-Structural protein 5 from the Kyasanur forest disease virus

Sofosbuvir and its tri-phosphate metabolite inhibit the RNA-dependent RNA polymerase activity of non-Structural protein 5 from the Kyasanur forest disease virus

Hepatitis B: Model Systems and Therapeutic Approaches

A Phase 2 open label study of ledipasvir/sofosbuvir for 12 weeks in subjects with hepatitis B virus infection

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