Toll-like receptor 7 agonist GS-9620 induces prolonged inhibition of HBV via a type I interferon-dependent mechanism

Niu, Congrong; Li, Li; Daffis, Stéphane; Lucifora, Julie; Bonnin, Marc; Maadadi, Sarah; Salas, Eduardo; Chu, Ruth; Ramos, Hilario J.; Livingston, Christine M.; Beran, Rudolf K. F.; Garg, Abhishek V.; Balsitis, Scott; Durantel, David; Zoulim, Fabien; Delaney, William E.; Fletcher, Simon P.

doi:10.1016/j.jhep.2017.12.007

Cited by 82 publications

(75 citation statements)

References 32 publications

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“…A recent study showed that GS-9620 could induce multiple HBV suppressive factors in human PBMCs, leading to prolonged type I IFN-associated HBV suppression in primary human hepatocytes (PHH) and HepaRG cells, as well as enhanced biosynthesis of immunoproteasome subunits and display of an immunodominant viral peptide in PHH with HBV-infection. The latter may promote T cell recognition and activation in the host and viral control, though GS-9620 itself could not reduce cccDNA levels in hepatocyte culture systems (68).…”

Section: Tlr Ligandsmentioning

confidence: 96%

Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection

Zhao

Chen

2020

Front. Immunol.

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Functional cure" is being pursued as the ultimate endpoint of antiviral treatment in chronic hepatitis B (CHB), which is characterized by loss of HBsAg whether or not anti-HBs antibodies are present. "Functional cure" can be achieved in <10% of CHB patients with currently available therapeutic agents. The dysfunction of specific immune responses to hepatitis B virus (HBV) is considered the major cause of persistent HBV infection. Thus, modulating the host immune system to strengthen specific cellular immune reactions might help eliminate HBV. Strategies are needed to restore/enhance innate immunity and induce HBV-specific adaptive immune responses in a coordinated way. Immune and resident cells express pattern recognition receptors like TLRs and RIG I/MDA5, which play important roles in the induction of innate immunity through sensing of pathogen-associated molecular patterns (PAMPs) and bridging to adaptive immunity for pathogen-specific immune control. TLR/RIG I agonists activate innate immune responses and suppress HBV replication in vitro and in vivo, and are being investigated in clinical trials. On the other hand, HBV-specific immune responses could be induced by therapeutic vaccines, including protein (HBsAg/preS and HBcAg), DNA, and viral vector-based vaccines. More than 50 clinical trials have been performed to assess therapeutic vaccines in CHB treatment, some of which display potential effects. Most recently, using genetic editing technology to generate CAR-T or TCR-T, HBV-specific T cells have been produced to efficiently clear HBV. This review summarizes the progress in basic and clinical research investigating immunomodulatory strategies for curing chronic HBV infection, and critically discusses the rather disappointing results of current clinical trials and future strategies.

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Section: Tlr Ligandsmentioning

confidence: 96%

Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection

Zhao

Chen

2020

Front. Immunol.

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“…Phase II Dose-dependent pharmacodynamic induction of ISG15 and host NK and HBVspecific T cell responses but no HBsAg reduction in patients. (87,88) Lack of effect for cccDNA in vitro (126) TLR 7 agonist JNJ-4964 (Janssen) Preclinical Antiviral efficacy (HBV DNA, HBsAg, liver HBV DNA, HBV RNA) in a mouse model (127) TLR 7 agonist GS-9688 (Gilead) Phase I Induced IL-12 and IL-RA1 in humans. Short duration did not result in HBsAg decline (128) TLR 8 agonist…”

Section: Tlr 7 Agonistmentioning

confidence: 99%

Guidance for Design and Endpoints of Clinical Trials in Chronic Hepatitis B—Report From the 2019 EASL‐AASLD HBV Treatment Endpoints Conference

et al. 2020

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Representatives from academia, industry, regulatory agencies, and patient groups convened in March 2019 with the primary goal of developing agreement on chronic hepatitis B virus (HBV) treatment endpoints to guide clinical trials aiming to “cure” HBV. Agreement among the conference participants was reached on some key points. “Functional” but not sterilising cure is achievable and should be defined as sustained HBsAg loss in addition to undetectable HBV DNA 6 months post‐treatment. The primary endpoint of phase III trials should be functional cure; HBsAg loss in ≥30% of patients was suggested as an acceptable rate of response in these trials. Sustained virologic suppression (undetectable serum HBV DNA) without HBsAg loss 6 months after discontinuation of treatment would be an intermediate goal. Demonstrated validity for the prediction of sustained HBsAg loss was considered the most appropriate criterion for the approval of new HBV assays to determine efficacy endpoints. Clinical trials aimed at HBV functional cure should initially focus on patients with HBeAg‐positive or negative chronic hepatitis, who are treatment‐naïve or virally suppressed on nucleos(t)ide analogues. A hepatitis flare associated with an increase in bilirubin or international normalised ratio should prompt temporary or permanent cessation of an investigational treatment. New treatments must be as safe as existing nucleos(t)ide analogues. The primary endpoint for phase III trials for HDV coinfection should be undetectable serum HDV RNA 6 months after stopping treatment. On treatment HDV RNA suppression associated with normalisation of alanine aminotransferase is considered an intermediate goal. In conclusion, regarding HBV “functional cure”, the primary goal is sustained HBsAg loss with undetectable HBV DNA after completion of treatment and the intermediate goal is sustained undetectable HBV DNA without HBsAg loss after stopping treatment.

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“…As mentioned above, the TLR7 agonist GS-9620 also showed strong and sustained antiviral effects against WHV and HBV when it was administrated orally in the woodchuck [ 56 ] and chimpanzee models [ 20 ]. The antiviral activity of GS-9620 was mainly dependent on induction of IFNs from innate immune cells, such as monocytes, but not activation of the antiviral pathway in hepatocytes [ 80 ]. Moreover, the GS-9620 also showed the immune modulatory effect on an HBV-specific immune response by enhancing antigen presentation in hepatocytes [ 80 ].…”

Section: Potential Therapeutic Approaches For Eliminating Chronic mentioning

confidence: 99%

Interaction between Hepatitis B Virus and Toll-Like Receptors: Current Status and Potential Therapeutic Use for Chronic Hepatitis B

Cao

Xiong

et al. 2018

Vaccines

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Immune defense against infection with the hepatitis B virus (HBV) is complex and involves both host innate and adaptive immune systems. It is well accepted that the development of sufficient HBV-specific T cell and B cell responses are required for controlling an HBV infection. However, the contribution of innate immunity to removing HBV has been explored in recent years. Toll-like receptors (TLRs) are recognized as the first line of antiviral immunity because they initiate intracellular signaling pathways to induce antiviral mediators such as interferons (IFNs) and other cytokines. Recent studies show that the activation of TLR-mediated signaling pathways results in a suppression of HBV replication in vitro and in vivo. However, HBV has also evolved strategies to counter TLR responses including the suppression of TLR expression and the blockage of downstream signaling pathways. Antiviral treatment in chronic HBV-infected patients leads to an upregulation of TLR expression and the restoration of its innate antiviral functions. Thus, TLR activation may serve as an additional immunotherapeutic option for treating chronic HBV infection in combination with antiviral treatment.

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Toll-like receptor 7 agonist GS-9620 induces prolonged inhibition of HBV via a type I interferon-dependent mechanism

Cited by 82 publications

References 32 publications

Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection

Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection

Guidance for Design and Endpoints of Clinical Trials in Chronic Hepatitis B—Report From the 2019 EASL‐AASLD HBV Treatment Endpoints Conference

Interaction between Hepatitis B Virus and Toll-Like Receptors: Current Status and Potential Therapeutic Use for Chronic Hepatitis B

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