gs-9620 and Hepatitis-B--Chronic

Vesatolimod is a toll-like receptor (TLR) agonist that is thought to suppress chronic hepatitis B (HBV) infection. This systematic review aimed to assess the safety and efficacy of vesatolimod in treating chronic hepatitis B.. We included randomized clinical trials (RCTs) that assessed vesatolimod in patients with hepatitis B infection without hepatocellular carcinoma or liver transplantation and with reported levels of hepatitis B surface antigen (HBsAg) or liver transaminases post-intervention. We searched MEDLINE, SCOPUS, Springer, Google Scholar, ClinicalTrials.gov, and Cochrane Central Register of Clinical Trials for all related articles during May 2022. Two independent authors screened articles for inclusion, and discrepancies were resolved by consensus and a third reviewer. Two independent reviewers assessed studies included in this systematic review using the Critical Appraisal Skills Programme checklist for RCTs.. Only 4 were considered eligible from 391 articles identified through our search. All eligible studies did not report any clinically significant outcomes following the use of vesatolimod, as evidenced by the persistence of HBsAg. However, vesatolimod was associated with induction of interferon-stimulated genes (ISGs) and only mild side effects, warranting further studies to evaluate its potential for future use as a safe, tolerable anti-HBV medication. No significant differences were noted amongst trials included in either of Vesatolimod doses (Vesatolimod 1 mg, RR = 0.99, 95% CI 0.76-1.30, P = .95, I2 = 0%; Vesatolimod 2 mg, RR = 1.06, 95% CI 0.82-1.37, P = .66, I2 = 0%; Vesatolimod 4 mg, RR = 1.06, 95% CI 0.82-1.37, P = .66, I2 = 0%;), further suggesting its comparable safety in comparison to oral antiviral agents.

Topics: Antiviral Agents; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B, Chronic; Humans

Chronic infection with hepatitis B virus (HBV) is endemic to several populous parts of the world, where resulting complicating cirrhosis and hepatocellular carcinoma occur commonly. Licensed drugs to treat the infection have limited curative efficacy, and development of therapies that eliminate all replication intermediates of HBV is a priority. Areas covered: The recent demonstration that the activation of the innate immune response may eradicate HBV from infected hepatocytes has a promising therapeutic application. Small molecule stimulators of Toll-like receptors (TLRs) inhibit replication of woodchuck hepatitis virus in woodchucks and HBV in chimpanzees and mice. Early stage clinical trials using GS-9620, a TLR7 agonist, indicate that this candidate antiviral is well tolerated in humans. Using an alternative approach, triggering the innate immune response with agonists of lymphotoxin-β receptor caused efficient APOBEC-mediated deamination and degradation of viral covalently closed circular DNA. Expert opinion: Eliminating HBV cccDNA from infected individuals would constitute a cure, and has become the focus of intensive research that employs various therapeutic approaches, including gene therapy. Immunomodulation through innate immune activation shows promise for the treatment of chronic infection of HBV (CHB) and, used in combination with other therapeutics, may contribute to the global control of infections and ultimately to the eradication of HBV.

Topics: Animals; Antiviral Agents; DNA Replication; DNA, Viral; Hepatitis B virus; Hepatitis B, Chronic; Humans; Immunity, Innate; Immunomodulation; Pteridines; Toll-Like Receptor 7; Virus Replication

Chronic hepatitis B infection remains a major global health problem despite the existence of an effective vaccine. The current treatment options are either nucleos(t)ide analog therapy, which inhibits viral replication, or peginterferon-α, which has mainly immunomodulatory effects. However, treatment-induced HBeAg seroconversion with suppressed viral replication is mostly not sustainable, and loss of HBsAg is a rarely achieved endpoint. In addition, the hepatitis B virus persists in hepatocytes even after HBsAg clearance as covalently closed circular DNA is not eliminated from the hepatocytes. Because the course of chronic hepatitis B is determined by an ongoing interaction between the virus and the host immune system, immunomodulation may be the most logical approach in attempting to accomplish control or even cure of chronic hepatitis B. In the last years, methods for measuring the degree of immune control have been a major area of interest, with an important role for monitoring of HBsAg levels. In addition, new immunomodulatory agents are being developed and tested, providing promising options for future treatment.

Topics: Antiviral Agents; Biomarkers; DNA, Circular; DNA, Viral; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Immunomodulation; Interferon-alpha; Interleukins; Lamivudine; Polyethylene Glycols; Pteridines; Telbivudine; Thymidine

Chronic infections with hepatitis B or C (HBV and HCV) are associated with adverse clinical outcomes and patient-reported outcomes (PROs). The aim is to compare PRO scores in patients with chronic HBV and HCV without advanced liver disease before and after suppression/clearance of their infection.. Patients with HCV and HBV infection prior to initiation of antiviral treatment and after viral suppression/eradication completed PRO questionnaires.. We included 132 patients with HBV and 132 matched patients with HCV. Baseline PRO scores were significantly higher in patients with HBV in the domains of Physical Functioning, Role Physical, Bodily Pain, Social Functioning, and Role Emotional of SF-36, SF-6D utility, Emotional and Fatigue domains of CLDQ, Presenteeism and total Work Productivity Impairment of WPAI:SHP in comparison to patients with HCV by 5.8%-13.2% of a PRO score range (all P < 0.05). After viral suppression (HBV DNA < 20 IU/mL after 48 weeks of treatment for HBV) or eradication (SVR-12 for HCV), only Physical Functioning and Role Physical scores remained higher in HBV by 6.7%-9.9%, while other PRO scores became similar between HBV and HCV groups (P > 0.05). The most prominent improvement of PROs in HCV was noted in Vitality, Emotional, Fatigue and Worry domains. In addition, General Health, Worry and Work Productivity scores were the most improved in HBV.. Prior to treatment, PRO scores were lower in patients with HCV in comparison to HBV. After successful treatment, both groups of patients experienced improvement in some PRO domains confirming the positive impact of treatment.

Topics: Adult; Antiviral Agents; Drug Therapy, Combination; Female; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Internationality; Liver Cirrhosis; Male; Middle Aged; Patient Reported Outcome Measures; Pteridines; Quality of Life; Sofosbuvir; Surveys and Questionnaires; Treatment Outcome; Viral Load; Virus Replication

Vesatolimod (GS-9620) is an oral agonist of toll-like receptor 7, an activator of innate and adaptive immune responses. Herein the safety and efficacy of vesatolimod is assessed after once-weekly treatment in patients with chronic hepatitis B (CHB) infection suppressed on oral antiviral treatment.. The majority of patients were male (76%) and HBeAg-negative (79%) at baseline. Most (41-80%) experienced ≥1 AE during the study with the majority of AEs mild or moderate in severity. No significant declines in HBsAg were observed at the primary (Week 24) or secondary endpoints (Weeks 4, 8, 12, and 48). ISG15 induction was dose-dependent and consistent after repeat dosing, returning closer to baseline by one week after treatment at all dose levels; no patient demonstrated significant serum interferon alpha (IFNα) expression at any timepoint evaluated. Multivariate analyses showed that ≥2-fold ISG15 induction is associated with 2- or 4-mg vesatolimod dose and female sex.. Vesatolimod was safe and well-tolerated in patients with CHB, demonstrating consistent dose-dependent pharmacodynamic induction of ISG15 without significant systemic induction of IFNα expression or related symptoms. However, no significant HBsAg declines were observed.. In a phase II study, vesatolimod, an oral, once-weekly, experimental immune-activating drug for the treatment of hepatitis B virus (HBV), is safe and well-tolerated in chronic HBV patients who are virally suppressed on oral antiviral treatment. Despite demonstrating on-target biomarker responses in patients, no significant declines in hepatitis B surface antigen were observed. Clinical Trial Number: GS-US-283-1059; NCT 02166047.

Topics: Adaptive Immunity; Administration, Oral; Adult; Antiviral Agents; Double-Blind Method; Drug Monitoring; Female; Hepatitis B virus; Hepatitis B, Chronic; Humans; Immunity, Innate; Male; Middle Aged; Monitoring, Immunologic; Pteridines; Toll-Like Receptor 7; Treatment Outcome

The oral Toll-like receptor (TLR) 7 agonist GS-9620 has antiviral effects in woodchuck and chimpanzee models of chronic hepatitis B virus (HBV) infection. We investigated, in a clinical trial, the capacity of this agent to reconstitute protective immunity in patients with chronic HBV infection.. We performed a prospective study of 28 patients with suppression of HBV infection by nucleos(t)ide analogue therapy and who tested negative for hepatitis B e antigen at 4 medical centers in Italy. Patients were randomly assigned (1:3:3:3) to groups given placebo or different doses of GS-9620 (1, 2, and 4 mg, weekly for 12 weeks). We added data from 8 patients receiving nucleos(t)ide analogue therapy to the placebo group (controls); 13 treatment-naïve patients with chronic HBV infection and 15 subjects who spontaneously recovered from an acute HBV infection served as additional controls. Peripheral blood mononuclear cells were collected at baseline, during administration of GS-9620 or placebo, and 12 weeks afterward. Phenotype and function of natural killer (NK) and HBV-specific T cells were analyzed by flow cytometry. T cells were expanded by incubation with peptides from the entire HBV proteome and studied after overnight or 10 days culture. NK-cell inhibition of T-cell responses was measured by assessing cytokine production by T cells stimulated with peptides in the presence or absence of NK cells.. T cells collected at baseline before addition of GS-9620, when patients were receiving only nucleos(t)ide therapy, had greater responses to HBV than T cells from treatment-naïve patients, based on cytokine production in response to HBV peptides. However, during or after administration of GS-9620, T cells produced higher levels of cytokines compared to baseline. NK-cell activation and function increased after patients were given GS-9620, but the ability of NK cells to suppress T-cell responses was lower during GS-9620 therapy than before. Changes in T-cell or NK-cell function did not correlate with levels of hepatitis B surface antigen. Serum levels of hepatitis B surface antigen did not decrease significantly compared to baseline in patients given any dose of GS-9620.. Twelve weeks administration of GS-9620 had no significant effect on serum hepatitis B surface antigen levels, but did appear to increase T-cell and NK-cell responses and reduce the ability of NK to suppress T cells. GS-9620 might therefore be included in therapies to increase the immune response to HBV.

Topics: Adult; Antiviral Agents; Female; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Killer Cells, Natural; Male; Middle Aged; Nucleosides; Prospective Studies; Pteridines; T-Lymphocytes; Toll-Like Receptor 7

Vesatolimod is an oral agonist of toll-like receptor 7 designed to minimize systemic exposure and side effects. We assessed the safety and efficacy of vesatolimod in viremic chronic hepatitis B (CHB) patients not currently on oral antiviral treatment (OAV) in a phase 2, multicentre, double-blind, randomized, placebo-controlled study. A total of 192 patients stratified by HBeAg status and alanine aminotransferase level were randomized 2:2:2:1 to receive oral vesatolimod (1-, 2- or 4-mg) or placebo once weekly for 12 weeks; tenofovir disoproxil fumarate (300-mg daily) was administered daily for 48 weeks. Efficacy was assessed by quantitative serum HBsAg decline at Week 24 from baseline. In addition to safety assessments, changes in whole-blood interferon-stimulated gene (ISG) transcripts and serum cytokines were explored. Most patients were male (64.1%) and HBeAg-negative (60.9%) at baseline. Among vesatolimod-treated patients, most (60.4%-69.1%) experienced ≥1 treatment-emergent adverse event; the majority were mild or moderate in severity. No clinically meaningful differences in HBsAg changes from baseline were observed between treatment groups. No patients experienced HBsAg loss, while 3 patients experienced HBeAg loss and hepatitis B e-antibody seroconversion at week 48. HBV DNA suppression rates were similar across all treatment arms at Week 24. ISG15 induction was dose-dependent and did not correlate with HBsAg changes. A small proportion of patients exhibited dose-dependent interferon-α induction that correlated with grade of influenza-like adverse events. Overall, vesatolimod is safe and well tolerated in CHB patients. Although consistent dose-dependent pharmacodynamic induction of ISGs was demonstrated, it did not result in clinically significant HBsAg decline.

Topics: Adult; Aged; Antiviral Agents; Cytokines; DNA, Viral; Double-Blind Method; Drug Therapy, Combination; Female; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon-alpha; Male; Middle Aged; Pteridines; Seroconversion; Tenofovir; Treatment Outcome; Viral Load; Young Adult

GS-9620 is an oral agonist of toll-like receptor 7, a pattern-recognition receptor whose activation results in innate and adaptive immune stimulation. We evaluated the safety, pharmacokinetics, and pharmacodynamics of GS-9620 in patients with chronic hepatitis B.. In two double-blind, phase 1b trials of identical design, 49 treatment-naïve and 51 virologically suppressed patients were randomized 5:1 to receive GS-9620 (at doses of 0.3mg, 1mg, 2mg, 4mg) or placebo as a single dose or as two doses seven days apart. Pharmacodynamic assessment included evaluation of peripheral mRNA expression of interferon-stimulated gene 15 (ISG15), serum interferon gamma-induced protein 10 and serum interferon (IFN)-alpha.. Overall, 74% of patients were male and 75% were HBeAg negative at baseline. No subject discontinued treatment due to adverse events. Fifty-eight percent experienced ⩾1 adverse event, all of which were mild to moderate in severity. The most common adverse event was headache. No clinically significant changes in HBsAg or HBV DNA levels were observed. Overall, a transient dose-dependent induction of peripheral ISG15 gene expression was observed peaking within 48 hours of dosing followed by return to baseline levels within seven days. Higher GS-9620 dose, HBeAg positive status, and low HBsAg level at baseline were independently associated with greater probability of ISG15 response. Most patients (88%) did not show detectable levels of serum IFN-alpha at any time point.. Oral GS-9620 was safe, well tolerated, and associated with induction of peripheral ISG15 production in the absence of significant systemic IFN-alpha levels or related symptoms.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antiviral Agents; DNA, Viral; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Genotype; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Middle Aged; Pteridines; Retrospective Studies; Toll-Like Receptor 7; Treatment Outcome; Young Adult

Toll-like receptor (TLR) agonists have been developed as adjuvants to efficiently induce antiviral immune responses. Specificity and potency of these compounds are essential requirements for clinical trial applications. In patients with hepatitis B virus (HBV) infections, sustained loss of hepatitis B surface antigen (HBsAg) is a therapeutic goal, which may be achievable by the sequential activation of follicular helper T cells (Tfh) and antibody-secreting B cells. We aimed to elucidate whether novel TLR7 agonist, GS-986, could activate immune responses involved in HBV elimination.. To clarify the impact of GS-986 on pDCs, we quantified the expression levels of surface markers and evaluated for Tfh induction in a culture model consisting of human pDCs with allogeneic naïve CD4. pDCs from CHB patients had lower OX40L expression and as well as impaired capacity for Tfh induction compared with those from healthy donors. However, GS-986-stimulated pDCs from CHB patients expressed OX40L and produced IL-6 and IL-12, resulting in the induction of IL-21-producing Tfh cells (CXCR5. GS-986 is an adjuvant that stimulates pDCs to induce Tfh differentiation and antigen-specific B-cell production. This immune profile may be beneficial for therapeutic application as an immune modulator in CHB patients.

Topics: Antibodies, Viral; Antiviral Agents; CD4-Positive T-Lymphocytes; Cell Differentiation; Dendritic Cells; Female; Hepatitis B Surface Antigens; Hepatitis B, Chronic; Humans; Male; Middle Aged; T Follicular Helper Cells; Toll-Like Receptor 7; Up-Regulation

GS-9620, an oral agonist of toll-like receptor 7, is in clinical development for the treatment of chronic hepatitis B (CHB). GS-9620 was previously shown to induce prolonged suppression of serum viral DNA and antigens in the chimpanzee and woodchuck models of CHB. Herein, we investigated the immunomodulatory mechanisms underlying these antiviral effects.. Archived liver biopsies and paired peripheral blood mononuclear cell samples from a previous chimpanzee study were analyzed by RNA sequencing, quantitative reverse transcription PCR, immunohistochemistry (IHC) and in situ hybridization (ISH).. GS-9620 treatment of CHB chimpanzees induced an intrahepatic transcriptional profile significantly enriched with genes associated with hepatitis B virus (HBV) clearance in acutely infected chimpanzees. Type I and II interferon, CD8. The antiviral response to GS-9620 treatment in CHB chimpanzees was associated with an intrahepatic interferon response and formation of lymphoid aggregates in the liver. Our data indicate these intrahepatic structures are not fully differentiated follicles containing germinal center reactions. However, the temporal correlation between development of these T and B cell aggregates and the antiviral response to treatment suggests they play a role in promoting an effective immune response against HBV.. New therapies to treat chronic hepatitis B (CHB) are urgently needed. In this study we performed a retrospective analysis of liver and blood samples from a chimpanzee model of CHB to help understand how GS-9620, a drug in clinical trials, suppressed hepatitis B virus (HBV). We found that the antiviral response to GS-9620 was associated with accumulation of immune cells in the liver that can either kill cells infected with HBV or can produce antibodies that may prevent HBV from infecting new liver cells. These findings have important implications for how GS-9620 may be used in patients and may also help guide the development of new therapies to treat chronic HBV infection.

Topics: Animals; Antiviral Agents; B-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Aggregation; Disease Models, Animal; Gene Expression Profiling; Hepatitis B, Chronic; Humans; Liver; Pan troglodytes; Pteridines; Toll-Like Receptor 7

GS-9620, an oral agonist of toll-like receptor 7 (TLR7), is in clinical development for the treatment of chronic hepatitis B (CHB). GS-9620 was previously shown to induce prolonged suppression of serum viral DNA and antigens in the woodchuck and chimpanzee models of CHB. Herein, we investigated the molecular mechanisms that contribute to the antiviral response to GS-9620 using in vitro models of hepatitis B virus (HBV) infection.. Cryopreserved primary human hepatocytes (PHH) and differentiated HepaRG (dHepaRG) cells were infected with HBV and treated with GS-9620, conditioned media from human peripheral blood mononuclear cells treated with GS-9620 (GS-9620 conditioned media [GS-9620-CM]), or other innate immune stimuli. The antiviral and transcriptional response to these agents was determined.. GS-9620 had no antiviral activity in HBV-infected PHH, consistent with low level TLR7 mRNA expression in human hepatocytes. In contrast, GS-9620-CM induced prolonged reduction of HBV DNA, RNA, and antigen levels in PHH and dHepaRG cells via a type I interferon (IFN)-dependent mechanism. GS-9620-CM did not reduce covalently closed circular DNA (cccDNA) levels in either cell type. Transcriptional profiling demonstrated that GS-9620-CM strongly induced various HBV restriction factors - although not APOBEC3A or the Smc5/6 complex - and indicated that established HBV infection does not modulate innate immune sensing or signaling in cryopreserved PHH. GS-9620-CM also induced expression of immunoproteasome subunits and enhanced presentation of an immunodominant viral peptide in HBV-infected PHH.. Type I IFN induced by GS-9620 durably suppressed HBV in human hepatocytes without reducing cccDNA levels. Moreover, HBV antigen presentation was enhanced, suggesting additional components of the TLR7-induced immune response played a role in the antiviral response to GS-9620 in animal models of CHB.. GS-9620 is a drug currently being tested in clinical trials for the treatment of chronic hepatitis B virus (HBV) infection. GS-9620 has previously been shown to suppress HBV in various animal models, but the underlying antiviral mechanisms were not completely understood. In this study, we determined that GS-9620 does not directly activate antiviral pathways in human liver cells, but can induce prolonged suppression of HBV via induction of an antiviral cytokine called interferon. However, interferon did not destroy the HBV genome, suggesting that other parts of the immune response (e.g. activation of immune cells that kill infected cells) also play an important role in the antiviral response to GS-9620.

Topics: Animals; Antigen Presentation; Antiviral Agents; Cells, Cultured; Cytokines; DNA, Circular; DNA, Viral; Hepatitis B Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Humans; Immunity, Innate; Interferon Type I; Pteridines; RNA, Messenger; RNA, Viral; Toll-Like Receptor 7

Pteridinone-based Toll-like receptor 7 (TLR7) agonists were identified as potent and selective alternatives to the previously reported adenine-based agonists, leading to the discovery of GS-9620. Analogues were optimized for the immunomodulatory activity and selectivity versus other TLRs, based on differential induction of key cytokines including interferon α (IFN-α) and tumor necrosis factor α (TNF-α). In addition, physicochemical properties were adjusted to achieve desirable in vivo pharmacokinetic and pharmacodynamic properties. GS-9620 is currently in clinical evaluation for the treatment of chronic hepatitis B (HBV) infection.

Topics: Administration, Oral; Animals; Antiviral Agents; Dogs; Drug Evaluation, Preclinical; Female; Hepatitis B, Chronic; Humans; Male; Mice; Microsomes, Liver; Models, Molecular; Protein Conformation; Pteridines; Rats; Structure-Activity Relationship; Substrate Specificity; Toll-Like Receptor 7

Direct-acting antiviral agents suppress hepatitis B virus (HBV) load, but they require life-long use. Stimulation of the innate immune system could increase its ability to control the virus and have long-lasting effects after a finite regimen. We investigated the effects of immune activation with GS-9620--a potent and selective orally active small molecule agonist of Toll-like receptor 7--in chimpanzees with chronic HBV infection.. GS-9620 was administered to chimpanzees every other day (3 times each week) for 4 weeks at 1 mg/kg and, after a 1-week rest, for 4 weeks at 2 mg/kg. We measured viral load in plasma and liver samples, the pharmacokinetics of GS-9620, and the following pharmacodynamics parameters: interferon-stimulated gene expression, cytokine and chemokine levels, lymphocyte and natural killer cell activation, and viral antigen expression. Clinical pathology parameters were monitored to determine the safety and tolerability of GS-9620.. Short-term oral administration of GS-9620 provided long-term suppression of serum and liver HBV DNA. The mean maximum reduction of viral DNA was 2.2 logs, which occurred within 1 week of the end of GS-9620 administration; reductions of >1 log persisted for months. Serum levels of HBV surface antigen and HBV e antigen, and numbers of HBV antigen-positive hepatocytes, were reduced as hepatocyte apoptosis increased. GS-9620 administration induced production of interferon-α and other cytokines and chemokines, and activated interferon-stimulated genes, natural killer cells, and lymphocyte subsets.. The small molecule GS-9620 activates Toll-like receptor 7 signaling in immune cells of chimpanzees to induce clearance of HBV-infected cells. This reagent might be developed for treatment of patients with chronic HBV infection.

Topics: Administration, Oral; Animals; Antiviral Agents; Hepatitis B virus; Hepatitis B, Chronic; Immunity, Innate; Immunologic Factors; Pan troglodytes; Pteridines; Toll-Like Receptor 7; Viral Load

Topics: Animals; Antiviral Agents; Hepatitis B virus; Hepatitis B, Chronic; Immunologic Factors; Pteridines; Toll-Like Receptor 7; Viral Load