Hepatitis B virus (HBV) infection affects approximately 300 million people worldwide. Although antiviral therapies have improved the long-term outcomes, patients often require life-long treatment and ...there is no cure for HBV infection. New technologies can help us learn more about the pathogenesis of HBV infection and develop therapeutic agents to reduce its burden. We review recent advances in development of direct-acting antiviral and host-targeting agents, some of which have entered clinical trials. We also discuss strategies for unbiased high-throughput screens to identify compounds that inhibit HBV and for repurposing existing drugs.
A safe and effective vaccine to prevent chronic hepatitis C virus (HCV) infection is a critical component of efforts to eliminate the disease.
In this phase 1-2 randomized, double-blind, ...placebo-controlled trial, we evaluated a recombinant chimpanzee adenovirus 3 vector priming vaccination followed by a recombinant modified vaccinia Ankara boost; both vaccines encode HCV nonstructural proteins. Adults who were considered to be at risk for HCV infection on the basis of a history of recent injection drug use were randomly assigned (in a 1:1 ratio) to receive vaccine or placebo on days 0 and 56. Vaccine-related serious adverse events, severe local or systemic adverse events, and laboratory adverse events were the primary safety end points. The primary efficacy end point was chronic HCV infection, defined as persistent viremia for 6 months.
A total of 548 participants underwent randomization, with 274 assigned to each group. There was no significant difference in the incidence of chronic HCV infection between the groups. In the per-protocol population, chronic HCV infection developed in 14 participants in each group (hazard ratio vaccine vs. placebo, 1.53; 95% confidence interval CI, 0.66 to 3.55; vaccine efficacy, -53%; 95% CI, -255 to 34). In the modified intention-to-treat population, chronic HCV infection developed in 19 participants in the vaccine group and 17 in placebo group (hazard ratio, 1.66; 95% CI, 0.79 to 3.50; vaccine efficacy, -66%; 95% CI, -250 to 21). The geometric mean peak HCV RNA level after infection differed between the vaccine group and the placebo group (152.51×10
IU per milliliter and 1804.93×10
IU per milliliter, respectively). T-cell responses to HCV were detected in 78% of the participants in the vaccine group. The percentages of participants with serious adverse events were similar in the two groups.
In this trial, the HCV vaccine regimen did not cause serious adverse events, produced HCV-specific T-cell responses, and lowered the peak HCV RNA level, but it did not prevent chronic HCV infection. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT01436357.).
Lamivudine is increasingly being used to prevent hepatitis B reactivation in patients with cancer who test positive for hepatitis B surface antigen (HBsAg) and are undergoing chemotherapy.
To ...determine whether preventive lamivudine reduces chemotherapy-induced hepatitis B virus (HBV)-related morbidity and mortality in patients with cancer who test positive for HBsAg.
MEDLINE, Ovid MEDLINE, TOXNET, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials were searched in all languages until June 2007.
Clinical trials and cohort studies that reported the efficacy of preventive lamivudine versus control on HBV reactivation in patients who tested positive for HBsAg and were receiving chemotherapy were included. Additional requirements included minimum sample size (>5 participants per treatment group) and reported HBV-related morbidity and mortality data.
Two investigators independently did literature searches and data extraction, and 2 other investigators independently confirmed study eligibility and data retrieval.
Fourteen studies (2 randomized, controlled trials; 8 prospective cohort studies; and 4 retrospective cohort studies) met the predefined criteria for analysis. There were 275 patients in the preventive lamivudine group and 475 control participants for the primary end point of HBV reactivation. With preventive lamivudine, the relative risk for both HBV reactivation and HBV-related hepatitis ranged from 0.00 to 0.21. None of the patients in the preventive lamivudine group developed HBV-related hepatic failure (0 of 108 patients vs. 21 of 162 patients), and only 4 deaths were attributable to HBV (4 of 208 patients vs. 27 of 394 patients) in the preventive lamivudine group. Lamivudine was well tolerated, and no adverse effects were noted.
The studies included in the meta-analysis did not consistently report all of the outcomes of interest. Sample sizes were small and only 2 studies had a randomized, controlled design.
Preventive therapy with lamivudine for patients who test positive for HBsAg and are undergoing chemotherapy may reduce the risk for HBV reactivation and HBV-associated morbidity and mortality.
Hepatitis B virus (HBV) infects hepatocytes specifically and causes immune‐mediated liver damage. How HBV interacts with the innate immunity at the early phase of infection, either with hepatocytes ...or other cells in the liver, remains controversial. To address this question, we utilized various human cell‐culture models and humanized Alb‐uPA/SCID mice. All these models were unable to mount an interferon (IFN) response despite robust HBV replication. To elucidate the mechanisms involved in the lack of IFN response, we examined whether HBV actively inhibits innate immune functions of hepatocytes. By treating HBV‐infected cells with known inducers of the IFN signaling pathway, we observed no alteration of either sensing or downstream IFN response by HBV. We showed that the DNA innate sensing pathways are poorly active in hepatocytes, consistent with muted innate immune recognition of HBV. Upon exposure to high‐level HBV, human macrophages could be activated with increased inflammatory cytokine expressions. Conclusion: HBV behaves like a “stealth” virus and is not sensed by, nor actively interferes with, the intrinsic innate immunity of infected hepatocytes. Macrophages are capable of sensing HBV, but require exposure to high HBV titers, potentially explaining the long “window period” during acute infection and HBV's propensity to chronic infection. (Hepatology 2017;66:1779–1793)
Background & Aims Chronic hepatitis C virus infection activates an intrahepatic immune response, leading to increased expression of interferon (IFN)-stimulated genes and activation of natural killer ...(NK) cells—the most prevalent innate immune cell in the liver. We investigated whether the elimination of hepatitis C virus with direct-acting antiviral normalizes expression of IFN-stimulated genes and NK cell function. Methods We used multicolor flow cytometry to analyze NK cells from the liver and blood of 13 HCV-infected patients who did not respond to treatment with pegylated interferon and ribavirin. Samples were collected before and during IFN-free treatment with daclatasvir and asunaprevir and compared with samples from the blood of 13 healthy individuals (controls). Serum levels of chemokine C-X-C motif ligand (CXCL) 10 or CXCL11 were measured by enzyme-linked immunosorbent assay. Results Before treatment, all patients had increased levels of CXCL10 or CXCL11 and a different NK cell phenotype from controls, characterized by increased expression of HLA-DR, NKp46, NKG2A, CD85j, signal transducer and activator of transcription 1 (STAT1), phosphorylated STAT1, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). NK cells from patients also had increased degranulation and decreased production of IFNγ and tumor necrosis factor α compared with NK cells from controls. Nine patients had an end-of-treatment response (undetectable virus) and 4 had virologic breakthrough between weeks 4 and 12 of therapy. A rapid decrease in viremia and level of inflammatory cytokines in all patients was associated with decreased activation of intrahepatic and blood NK cells; it was followed by restoration of a normal NK cell phenotype and function by week 8 in patients with undetectable viremia. This normalized NK cell phenotype was maintained until week 24 (end of treatment). Conclusions Direct-acting antiviral–mediated clearance of HCV is associated with loss of intrahepatic immune activation by IFNα, which is indicated by decreased levels of CXCL10 and CXCL11 and normalization of NK cell phenotype and function.
Hepatitis B virus (HBV) is a significant global pathogen, infecting more than 240 million people worldwide. While treatment for HBV has improved, HBV patients often require lifelong therapies and ...cure is still a challenging goal. Recent advances in technologies and pharmaceutical sciences have heralded a new horizon of innovative therapeutic approaches that are bringing us closer to the possibility of a functional cure of chronic HBV infection. In this article, we review the current state of science in HBV therapy and highlight new and exciting therapeutic strategies spurred by recent scientific advances. Some of these therapies have already entered into clinical phase, and we will likely see more of them moving along the development pipeline. Conclusion: With growing interest in developing and efforts to develop more effective therapies for HBV, the challenging goal of a cure may be well within reach in the near future.(Hepatology 2015;62:1893–1908)
PDF
