Acute Hepatitis B Virus Infection Research Articles

Covering the Cover

Covering the Cover

ADCC-Mediated CD56dim NK Cell Responses Are Associated with Early HBsAg Clearance in Acute HBV Infection

Hepatitis B virus (HBV) affects up to 400 million people worldwide and accounts for approximately one million deaths per year from liver pathologies. Current treatment regimens are effective in suppressing viremia but usually have to be taken indefinitely, warranting research into new therapeutic approaches. Acute HBV infection in adults almost universally results in resolution of viremia, with the exception of immunocompromised persons, suggesting that the immune response can functionally cure or even eradicate HBV infection. Because immunophenotypic and functional studies have implicated a role for Natural Killer (NK) cells in HBV clearance during acute infection, we hypothesized that a distinct NK-cell profile exists in acute HBV infection that could provide information for the mechanism of HBV clearance. Using multivariate flow cytometry, we evaluated the expression of key activating and inhibitory receptors on NK cells, and their ability to respond to classic target cell lines. Multivariate analysis revealed selective perturbation of the CD56 dim NK-cell subset during acute infection, displaying low levels of NKp46+, NKp30+, CD160+ and CD161+ cells. Intriguingly, the CD56 dim NK-cell profile predicted time to HBV surface antigen (HBsAg) clearance from the blood, and distinct NK-cell profiles predicted early (NKp30, CD94, CD161) and late clearance (KIR3DL1, CD158a, perforin, NKp46). Finally, functional analysis demonstrated that early and late clearance tracked with elevated degranulation (CD107a) or IFNγ production, respectively, in response to ADCC-mediated activation. In conclusion, the cytolytic CD56dim NK-cell subset is selectively activated in acute HBV infection and displays distinct phenotypic and functional profiles associated with efficient and early control of HBV, implicating antibody-mediated cytolytic NK-cell responses in the early control and functional cure of HBV infection.

ADCC-Mediated CD56DIM NK Cell Responses Are Associated with Early HBsAg Clearance in Acute HBV Infection.

Background:Hepatitis B virus (HBV) affects up to 400 million people worldwide and accounts for approximately one million deaths per year from liver pathologies. Current treatment regimens are effective in suppressing viremia but usually have to be taken indefinitely, warranting research into new therapeutic approaches. Acute HBV infection in adults almost universally results in resolution of viremia, with the exception of immunocompromised persons, suggesting that the immune response can functionally cure or even eradicate HBV infection.Methods:Because immunophenotypic and functional studies have implicated a role for Natural Killer (NK) cells in HBV clearance during acute infection, we hypothesized that a distinct NK-cell profile exists in acute HBV infection that could provide information for the mechanism of HBV clearance. Using multivariate flow cytometry, we evaluated the expression of key activating and inhibitory receptors on NK cells, and their ability to respond to classic target cell lines.Results:Multivariate analysis revealed selective perturbation of the CD56,dim NK-cell subset during acute infection, displaying low levels of NKp46+, NKp30+, CD160+ and CD161+ cells. Intriguingly, the CD56,dim NK-cell profile predicted time to HBV surface antigen (HBsAg) clearance from the blood, and distinct NK-cell profiles predicted early (NKp30, CD94, CD161) and late clearance (KIR3DL1, CD158a, perforin, NKp46). Finally, functional analysis demonstrated that early and late clearance tracked with elevated degranulation (CD107a) or IFNγ production, respectively, in response to ADCC-mediated activation.Conclusion:The cytolytic CD56,dim NK-cell subset is selectively activated in acute HBV infection and displays distinct phenotypic and functional profiles associated with efficient and early control of HBV, implicating antibody-mediated cytolytic NK-cell responses in the early control and functional cure of HBV infection.

Hepatitis B Virus-Specific CD8+ T Cells Maintain Functional Exhaustion after Antigen Reexposure in an Acute Activation Immune Environment.

Chronic hepatitis B virus (HBV) infection is characterized by the presence of functionally exhausted HBV-specific CD8+ T cells. To characterize the possible residual effector ability of these cells, we reexposed CD8+ T cells from chronically HBV replicating mice to HBV antigens in an acute activation immune environment. We found that after transfer into naive mice, exhausted CD8+ T cells reexpanded in a comparable magnitude as naive CD8+ T cells in response to acute HBV infection; however, their proliferation intensity was significantly lower than that of CD8+ T cells from acute-resolving HBV replicating mice (AR mice). The differentiation phenotypes driven by acute HBV replication of donor exhausted and naive CD8+ T cells were similar, but were different from those of their counterparts from AR mice. Nevertheless, exhausted CD8+ T cells maintained less activated phenotype, an absence of effector cytokine production and poor antiviral function after HBV reexposure in an acute activation immune environment. We thus conclude that exhausted CD8+ T cells undergo a stable form of dysfunctional differentiation during chronic HBV replication and switching immune environment alone is not sufficient for the antiviral functional reconstitution of these cells.

Impact of hepatitis B vaccination on acute hepatitis B epidemiology in European Union/European Economic Area countries, 2006 to 2014.

Hepatitis B prevention in European Union/European Economic Area (EU/EEA) countries relies on vaccination programmes. We describe the epidemiology of acute hepatitis B virus (HBV) at country and EU/EEA level during 2006–2014. Using a multi-level mixed-effects Poisson regression model we assessed differences in the acute HBV infection notification rates between groups of countries that started universal HBV vaccination before/in vs after 1995; implemented or not a catch-up strategy; reached a vaccine coverage ≥ 95% vs < 95% and had a hepatitis B surface antigen prevalence ≥ 1% vs < 1%. Joinpoint regression analysis was used to assess trends by groups of countries, and additional Poisson regression models to evaluate the association between three-dose HBV vaccine coverage and acute HBV infection notification rates at country and EU/EEA level. The EU/EEA acute HBV infection notification rate decreased from 1.6 per 100,000 population in 2006 to 0.7 in 2014. No differences (p > 0.05) were found in the acute HBV infection notification rates between groups of countries, while as vaccine coverage increased, such rates decreased (p < 0.01). Countries with universal HBV vaccination before 1995, a catch-up strategy, and a vaccine coverage ≥ 95% had significant decreasing trends (p < 0.01). Ending HBV transmission in Europe by 2030 will require high vaccine coverage delivered through universal programmes, supported, where appropriate, by catch-up vaccination campaigns.

TLR7 Agonist Increases Responses of Hepatitis B Virus–Specific T Cells and Natural Killer Cells in Patients With Chronic Hepatitis B Treated With Nucleos(T)Ide Analogues

The oral Toll-like receptor (TLR) 7agonist 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 28patients 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. Tcells 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.

Analysis of hepatitis B virus (HBV) preS1, preS2 and S gene regions from patient groups infected with HBV genotype D

Mutations in preS and S gene regions of hepatitis B virus genome may cause immune escape and diagnostic escape HBV mutants. The aim of this study was to determine preS1, preS2 and S gene regions of HBV from HBV infected patient groups by sequence analysis and contribute to the relevant literature. Nucleic acid sequence analysis of preS and S genes of HBV PCR products from 56 archived plasma samples sent to Ege University Faculty of Medicine Medical Microbiology Department Molecular Virology laboratory, for HBV tests were determined by chain termination reaction. Amino acid (aa) sequences were compared with the reference sequences obtained from GenBank. Plasma samples belonged to four groups of patients: A- Chronic HBV infected patients with typical HBV serological profiles (22 samples), B- HBV infected patients with atypical HBV serological profiles (26 samples), C- HBV re-infected patients after liver transplantation (5 samples), D- Seroconversion phase following acute HBV infection (3 samples). One of two vaccine escape mutant samples was also diagnostic escape mutant; the other diagnostic escape mutant was isolated from anti-HBc positive sample. All of the sequences were determined as genotype D. HBsAg subtypes were determined as; two ayw1, six ayw3, two mix, 46 ayw2. Among the 304 codons analysed between preS 33rd and S 162nd amino acids; aa variants were determinedin 105 codons (34.5%). Sequences can be found in GenBank with accession numbers FJ001941-FJ001996. At least one aa variation was detected in 48 of 56 samples (85.7%). The amino acid variants were as follows; PreS1: A33T, A39T, P41K, D44del, D50N, T51P, D54N, L65P/M, F67L, W77T, A81S, Q82E, I84T, L85I/M, Q86H/T, L88S, A90T/V, N91K/del, A95P, S96A, T97I/A, N98K, Q100K, S101T, S109T, P110S, N114D/E, PreS2: M1V, Q2R, S5H, F8S, H9Q, Q13L, D14N, R16K, R18K, G19S/D, F22L/S, S28T, G30E, N33T, V39A, P41H/L, I42T/L, I45T, F46Y, S47L, R48K, I49T, D51V/G, P52L, A53V, L54R/G, N55K; S gene: E2D, I4F, F8L, G10A, V14A, F20S, L22del, R24K, P29L, Q30K, N40S, F41del, G44E, T45L, T46P, V47A, L49R, Q54R, P56L, S64F, P70A, M75I, C76Y, R79H, I81T, F83C, L88P, L94S, Y100F, Q101H/R, M103L, L104F, L109I/M, I110L, G112S/R, S113N/P, S114A/del, T115I, T116N, T118A/K, P120A/T, T123A, in "a" determinant; T126I, Q129H/R, T131N, M133T, Y134N, S136Y, S143L/M/T, D144E, G145A/R. Deletions were also found in all three preS/S gene regions. The highest number of aa variations were detectedin the isolated anti-HBc positive sample (in 24 codons), followed by liver transplant group (8-13 codons). Point mutation was detected in the preS2/S promoter CCAAT box. Major hydrophilic region (MHR) variants were determined in 41.1% of 56 samples. The highest number of MHR variants belonged to atypical HBV serological profile group (group B; 61.5%) and liver transplantation group with HBV re-infection (all C group). Among the diagnostic escape and immune escape mutant (anti-HBs positive) samples, reported MHR and "a" determinant mutations were detected. In conclusion, the study population carries HBV preS/S variants; MHR and "a" determinant variant rates are high among diagnostic or immune escape mutants. It is important to evaluate the mutant detection performance of HBsAg tests.

A Case Report of Fatal Necrotizing Encephalitis and Acute HBV Infection: Coincidence or Comorbidity?

AbstractWe report the first fatal pediatric case of encephalitis associated with hepatitis B virus (HBV) infection. A Caucasian, previously healthy, and vaccinated 7-year-old girl was evaluated at our hospital for fever, vomiting, tremors, and loss of consciousness. At admission, she underwent brain computed tomographic scan, electroencephalogram, lumbar puncture, and blood examination. In 12 hours, her clinical condition deteriorated and the patient entered coma and died. A laboratory error was useful to reach a predeath diagnosis, showing HBV–DNA on blood. Autopsy confirmed HBV–PCR DNA in brain, lymphnodes, lungs, liver, and spleen. We generally do not search HBV–DNA in organic fluid of Italian children with encephalitis, as they are currently all vaccinated. Consequently, as a teaching lesson, we would suggest not to take anything obvious.

The Role of Infected Cell Proliferation in the Clearance of Acute HBV Infection in Humans.

Around 90–95% of hepatitis B virus (HBV) infected adults do not progress to the chronic phase and, instead, recover naturally. The strengths of the cytolytic and non-cytolytic immune responses are key players that decide the fate of acute HBV infection. In addition, it has been hypothesized that proliferation of infected cells resulting in uninfected progeny and/or cytokine-mediated degradation of covalently closed circular DNA (cccDNA) leading to the cure of infected cells are two major mechanisms assisting the adaptive immune response in the clearance of acute HBV infection in humans. We employed fitting of mathematical models to human acute infection data together with physiological constraints to investigate the role of these hypothesized mechanisms in the clearance of infection. Results suggest that cellular proliferation of infected cells resulting in two uninfected cells is required to minimize the destruction of the liver during the clearance of acute HBV infection. In contrast, we find that a cytokine-mediated cure of infected cells alone is insufficient to clear acute HBV infection. In conclusion, our modeling indicates that HBV clearance without lethal loss of liver mass is associated with the production of two uninfected cells upon proliferation of an infected cell.

Acute hepatitis B virus infection and severe non-immune haemolytic anaemia: a rare relationship

The clinical presentation of acute hepatitis B virus (HBV) infection is usually related to the onset of liver failure and damage. Anaemia may occur, but it is only rarely attributed...

The CCR5-∆32 Mutation: Impact on Disease Outcome in Individuals with Hepatitis B Infection in the Southern Khorasan Population (East of Iran)

Background: Hepatitis B virus (HBV) is the main infectious agent that causes liver disease and may lead to an acute or chronic HBV infection. Evidence from many studies have determined that host genetic factors play a significant role in determining immunization, clinical course, and recovery from HBV infection. A 32-bp deletion in the region of CCR5 gene (CCR5 ∆32) is one of the mutations that is known to provide genetic protection against chronic HBV infections. Objectives: In this study, the researchers aimed at assessing the protective effect of CCR5 ∆32 in subjects, who had recovered from HBV infection, as well as subjects that developed chronic HBV infection, in Birjand, Iran. Methods: The study consisted of 60 patients with chronic HBV infection (patient group) and 120 patients, who had previously recovered from HBV infection (control group). Genomic DNA was extracted from blood samples by the salting out method, and then samples were analyzed for the CCR5 ∆32 genotype utilizing the gap-polymerase chain reaction (Gap-PCR) technique. Variables were analyzed using the Chi-square test and P values less than 0.05 were considered as statistically significant. Results: The researchers found only one heterozygous CCR5 ∆32 mutation in the control group and absolutely no homozygous CCR5 Δ32 mutation in either the patient or control group. Conclusions: Because of no significant visible correlation between carrying the mutation and the possibility of recovery from HBV infection in the city of Birjand, it seems the protective effect of this mutation is absent in Birjand’s population.

Dynamics of the Immune Response in Acute Hepatitis B Infection.

BackgroundAcute hepatitis B virus infection in adults is generally self-limiting but may lead to chronicity in a minority of patients.MethodsWe included 9 patients with acute hepatitis B virus (HBV) infection and collected longitudinal follow-up samples. Natural killer (NK) cell characteristics were analyzed by flowcytometry. HBV-specific T-cell function was analyzed by in vitro stimulation with HBV peptide pools and intracellular cytokine staining.ResultsMedian baseline HBV DNA load was 5.12 log IU/mL, and median ALT was 2652 U/mL. Of 9 patients, 8 cleared HBsAg within 6 months whereas 1 patient became chronically infected. Early time points after infection showed increased CD56bright NK cells and an increased proportion of cells expressing activation markers. Most of these had normalized at week 24, while the proportion of TRAIL-positive CD56bright NK cells remained high in the chronically infected patient. In patients who cleared HBV, functional HBV-specific CD8+ and CD4+ responses could be observed, whereas in the patient who developed chronic infection, only low HBV-specific T-cell responses were observed.ConclusionsNK cells are activated early in the course of acute HBV infection. Broad and multispecific T-cell responses are observed in patients who clear acute HBV infection, but not in a patient who became chronically infected.

Isolation and functional characterization of hepatitis B virus-specific T-cell receptors as new tools for experimental and clinical use.

T-cell therapy of chronic hepatitis B is a novel approach to restore antiviral T-cell immunity and cure the infection. We aimed at identifying T-cell receptors (TCR) with high functional avidity that have the potential to be used for adoptive T-cell therapy. To this end, we cloned HLA-A*02-restricted, hepatitis B virus (HBV)-specific T cells from patients with acute or resolved HBV infection. We isolated 11 envelope- or core-specific TCRs and evaluated them in comprehensive functional analyses. T cells were genetically modified by retroviral transduction to express HBV-specific TCRs. CD8+ as well as CD4+ T cells became effector T cells recognizing even picomolar concentrations of cognate peptide. TCR-transduced T cells were polyfunctional, secreting the cytokines interferon gamma, tumor necrosis factor alpha and interleukin-2, and effectively killed hepatoma cells replicating HBV. Notably, our collection of HBV-specific TCRs recognized peptides derived from HBV genotypes A, B, C and D presented on different HLA-A*02 subtypes common in areas with high HBV prevalence. When co-cultured with HBV-infected cells, TCR-transduced T cells rapidly reduced viral markers within two days. Our unique set of HBV-specific TCRs with different affinities represents an interesting tool for elucidating mechanisms of TCR-MHC interaction and dissecting specific anti-HBV mechanisms exerted by T cells. TCRs with high functional avidity might be suited to redirect T cells for adoptive T-cell therapy of chronic hepatitis B and HBV-induced hepatocellular carcinoma.

Clinical course and core variability in HBV infected patients without detectable anti-HBc antibodies

BackgroundThe presence of anti-HBc antibodies indicates direct encounter of the immune system with hepatitis B virus (HBV). ObjectivesAim of our study was to seek for anti-HBc negative but HBV replicating patients and analyze their clinical course and preconditions. Study designFrom 1568 HBV-DNA positive patients, 29 patients (1.85%) tested negative for anti-HBc. The absence of anti-HBc could be confirmed in 19 patients using an alternative assay. In 16 of 19 cases, a partial or full HBV genome analysis was performed with NGS sequencing to evaluate if specific mutations were associated with anti-HBc absence. As a control group samples from 32 matched HBV infected patients with detectable anti-HBc were sequenced. ResultsPatients with detectable HBV-DNA and sequenced HBV core region in the confirmed absence of anti-HBc were diagnosed with acute HBV infection (n=3), HBV reactivation (n=9) and chronic hepatitis B (n=4). Most patients (12/16) were immunosuppressed: 3/16 patients had an HIV coinfection, 7/16 patients suffered from a malignant disease and 4/16 patients underwent solid organ transplantation (from which 2/4 had a malignant disease). Compared to the control cohort, HBV variants from anti-HBc negative patients showed less variability in the core region. ConclusionsIn the absence of anti-HBc, HBV-DNA was most often found in immunocompromised hosts. Distinct mutations or deletions in the core region did not explain anti-HBc negativity. It would be advisable not to rely only on a single result of anti-HBc negativity to exclude HBV infection in immunocompromised hosts, but to measure anti-HBc repeatedly or with different methods

Hepatitis B in Egypt: A cross-sectional analysis of prevalence and risk factors for active infection from a nationwide survey.

Viral hepatitis is a major public health challenge in Egypt but little is known about the epidemiology of the hepatitis B virus (HBV) infection, its geographical distribution, or risk factors for infection in the Egyptian context. This study addresses this deficit using data from a nationally representative survey. Cross-sectional analysis of data gathered from men and women aged 15-59 in the Egypt Health Issues Survey (EHIS) 2015, including logistic regression to evaluate the contribution of different factors to risk of HBV infection. This was supplemented by spatial analysis of the distribution of acute or chronic HBV infection at governorate level, and the ecological relationship between HBV and HCV infections. Population HBV prevalence was 1.4% (95% confidence interval [CI] 1.2-1.6), with a HBV-HCV co-infection rate of 0.06%. Spatial analysis showed localisation of HBV infected individuals primarily to urban areas of Upper Egypt (in contrast to HCV for which prevalence is highest in rural Lower Egypt), and those in early middle age (Adjusted Odds Ratio [AOR] 3.32, 95% CI: 1.66-6.63). HBV positive status among other household members emerged as a powerful driver of infection risk in this analysis (AOR=10.75, 95% CI: 4.98-23.24). Spatial distribution of HBV infection in Egypt differs markedly from HCV and co-infection rates are low. Within-household transmissions appear to be particularly important in explaining the persistence of HBV infection in the general population. Prevention strategies should focus on urban Upper Egypt, and particularly those households with documented cases of infection.

Loss of CCR5 signaling results in early NK cell and neutrophil recruitment into the liver and increased hepatic inflammation in a mouse model of acute hepatitis B

Abstract Human genetic studies demonstrate that a non-functional CCR5 receptor sequence variant is associated with enhanced control of acute hepatitis B virus (HBV) infection. To better understand the role of CCR5 in immune responses to HBV, we employed a mouse model of acute HBV in which Ccr5 +/+(WT) or Ccr5 −/−(KO) C57BL/6 mice were intravenously infected with adenovirus containing an overlapping HBV1.3 construct (AdHBV) or vector control (AdShuttle). Mice (N=4–6/group) were euthanized at days 2, 3, 7, 10, and 14 post injection. Increased plasma ALT levels were observed in both Ccr5 WT and KO AdHBV mice at day 7, but levels were significantly higher in the Ccr5 KO compared to WT mice by day 14 (554 vs 274 U/L, p &amp;lt; 0.05). Plasma ALT levels were not significantly different between Ccr5 WT and KO AdShuttle mice. Analysis of intrahepatic leukocytes by flow cytometry revealed significantly increased intrahepatic CD11b+ NK cells (26.3 vs 6.9, % of live leukocytes, p&amp;lt; 0.01) and neutrophils (7.3 vs 1.3, % of live leukocytes, p&amp;lt; 0.05) at day 3 in Ccr5 KO compared to WT AdHBV mice. By day 7, these differences in cell populations were no longer present. At Day 14, significantly higher levels of intrahepatic Ly6c+ macrophages were detected in Ccr5 KO compared to WT AdHBV mice (17.0 vs 6.4, % of live leukocytes, p&amp;lt; 0.01). These differences in intrahepatic leukocytes were not observed in AdShuttle mice. Loss of Ccr5 function did not significantly alter intrahepatic CD4+ and CD8+ populations at the time points investigated. Taken together, these findings suggest that loss of Ccr5 signaling increases intrahepatic innate cells and inflammation during acute HBV infection, providing evidence for a role of CCR5 in regulation of innate immune responses to acute HBV infection.

Pharmacological interventions for acute hepatitis B infection: an attempted network meta-analysis.

Pharmacological interventions for acute hepatitis B infection: an attempted network meta-analysis.

Acute Hepatitis B Co-infection in HIV-Infected Patients Despite Prior Hepatitis B Vaccination

Clinicians often assume that patients vaccinated for hepatitis B virus (HBV) have immunity. We report three cases of acute HBV infection in HBV-vaccinated HIV patients. These cases illustrate that patients at an elevated risk of HBV exposure presenting with acute hepatitis should be tested for HBV infection regardless of previous vaccination status.

Reduction of acute hepatitis B through vaccina-tion of adolescents with no decrease in chronic hepatitis B due to immigration in a low ende-micity country.

With a hepatitis B prevalence of 0.3%, Switzerland is a country with low endemicity. Unlike most other countries, Switzerland's recommendation for vaccination against hepatitis B has since 1998 focused on adolescents aged 11 to 15 years rather than on infants, in addition to risk groups since 1982. This paper describes the evolution of the incidence of acute hepatitis B virus (HBV) infection and newly reported chronic cases in Switzerland, as well as their epidemiological features, in order to discuss the implications for the control of hepatitis B through vaccination. Data from mandatory notifications by physicians and laboratories between 1988 and 2015 were analysed for acute and chronic HBV infection. Crude and stratified incidence and notification rates (IR, NR), and incidence and notification rate ratios (NRR, IRR) by year were calculated by means of a Poisson regression. Acute HBV incidence peaked in 1992 at 7.5 cases per 100 000 population and subsequently declined by 11% annually (IRR 0.89, p <0.001) to the lowest rate of 0.4/100 000 in 2015. The decrease in incidence accelerated after the introduction of vaccination for adolescents (IRR 0.93, p <0.001 vs 0.91, p <0.001), and was more pronounced in the targeted age groups (IRR 0.90, p <0.001 vs 0.84, p <0.001 for age 15-19 years and IRR 0.92, p <0.001 vs 0.83, p <0.001 for age 20-24). The use of injectable drugs as an assumed source of exposure decreased from 58.1% to 1.9% of all exposures between 1988-1991 and 2012-2015, while sexual contact with an infected person increased from 10.3% to 67.9%. The NR of chronic cases increased until 1995, then stabilised at around 15/100 000. A growing majority of the chronic cases originated abroad (58.4% in 1988-1991 and 82.2% in 2012-2015), and the NR was significantly higher for foreigners than for Swiss nationals (NRR 7.92, p <0.001), especially when compared with the IRR of 1.55 (p <0.001) for acute cases. The introduction of universal vaccination of adolescents combined with vaccination of risk groups and other nonvaccine-related measures has brought acute HBV infection under control in Switzerland. However, the rate of new notifications of chronic HBV infection has remained stable, largely as a result of the immigration of people chronically infected prior to arrival. The burden of disease is thus likely to increase, requiring the strengthening of secondary prevention of chronic HBV infection, in addition to renewed efforts to vaccinate people and their families originating from countries with high endemicity, and persons who frequently change sexual partners.

Bone Marrow-Derived Mesenchymal Stem Cells Attenuate Immune-Mediated Liver Injury and Compromise Virus Control During Acute Hepatitis B Virus Infection in Mice.

Mesenchymal stem cells (MSCs) have been used as therapeutic tools not only for their ability to differentiate toward different cells, but also for their unique immunomodulatory properties. However, it is still unknown how MSCs may affect immunity during hepatitis B virus (HBV) infection. This study was designed to explore the effect of bone marrow-derived MSCs (BM-MSCs) on hepatic natural killer (NK) cells in a mouse model of acute HBV infection. Mice were injected with 1 × 106 BM-MSCs, which stained with chloromethyl derivatives of fluorescein diacetate fluorescent probe, 24 h before hydrodynamic injection of viral DNA (pHBV1.3) through the tail vein. In vivo imaging system revealed that BM-MSCs were accumulated in the injured liver, and they attenuated immune-mediated liver injury during HBV infection, as shown by lower alanine aminotransferase levels, reduced proinflammatory cytokine production, and decreased inflammatory cell infiltration in the liver. Importantly, administration of BM-MSCs restrained the increased expression of natural-killer group 2, member D (NKG2D), an important receptor required for NK cell activation in the liver from HBV-infected mice. BM-MSCs also reduced NKG2D expression on NK cells and suppressed the cytotoxicity of NK cells in vitro. Furthermore, BM-MSC-derived transforming growth factor-β1 suppressed NKG2D expression on NK cells. As a consequence, BM-MSC treatment enhanced HBV gene expression and replication in vivo. These results demonstrate that adoptive transfer of BM-MSCs influences innate immunity and limits immune-mediated liver injury during acute HBV infection by suppressing NK cell activity. Meanwhile, the effect of BM-MSCs on prolonging virus clearance needs to be considered in the future.