The Shifting Epidemiology of Hepatitis A in the World Health Organization Western Pacific Region.

Within the past few decades, improvement in sanitation and economic growth has driven a changing epidemiology of hepatitis A in the Western Pacific Region (WPR) of the World Health Organization (WHO). In this review, we gathered available published information on hepatitis A epidemiology of the countries in the WPR and reviewed the trends reported in the literature from the years 2000 to 2021. Many countries have shifted from high endemicity to low endemicity. Moreover, the administration of the hepatitis A vaccine among children in recent years has shifted disease susceptibility to the older population. Seroprevalence among children has decreased in most countries, while nearly 100% seropositivity is seen in mid adulthood. This is contrary to the epidemiology seen in previous decades when most children achieved immunity by age ten. This also presents a paradox in that better living conditions have caused more vulnerability to the older age groups who are at higher risk for severe disease. Given these trends, we recommend vaccination of vulnerable populations such as the older age groups and inclusion of the hepatitis A vaccine in government immunization programs.

Peripheral B cells from patients with hepatitis C virus-associated lymphoma exhibit clonal expansion and an anergic-like transcriptional profile.

Chronic HCV infection remains a global health concern due to its involvement in hepatic and extrahepatic diseases, including B cell non-Hodgkin lymphoma (BNHL). Clinical and epidemiological evidence support a causal role for HCV in BNHL development, although mechanistic insight is lacking. We performed RNA-sequencing on peripheral B cells from patients with HCV alone, BNHL alone, and HCV-associated BNHL to identify unique and shared transcriptional profiles associated with transformation. In patients with HCV-associated BNHL, we observed the enrichment of an anergic-like gene signature and evidence of clonal expansion that was correlated with the expression of epigenetic regulatory genes. Our data support a role for viral-mediated clonal expansion of anergic-like B cells in HCV-associated BNHL development and suggest epigenetic dysregulation as a potential mechanism driving expansion. We propose epigenetic mechanisms may be involved in both HCV-associated lymphoma and regulation of B cell anergy, representing an attractive target for clinical interventions.

Effects of Decreased Immunization Coverage for Hepatitis B Virus Caused by COVID-19 in World Health Organization Western Pacific and African Regions, 2020.

The World Health Organization-designated Western Pacific Region (WPR) and African Region (AFR) have the highest number of chronic hepatitis B virus (HBV) infections worldwide. The COVID-19 pandemic has disrupted childhood immunization, threatening progress toward elimination of hepatitis B by 2030. We used a published mathematical model to estimate the number of expected and excess HBV infections and related deaths after 10% and 20% decreases in hepatitis B birth dose or third-dose hepatitis B vaccination coverage of children born in 2020 compared with prepandemic 2019 levels. Decreased vaccination coverage resulted in additional chronic HBV infections that were 36,342-395,594 in the WPR and 9,793-502,047 in the AFR; excess HBV-related deaths were 7,150-80,302 in the WPR and 1,177-67,727 in the AFR. These findings support the urgent need to sustain immunization services, implement catch-up vaccinations, and mitigate disruptions in hepatitis B vaccinations in future birth cohorts.

Hepatitis C Antibody Screening Among Baby Boomers by a Community-Based Health Insurance Company.

Infection with the hepatitis C virus (HCV) is the most commonly reported bloodborne infection in the United States. Individuals born between 1945-1965, the baby boomers, account for approximately 75% of all chronic HCV infections in the United States. The purpose of this study was to determine if a 6-week intervention, including outreach, education, and incentive, by a community-based health insurance company could improve uptake of HCV antibody screening among the 1945-1965 birth cohort. Individuals were eligible to participate in this campaign if they were born on or after January 1, 1945 and on or before December 31, 1965, had health insurance with Sendero Health Plans during the intervention period, and had no evidence of having received an HCV antibody test prior to the campaign start date. The 6-week campaign period was from November 14, 2018 through December 31, 2018. A gift card incentive was provided if HCV screening was completed on or before December 31, 2018. A total of 5287 individuals were eligible to participate in the campaign. Members who were baby boomers were 3.36 times more likely to receive HCV antibody screening during the intervention period in 2018 than during a similar period in 2017 (prevalence ratio = 3.36; P < 0.0001; 95% confidence interval: 2.71, 4.16). Health officials have established the identification, treatment, and elimination of HCV as a national policy objective. Using an outreach, education, and incentive approach, Sendero Health Plans improved uptake of HCV antibody screening among the high-risk baby boomer population.

A microarray-based pathogen chip for simultaneous molecular detection of transfusion-transmitted infectious agents.

BACKGROUND: New and emerging transfusion-transmitted infections remain a threat to the blood supply. Blood donors are currently screened for less than half of known agents, primarily by individual tests. A screening platform that could simultaneously detect all known transfusion-transmitted pathogens and allow rapid addition of new targets would significantly increase blood safety and could improve the response to new agents. We describe the early stage development and validation of a microarray-based platform (pathogen chip) for simultaneous molecular detection of transfusion-transmitted RNA viruses. METHODS: Sixteen RNA viruses that pose a significant risk for transfusion-transmission were selected for inclusion on the pathogen chip. Viruses were targeted for detection by 1769 oligonucleotide probes selected by Agilent eArray software. Differentially concentrated positive plasma samples were used to evaluate performance and limits of detection in the context of individual pathogens or combinations to simulate coinfection. RNA-viruses detection and concentration were validated by RT-qPCR. RESULTS: Hepatitis A, B and C, Chikungunya, dengue 1-4, HIV 1-2, HTLV I-II, West Nile and Zika viruses were all correctly identified by the pathogen chip within the range of 105 to 102 copies/mL; hepatitis E virus from 105 to 104. In mixtures of 3-8 different viruses, all were correctly identified between 105 and 103 copies/mL. CONCLUSIONS: This microarray-based multi-pathogen screening platform accurately and reproducibly detected individual and mixed RNA viruses in one test from single samples with limits of detection as low as 102 copies mL.

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8+ T cells for adoptive immunotherapy.

Adoptive T cell therapy has shown clinical potential for patients with cancer, though effective treatment is dependent on longevity and potency of the exploited tumor-reactive T cells. Previously, we showed that ex vivo inhibition of AKT using the research compound Akt-inhibitor VIII retained differentiation and improved functionality of minor histocompatibility antigen (MiHA)-specific CD8+ T cells. Here, we compared a panel of clinically applicable AKT-inhibitors with an allosteric or adenosine triphosphate-competitive mode of action. We analyzed phenotype, functionality, metabolism and transcriptome of AKT-inhibited CD8+ T cells using different T cell activation models. Most inhibitors facilitated T cell expansion while preserving an early memory phenotype, reflected by maintenance of CD62L, CCR7 and CXCR4 expression. Moreover, transcriptome profiling revealed that AKT-inhibited CD8+ T cells clustered closely to naturally occurring stem cell-memory CD8+ T cells, while control T cells resembled effector-memory T cells. Interestingly, AKT-inhibited CD8+ T cells showed enrichment of hypoxia-associated genes, which was consistent with enhanced glycolytic function. Notably, AKT-inhibition during MiHA-specific CD8+ T cell priming uncoupled preservation of early memory differentiation from ex vivo expansion. Furthermore, AKT-inhibited MiHA-specific CD8+ T cells showed increased polyfunctionality with co-secretion of IFN-γ and IL-2 upon antigen recall. Together, these data demonstrate that AKT-inhibitors with different modality of action promote the ex vivo generation of stem cell memory-like CD8+ T cells with a unique metabolic profile and retained polyfunctionality. Akt-inhibitor VIII and GDC-0068 outperformed other inhibitors, and are therefore promising candidates for ex vivo generation of superior tumor-reactive T cells for adoptive immunotherapy in cancer patients.

Binding of Free and Immune Complex-Associated Hepatitis C Virus to Erythrocytes Is Mediated by the Complement System.

Erythrocytes bind circulating immune complexes (ICs) and facilitate IC clearance from the circulation. Chronic hepatitis C virus (HCV) infection is associated with IC-related disorders. In this study, we investigated the kinetics and mechanism of HCV and HCV-IC binding to and dissociation from erythrocytes. Cell culture-produced HCV was mixed with erythrocytes from healthy blood donors, and erythrocyte-associated virus particles were quantified. Purified complement proteins, complement-depleted serum, and complement receptor antibodies were used to investigate complement-mediated HCV-erythrocyte binding. Purified HCV-specific immunoglobulin G (IgG) from a chronic HCV-infected patient was used to study complement-mediated HCV-IC/erythrocyte binding. Binding of HCV to erythrocytes increased 200- to 1,000-fold after adding complement active human serum in the absence of antibody. Opsonization of free HCV occurred within 10 minutes, and peak binding to erythrocytes was observed at 20-30 minutes. Complement protein C1 was required for binding, whereas C2, C3, and C4 significantly enhanced binding. Complement receptor 1 (CR1, CD35) antibodies blocked the binding of HCV to erythrocytes isolated from chronically infected HCV patients and healthy blood donors. HCV-ICs significantly enhanced complement-mediated binding to erythrocytes compared to unbound HCV. Dissociation of complement-opsonized HCV from erythrocytes depended on the presence of Factor I. HCV released by Factor I bound preferentially to CD19+ B cells compared to other leukocytes. Conclusion: These results demonstrate that complement mediates the binding of free and IC-associated HCV to CR1 on erythrocytes and provide a mechanistic rationale for investigating the differential phenotypic expression of HCV-IC-related disease.

Hepatitis B vaccine birth dose coverage correlates worldwide with rates of institutional deliveries and skilled attendance at birth.

BACKGROUND: Chronic hepatitis B virus (HBV) infection occurs in 90% of infants infected perinatally but is prevented when a hepatitis B vaccine is given within 24h of birth (HepB-BD), followed by 2-3 additional doses. METHODS: Using Spearman's rho correlation coefficients (rho), we analyzed global and regional data to assess correlations between HepB-BD coverage, institutional delivery rates (IDR), skilled birth attendance (SBA) rates, and other potential co-variates. RESULTS: Significant correlations were observed worldwide between HepB-BD and SBA rates (rho=0.44, p<0.001), IDR (rho=0.42, p<0.001), adult literacy rate (rho=0.37, p=0.003), total health expenditure per capita (rho=0.24, p=0.03) and live births (rho=-0.27, p=0.014). HepB-BD, IDR, and SBA rates were significantly correlated in the World Health Organization African, South-East Asia and Western Pacific Regions. CONCLUSIONS: Increasing IDR and SBA rates, training and supervising staff, increasing community awareness, and using HepB-BD outside the cold chain where needed would increase HepB-BD coverage and prevent chronic infections.

Hepatitis B control among children in the Eastern Mediterranean Region of the World Health Organization.

In the pre-vaccination era, the prevalence of chronic hepatitis B virus (HBV) infection in the World Health Organization (WHO) Eastern Mediterranean Region (EMR) ranged from two to seven percent in a total population of over 580 million people. Mortality estimates place cirrhosis among the top ten causes of years of life lost in the EMR. The region has made notable achievements, improving coverage from only 6% in 1992, when WHO recommended hepatitis B vaccination of all infants, to 83% in 2014. Member states adopted a hepatitis B control target in 2009 to reduce chronic hepatitis B virus infection prevalence to less than one percent among children aged <5 years by 2015. This report reviews progress toward achievement, challenges faced, and the next steps forward of hepatitis B control among children in the EMR.

The American College of Preventive Medicine Position Statement on Hepatitis C Virus Infection.

The American College of Preventive Medicine Prevention Practice Committee contributes to policy guidelines and recommendations on preventive health topics for clinicians and public health decision makers. After review of the currently available evidence, the College is providing a consensus-based set of recommendations designed to increase screening for and prevention of hepatitis C virus infection, increase linkage to care, improve access to treatment, and encourage development of hepatitis C virus-related quality measures.

Increased incidence of cancer and cancer-related mortality among persons with chronic hepatitis C infection, 2006-2010.

BACKGROUND & AIMS: Persons chronically infected with the hepatitis C virus (HCV) may be at higher risk for developing and dying from non-liver cancers than the general population. METHODS: 12,126 chronic HCV-infected persons in the Chronic Hepatitis Cohort Study (CHeCS) contributed 39,984 person-years of follow-up from 2006 to 2010 and were compared to 133,795,010 records from 13 Surveillance, Epidemiology and End Results Program (SEER) cancer registries, and approximately 12 million U.S. death certificates from Multiple Cause of Death (MCOD) data. Measurements included standardized rate ratios (SRR) and relative risk (RR). RESULTS: The incidence of the following cancers was significantly higher among patients with chronic HCV infection: liver (SRR, 48.6 [95% CI, 44.4-52.7]), pancreas (2.5 [1.7-3.2]), rectum (2.1 [1.3-2.8]), kidney (1.7 [1.1-2.2]), non-Hodgkin lymphoma (NHL) (1.6 [1.2-2.1]), and lung (1.6 [1.3-1.9]). Age-adjusted mortality was significantly higher among patients with: liver (RR, 29.6 [95% CI, 29.1-30.1]), oral (5.2 [5.1-5.4]), rectum (2.6 [2.5-2.7]), NHL (2.3 [2.2-2.31]), and pancreatic (1.63 [1.6-1.7]) cancers. The mean ages of cancer diagnosis and cancer-related death were significantly younger among CHeCS HCV cohort patients compared to the general population for many cancers. CONCLUSIONS: Incidence and mortality of many types of non-liver cancers were higher, and age at diagnosis and death younger, in patients with chronic HCV infection compared to the general population.

Focus on transitions of care: description and evaluation of an educational intervention for internal medicine residents.

Transitions of care between physicians and from inpatient to outpatient settings leave patients vulnerable to medical errors and adverse events. A transitions of care workshop consisting of 2 sessions, Sign-Out Success (SOS) and Transition To Home (TTH), taught sign-out and discharge skills to incoming internal medicine interns during orientation. The workshop used role-playing exercises, didactics, demonstrations, and peer and self-evaluations. Interns completed a survey at 3 months post workshop. Using pre-post workshop measures, SOS increased the quality of intern-rated sign-outs (P = .004). Interns reported more confidence in their ability to effectively sign out (P = .016) and a greater understanding of problems that might arise while on call (P = .012). TTH increased intern-reported confidence in their ability to communicate discharge instructions (P < .001) and to verify patient understanding of instructions (P < .001). A majority reported using SOS and TTH skills 3 months post workshop. This workshop may be replicable at other institutions.

Investigation of residual hepatitis C virus in presumed recovered subjects.

UNLABELLED: Recent studies have found hepatitis C virus (HCV) RNA in peripheral blood mononuclear cells (PBMCs) of the majority of presumed recovered subjects. We investigated this unexpected finding using samples from patients whose HCV RNA and anti-HCV status had been serially confirmed. HCV RNA was detected in PBMCs from 66 of 67 chronic HCV carriers. Subpopulation analysis revealed that the viral load (log copies/10(6) cells) in B cells (4.14 ± 0.71) was higher than in total PBMCs (3.62 ± 0.71; P < 0.05), T cells (1.67 ± 0.88; P < 0.05), and non-B/T cells (2.48 ± 1.15; P < 0.05). HCV negative-strand RNA was not detected in PBMCs from any of 25 chronically infected patients. No residual viral RNA was detected in total PBMCs or plasma of 59 presumed recovered subjects (11 spontaneous and 48 treatment induced) using nested real-time polymerase chain reaction with a detection limit of 2 copies/µg RNA (from ≈ 1 × 10(6) cells). PBMCs from 2 healthy HCV-negative blood donors became HCV RNA positive, with B-cell predominance, when mixed in vitro with HCV RNA-positive plasma, thus passively mimicking cells from chronic HCV carriers. No residual HCV was detected in liver or other tissues from 2 spontaneously recovered chimpanzees. CONCLUSION: (1) HCV RNA was detected in PBMCs of most chronic HCV carriers and was predominant in the B-cell subpopulation; (2) HCV detected in PBMCs was in a nonreplicative form; (3) HCV passively adsorbed to PBMCs of healthy controls in vitro, becoming indistinguishable from PBMCs of chronic HCV carriers; and (4) residual HCV was not detected in plasma or PBMCs of any spontaneous or treatment-recovered subjects or in chimpanzee liver, suggesting that the classic pattern of recovery from HCV infection is generally equivalent to viral eradication.

A 25-year study of the clinical and histologic outcomes of hepatitis C virus infection and its modes of transmission in a cohort of initially asymptomatic blood donors.

BACKGROUND: A total of 738 volunteer blood donors who were positive for anti-hepatitis C virus (HCV) were assessed for risk factors and outcomes for up to 15 years within the study and up to 54 years from the estimated onset of infection. METHODS: A third-generation recombinant immunoblot assay (RIBA) was performed to distinguish true from false anti-HCV reactivity. Findings of HCV polymerase chain reaction classified subjects as having chronic HCV infection or as having recovered. Liver biopsy specimens were staged by Ishak fibrosis score and graded by histologic activity index. RESULTS: Of 738 anti-HCV-positive subjects, 469 (64%) had positive RIBA results, 217 (29%) had negative results, and 52 (7%) had indeterminate results. Primary independent risk factors were injection drug use (odds ratio [OR], 35.0; P < .0001), blood transfusion (OR, 9.9; P < .0001), and intranasal cocaine use, including 79 "snorters" who repeatedly denied injection drug use or blood transfusion (OR, 8.5; P < .0001). Classification and regression tree and random forest analyses confirmed these risk factors. A total of 384 RIBA-positive donors (82%) were HCV RNA positive; of these, liver biopsy specimens from 185 (48%) showed no fibrosis in 33%, mild fibrosis in 52%, bridging fibrosis in 12%, and cirrhosis in 2% a mean duration of 25 years after infection. Analysis of 63 repeat biopsy specimens showed that 8% progressed ≥2 Ishak stages over 5 years (mean progression, 0.06 Ishak stages/year). CONCLUSIONS: Injection drug use and blood transfusion before 1990 are dominant risk factors for HCV acquisition; intranasal cocaine use may be a surreptitious route of parenteral spread. After a mean of 25 years of HCV infection, histologic outcomes were relatively mild: 85% had no or mild fibrosis, and only 2% had cirrhosis. Nearly one-fifth spontaneously recovered.

The clinical relevance of persistent recombinant immunoblot assay-indeterminate reactions: insights into the natural history of hepatitis C virus infection and implications for donor counseling.

BACKGROUND: Recombinant immunoblot assay (RIBA) is used to determine the specificity of antibody to hepatitis C virus (anti-HCV). The RIBA result is recorded as positive, negative, or indeterminate. The interpretation and significance of RIBA-indeterminate reactions are unclear. We addressed the clinical relevance of these reactions in the context of the natural history of HCV infection in a prospectively followed cohort of anti-HCV-positive blood donors. STUDY DESIGN AND METHODS: Donor demographics, exposure history, and humoral and cell-mediated immunity (CMI) were compared in 15 RIBA-indeterminate subjects, nine chronic HCV carriers, and eight spontaneously recovered subjects. Serum samples were tested for anti-HCV by a quantitative, liquid luciferase immunoprecipitation system (LIPS). CMI was assessed by interferon-γ enzyme-linked immunosorbent spot assay. RESULTS: In the LIPS assay, the sum of antibody responses to six HCV antigens showed significant (p < 0.001) stepwise diminution progressing from chronic carriers to spontaneously recovered to RIBA-indeterminate subjects. CMI responses in RIBA-indeterminate subjects were similar to spontaneously recovered subjects and greater than chronic carriers and controls (p < 0.008). A parenteral risk factor was identified in only 13% of RIBA-indeterminate subjects compared to 89% of chronic carriers and 87% of spontaneously recovered subjects. RIBA-indeterminate donors were older than the other groups. CONCLUSION: The CMI and LIPS results suggest that persistent RIBA-indeterminate reactions represent waning anti-HCV responses in persons who have recovered from a remote HCV infection. In such cases, detectable antibody may ultimately disappear leaving no residual serologic evidence of prior HCV infection, as reported in a minority of long-term HCV-recovered subjects.

Association of interleukin-15-induced peripheral immune activation with hepatic stellate cell activation in persons coinfected with hepatitis C virus and HIV.

Hepatic stellate cells (HSCs) mediate hepatitis C virus (HCV)-related liver fibrosis, and increased HSC activation in human immunodeficiency virus (HIV)/HCV coinfection may be associated with accelerated fibrosis. We examined the level of HSC activation in HIV/HCV-coinfected and HCV-monoinfected subjects and its relationship to the level of activation and gene expression of peripheral immune cells in coinfected subjects. HSC activation levels positively correlated with peripheral CD4+ and CD8+ T cell immune activation and were associated with enhanced interleukin-15 (IL-15) gene expression, suggesting a pathogenic role for IL-15-driven immunomediated hepatic fibrosis. Future strategies that reduce immune activation and HSC activation may delay progression of liver fibrosis.