A Useful Method to Provide Infectious and Cultivable In Vitro Naked Viral Particles of Hepatitis A Virus.

Hepatitis A virus (HAV) is an enteric virus mainly transmitted by the faecal-oral route. Belonging to the Picornaviridae family, HAV was first described as small naked particles, like all viruses of this family. However, for about a decade, it was demonstrated that HAV particles can exist surrounded by a lipid bilayer. This type of particle, called enveloped HAV (eHAV), acquires its lipid bilayer by hijacking a part of cell membranes during the virion egress in the last steps of the viral cycle. In vitro culture systems produce mainly eHAV, and so, to date, most of the studies on HAV have been carried out using this type of viral particle. In this study, a method based on lipid bilayer removal by chemical delipidation is proposed for the production of naked HAV particles. The resulting naked HAV particles conserve their infectivity and are therefore fully cultivable in vitro. By using this method, naked HAV particles can easily be produced in vitro and can be useful to perform further studies such as inactivation processes for the food industry, as HAV is a main concern for food safety.

Use of passive samplers as sewage surveillance tool to monitor a hepatitis A outbreak at a school in Amsterdam, the Netherlands, Oct 2022 - March 2023.

BACKGROUND: Enteric hepatitis A virus (HAV) infections during childhood are often asymptomatic but may cause severe illness in adults. To improve public health surveillance we assessed the applicability of sewage monitoring during an HAV outbreak at a primary school. METHODS: Between October 19 and December 27, 2022, five symptomatic HAV cases were notified to the Public Health Service Amsterdam; all attended the same primary school. Passive samplers, small absorbent tools, were deployed in sewage near the school from November 14, 2022, to March 22, 2023. The absorbents were subjected to RNA extraction, HAV PCR testing, and, if positive, sequencing. PCR and sequencing were also performed on plasma and feces samples of HAV cases. RESULTS: In 22 out of 88 (25%) of sewage samples, HAV RNA was detected. All HAV-RNA-positive sewage samples until 8 February 2023 were subgenotype IB, matching the strain detected in all cases. Another strain of HAV (subgenotype IA) was detected in sewage from 15 February 2023 onwards, without associated cases. CONCLUSIONS: Passive sampler-based sewage monitoring is an effective method to rapidly detect HAV shedding linked to diagnosed cases. It detects unnoticed viral infections and allows monitoring of outbreaks. This suggests that passive sampler-based monitoring is a promising tool supporting the public health response during HAV and other outbreaks.

Molecular characterisation of hepatitis A in the Western Cape province, South Africa in 2023.

In 2023, passive laboratory-based surveillance showed an increase in hepatitis A virus (HAV) infection. We investigated hepatitis A incidence using the notifiable medical condition surveillance system (NMCSS) data and molecularly characterised positive blood samples from the Western Cape province for 2023. All HAV IgM seropositive cases from the NMCSS from 1 January to 31 October 2023 in South Africa were investigated. HAV RNA from blood samples that had tested positive for HAV IgM from Western Cape was amplified in the VP1/P2B junction and sequenced (3500Xl Genetic Analyser). Sequences were assembled, aligned (Sequencher) and analysed (Aliview 1.27 and MEGA11). Statistical analysis was performed using Excel and the CuSum2 Threshold to determine suspected outbreaks. In 2023, the incidence of HAV IgM was 6.28/100,000 in South Africa, with the highest incidence in Western Cape province (15.86/100,000). Children aged 5 to 14 years were affected the most in the Western Cape. The positive cases in the Western Cape were above the CuSum2 threshold from January to May 2023, with the highest incidence observed in the City of Cape Town Metropolitan (14.8/100,000). Genotyping was successfully performed on 92.7% (139/150) of serum samples, for which the IB sub-genotype was detected. Three primary mutations R63K, R71S and M104I were observed in more than 49% of the samples. Most of the samples sequenced belonged to patients residing in areas close to each other within the City of Cape Town Southern, Western, and Mitchells Plain sub-districts. The CuSum2 threshold method allowed the identification of suspected HAV outbreaks in the districts within the Western Cape in 2023 while genotyping identified clusters of sub-genotype IB. Genotyping could assist with determining the common source of infection during an outbreak, especially if coupled with epidemiological and geographical data. Further active surveillance can assist in investigating the HAV risk factors for targeted public health responses.

Analysis of Inflammatory and Thyroid Hormone Levels Based on Hepatitis A and B Virus Immunity Status: Age and Sex Stratification.

This study investigated the potential associations between hepatitis virus antibody status and thyroid and inflammatory function. The C-reactive protein (CRP), thyroid-stimulating hormone (TSH), and free thyroxine (FT4) levels were measured in individuals with and without antibodies to the hepatitis A virus (HAV) and hepatitis B virus (HBV). Participants were stratified by age, sex, and HAV/HBV antibody status. Participants with and without antibodies to HAV and HBV had normal CRP, TSH, and FT4 levels. However, notable discrepancies were observed in FT4 levels among participants with HAV antibodies and in CRP and FT4 levels among those with both HAV and HBV antibodies, suggesting potential associations between viral immunity and thyroid function, especially in younger participants. Significant variations in thyroid hormone levels were noted when the sample was stratified by sex and HAV and HBV antibody status, indicating that the association between antibody status and thyroid hormone levels varied by sex. This study underscores the need for further research on the effect of viral immunity on inflammatory parameters and thyroid hormone levels.

Hepatitis A in Latin America: The current scenario.

This review aims to gather and disseminate updated information regarding hepatitis A virus (HAV) in Latin America (LA) in the last 11 years, including seroprevalence, post-vaccination studies, virus detection in aqueous matrices and food samples, and outbreak reports. Only 24 seroprevalence studies were published between 2012 and 2023 with 55%-100% reported prevalences of anti-HAV IgG. Among the 25 LA countries, only eight of them have introduced HAV vaccines into their immunisation programs. Outbreaks of hepatitis A occurred between 2017-2019, mainly affecting men who have sex with men in Argentina, Brazil and Chile, probably as a consequence of the abrupt decline of young adults' immunity. This could be due to that young adult have never been infected in childhood (due to socio-health improvements) and are above the cut-off ages to be included when the vaccination programs were introduced. Although scarce, studies focused on environmental and food HAV surveillance have shown viral presence in these samples. Surface waters presented HAV detections between 1.2% and 86.7%, and untreated wastewaters between 2.8% and 70.9%. Genotypes found in all cases were IA and IC. The only wastewater-based epidemiology study showed to be a useful tool as a complement of traditional epidemiological surveillance. Only four LA countries have looked for HAV in food samples, with genome detection rates between 9% and 33%. Latin American HAV circulation scenario is changing. In countries where socioeconomic and sanitary conditions have not improved, the virus persists with high endemicity and the access to the vaccine should be re-evaluated by local governments. In countries where access to clean water, better sanitary conditions and HAV immunisation programs have been implemented, the number of cases among young adults seems to be increasing, alerting health authorities.

Hepatitis A virus subtype IB outbreak among MSM in Hungary with a link to a frozen berry source.

Men who have sex with men (MSM) are at high risk of acquiring hepatitis A virus (HAV) and in recent years several HAV outbreaks mostly affecting MSM have been described. These outbreaks were caused by subtype IA strains circulating in this high-risk population. After years of low incidence, an outbreak among MSM in Hungary caused a significant increase in reported HAV infections in 2022. Samples from 224 HAV IgM-positive patients diagnosed in 2022 were tested for HAV RNA and positive samples were genotyped by sequencing. In 171 patients a unique subtype IB virus was detected with 99.8-100% sequence identity in the VP1/P2A junction. It was distinct from previously published strains, but most closely related to an Egyptian isolate. Sequence analysis revealed one dominant and three minor variants based on VP1/P2A. Whole genome sequencing revealed limited variation among these variants, suggesting a recent common origin. Epidemiological data indicated that sexual transmission was driving the outbreak for most of the year, suggested by the high male to female ratio and the large number of coinfections with HIV and other sexually transmitted infections among the patients. The outbreak was also associated with a restaurant cluster, in which one of the variants was detected and frozen berries were implicated as the source of infections. The outbreak strain was also detected in other countries around Europe and remained frequently detectable in Hungary in 2023. This study provides insights into the molecular and epidemiological characteristics of the described HAV outbreak. The results show that sequencing is not only useful in connecting cases to an outbreak, but also helps to clarify the relatedness of detected variants. Prevention strategies focusing on vulnerable communities may reduce the burden of HAV infections in the future.

Biochemical analysis of the host factor activity of ZCCHC14 in hepatitis A virus replication.

Relatively little is known of the mechanisms underlying hepatitis A virus (HAV) genome replication. Unlike other well-studied picornaviruses, HAV RNA replication requires the zinc finger protein ZCCHC14 and non-canonical TENT4 poly(A) polymerases with which it forms a complex. The ZCCHC14-TENT4 complex binds to a stem-loop located within the internal ribosome entry site (IRES) in the 5' untranslated RNA (5'UTR) and is essential for viral RNA synthesis, but the underlying mechanism is unknown. Here, we describe how different ZCCHC14 domains contribute to its RNA-binding, TENT4-binding, and HAV host factor activities. We show that the RNA-binding activity of ZCCHC14 requires both a sterile alpha motif (SAM) and a downstream unstructured domain (D4) and that ZCCHC14 contains two TENT4-binding sites: one at the N-terminus and the other around D4. Both RNA-binding and TENT4-binding are required for HAV host factor activity of ZCCHC14. We also demonstrate that the location of the ZCCHC14-binding site within the 5'UTR is critical for its function. Our study provides a novel insight into the function of ZCCHC14 and helps elucidate the mechanism of the ZCCHC14-TENT4 complex in HAV replication.IMPORTANCEThe zinc finger protein ZCCHC14 is an essential host factor for both hepatitis A virus (HAV) and hepatitis B virus (HBV). It recruits the non-canonical TENT4 poly(A) polymerases to viral RNAs and most likely also a subset of cellular mRNAs. Little is known about the details of these interactions. We show here the functional domains of ZCCHC14 that are involved in binding to HAV RNA and interactions with TENT4 and describe previously unrecognized peptide sequences that are critical for the HAV host factor activity of ZCCHC14. Our study advances the understanding of the ZCCHC14-TENT4 complex and how it functions in regulating viral and cellular RNAs.

Circulation of a single hepatitis A virus genotype IIIA with two distinct clusters in different states of India.

With the changing hepatitis A epidemiology in India, focal viral outbreaks are being reported from different parts of the country. This study presents Hepatitis A Virus (HAV) strain characterization (period 2009-2020) from 18 states of India. For that, blood and stool samples (n â€‹= â€‹280) were screened for HAV RNA and sequences for 5'non-coding and VP3 regions were generated from positive samples (n â€‹= â€‹68). Presence of a single IIIA genotype in all samples indicated IIIA being the only HAV genotype currently circulating in India. Interestingly, it was evident that these strains form two distinct groups suggesting independent evolution of these two clusters.

The ZCCHC14/TENT4 complex is required for hepatitis A virus RNA synthesis.

Despite excellent vaccines, resurgent outbreaks of hepatitis A have caused thousands of hospitalizations and hundreds of deaths within the United States in recent years. There is no effective antiviral therapy for hepatitis A, and many aspects of the hepatitis A virus (HAV) replication cycle remain to be elucidated. Replication requires the zinc finger protein ZCCHC14 and noncanonical TENT4 poly(A) polymerases with which it associates, but the underlying mechanism is unknown. Here, we show that ZCCHC14 and TENT4A/B are required for viral RNA synthesis following translation of the viral genome in infected cells. Cross-linking immunoprecipitation sequencing (CLIP-seq) experiments revealed that ZCCHC14 binds a small stem-loop in the HAV 5' untranslated RNA possessing a Smaug recognition-like pentaloop to which it recruits TENT4. TENT4 polymerases lengthen and stabilize the 3' poly(A) tails of some cellular and viral mRNAs, but the chemical inhibition of TENT4A/B with the dihydroquinolizinone RG7834 had no impact on the length of the HAV 3' poly(A) tail, stability of HAV RNA, or cap-independent translation of the viral genome. By contrast, RG7834 inhibited the incorporation of 5-ethynyl uridine into nascent HAV RNA, indicating that TENT4A/B function in viral RNA synthesis. Consistent with potent in vitro antiviral activity against HAV (IC50 6.11 nM), orally administered RG7834 completely blocked HAV infection in Ifnar1-/- mice, and sharply reduced serum alanine aminotransferase activities, hepatocyte apoptosis, and intrahepatic inflammatory cell infiltrates in mice with acute hepatitis A. These results reveal requirements for ZCCHC14-TENT4A/B in hepatovirus RNA synthesis, and suggest that TENT4A/B inhibitors may be useful for preventing or treating hepatitis A in humans.

Hepatitis vaccination adherence and completion rates and factors associated with low compliance: A claims-based analysis of U.S. adults.

Poor compliance with multi-dose vaccine schedules by adults for whom hepatitis (Hep) A and B vaccines are recommended contributes to major Hep A and B disease burdens among high-risk U.S. adults. Evidence on hepatitis vaccine series adherence, completion, timeliness of completion, and factors associated with these outcomes, is limited and not readily generalizable for U.S. adults. This retrospective, observational study examined adherence, completion, its timeliness, and the impact of sociodemographic and clinical factors on these outcomes among a large, geographically representative sample of U.S. adults. We analyzed the Optum Clinformatics SES administrative claims database (1/1/2010-6/30/2020) for recipients of 2-dose (HepA, HepB2) or 3-dose (HepB3, HepAB) hepatitis vaccines. Adherence was defined as receipt of booster doses within specified assessment periods, per label-recommended schedules. Completion (receipt of all doses) was assessed at 6, 12, 18, and 24 months.The study included 356,828 adults ≥19 years old who were continuously enrolled in a medical benefit plan for one (HepB2), six (HepB3; HepAB), or 18 months (HepA) prior to and following the index date (first observed vaccine dose). Adherence and 24-month completion rates were: HepA (27.0%, 28.4%), HepB2 (32.2%, 44.8%), HepB3 (14.3%, 37.3%), HepAB, (15.3%, 33.8%). Kaplan-Meier completion curves plateaued after about 6 months for HepB2 and about 12 months for HepA, HepB3, and HepAB vaccines. Logistic regression analyses showed risk for low adherence/completion was generally associated with male gender, younger age, Black or Hispanic race/ethnicity, lower educational or household income attainment, and more comorbidities. Adherence and completion rates for all hepatitis vaccine series are low, especially for males, younger adults, those with lower socio-economic status and more comorbidities. To our knowledge, this is the largest claims-based analysis of adherence and completion rates for U.S. adults initiating all currently available HepA and HepB vaccines. Findings may inform hepatitis vaccination programming.

Increase in Hepatitis A Cases Linked to Imported Strains to Rio de Janeiro, Brazil: A Cross-Sectional Study.

This study aims to evaluate the epidemiological and molecular features associated with HAV transmission in adults in Rio de Janeiro during a period of increased registered cases of HAV (2017-2018). Socio-epidemiological data and serum samples from anti-HAV IgM+ individuals were obtained. HAV RNA was RT-PCR amplified and sequenced for further phylogenetic and phylogeographic analyses. From fifty-two HAV IgM+ individuals, most were men (78.85%; p = 0.024), aged 20-30 years old (84.61%; p < 0.001), resided in the Rio de Janeiro north zone (31/52; 59.62%; p = 0.001), and are men who have sex with men (MSM) (57.69%; p = 0.002). Sexual practices were more frequent (96%) than others risk factors (food-borne (44%), water-borne (42.31%), and parenteral (34.62%)). Individuals who traveled to endemic regions had a 7.19-fold (1.93-36.04; p < 0.01) increased risk of HAV. Phylogenetic analysis revealed four distinct clades of subgenotype IA, three of them comprised sequences from European/Asian MSM outbreaks and one from Brazilian endemic strains. Bayesian Inference showed that the imported strains were introduced to Brazil during large mass sportive events. Sexual orientation and sexual practices may play a role in acquiring HAV infection. Public policies targeting key populations must be implemented to prevent further dissemination of HAV and other STIs.

Development and Evaluation of a Molecular Hepatitis A Virus Assay for Serum and Stool Specimens.

Hepatitis A virus (HAV) is an emerging public health concern and there is an urgent need for ways to rapidly identify cases so that outbreaks can be managed effectively. Conventional testing for HAV relies on anti-HAV IgM seropositivity. However, studies estimate that 10-30% of patients may not be diagnosed by serology. Molecular assays that can directly detect viral nucleic acids have the potential to improve diagnosis, which is key to prevent the spread of infections. In this study, we developed a real-time PCR (RT-PCR) assay to detect HAV RNA for the identification of acute HAV infection. Primers were designed to target the conserved 5'-untranslated region (5'-UTR) of HAV, and the assay was optimized on both the Qiagen Rotor-Gene and the BD MAX. We successfully detected HAV from patient serum and stool samples with moderate differences in sensitivity and specificity depending on the platform used. Our results highlight the clinical utility of using a molecular assay to detect HAV from various specimen types that can be implemented in hospitals to assist with diagnostics, treatment and prevention.

Prolonged Gut Dysbiosis and Fecal Excretion of Hepatitis A Virus in Patients Infected with Human Immunodeficiency Virus.

Hepatitis A virus (HAV) causes transient acute infection, and little is known of viral shedding via the duodenum and into the intestinal environment, including the gut microbiome, from the period of infection until after the recovery of symptoms. Therefore, in this study, we aimed to comprehensively observe the amount of virus excreted into the intestinal tract, the changes in the intestinal microbiome, and the level of inflammation during the healing process. We used blood and stool specimens from patients with human immunodeficiency virus who were infected with HAV during the HAV outbreak in Japan in 2018. Moreover, we observed changes in fecal HAV RNA and quantified the plasma cytokine level and gut microbiome by 16S rRNA analysis from clinical onset to at least 6 months after healing. HAV was detected from clinical onset up to a period of more than 150 days. Immediately after infection, many pro-inflammatory cytokines were elicited, and some cytokines showed different behaviors. The intestinal microbiome changed significantly after infection (dysbiosis), and the dysbiosis continued for a long time after healing. These observations suggest that the immunocompromised state is associated with prolonged viral shedding into the intestinal tract and delayed recovery of the intestinal environment.

Synthesis, delivery, and molecular docking of fused quinolines as inhibitor of Hepatitis A virus 3C proteinase.

It is widely accepted that Hepatitis A virus (HAV) is responsible for liver failure and even death in older people and in people with other serious health issues; so, proposing new compounds with inhibitory activity can help to treated of these disease's. In current study, a new class of quinolines is proposed with inhibitor activity of the HAV proteinase. So, in the first step, fused quinoline derivatives has been synthesized in short reaction time (12.0 min) and high efficiency yields (94%) in presence of 1-carboxymethyl-2,3-dimethylimidazolium iodide ([cmdmim]I) ionic liquid catalyst using a new method. In the following, chemical reactivity and inhibitory activity of synthesized quinolines were evaluated in density functional theory (DFT) framework and molecular docking methodologies. High global softness (0.67 eV), low HOMOSWBNNT-LUMO4a gap (4.78 eV), and more negative adsorption energy (- 87.9 kJ mol-1) in these quinolines reveal that the 4a and 4b compounds have better delivery than other quinolines using SWBNNT as suitable carrier to target cells. Molecular docking shows that the best cavity of the HAV has - 134.2 kJ mol-1 interaction energy involving bonding and non-bonding interactions. In fact, these interactions are between fused quinolines with especial geometries and sidechain flexibility amino acids residues inside the best binding site of the HAV, as hydrogen bonding, steric, and electrostatic interactions. So, these interactions imply that proposed fused quinolines have good inhibitor activity for the HAV.

Evidence of Circulation of Several HAV Genetic Variants and Emergence of Potential Antigenic Variants in an Endemo-Epidemic Country before Vaccine Introduction.

Similar to several other countries in the world, the epidemiology of hepatitis A virus changed from high to intermediate endemicity level in Tunisia, which led to the occurrence of outbreaks. This study aimed to determine the genetic and antigenic variability of HAV strains circulating in Tunisia during the last few years. Genotyping using complete VP1 gene and VP1-2A junction confirmed the predominance of genotype IA, with co-circulation of several genetic and antigenic variants. Phylogenetic analysis including Tunisian and strains from other regions of the world showed the presence of at least two IA-variants within IA subgenotype. Amino-acid analysis showed several mutations in or close to epitope regions in the VP1-region. This study provides a baseline on the genetic and antigenic variability of HAV circulating strains before the introduction of vaccination into the national immunization schedule.

Knockdown of Mitogen-Activated Protein Kinase Kinase 3 Negatively Regulates Hepatitis A Virus Replication.

Zinc chloride is known to be effective in combatting hepatitis A virus (HAV) infection, and zinc ions seem to be especially involved in Toll-like receptor (TLR) signaling pathways. In the present study, we examined this involvement in human hepatoma cell lines using a human TLR signaling target RT-PCR array. We also observed that zinc chloride inhibited mitogen-activated protein kinase kinase 3 (MAP2K3) expression, which could downregulate HAV replication in human hepatocytes. It is possible that zinc chloride may inhibit HAV replication in association with its inhibition of MAP2K3. In that regard, this study set out to determine whether MAP2K3 could be considered a modulating factor in the development of the HAV pathogen-associated molecular pattern (PAMP) and its triggering of interferon-ß production. Because MAP2K3 seems to play a role in antiviral immunity against HAV infection, it is a promising target for drug development. The inhibition of MAP2K3 may also prevent HAV patients from developing a severe hepatitis A infection.

An outbreak of acute jaundice syndrome (AJS) among the Rohingya refugees in Cox's Bazar, Bangladesh: Findings from enhanced epidemiological surveillance.

In the summer of 2017, an estimated 745,000 Rohingya fled to Bangladesh in what has been described as one of the largest and fastest growing refugee crises in the world. Among numerous health concerns, an outbreak of acute jaundice syndrome (AJS) was detected by the disease surveillance system in early 2018 among the refugee population. This paper describes the investigation into the increase in AJS cases, the process and results of the investigation, which were strongly suggestive of a large outbreak due to hepatitis A virus (HAV). An enhanced serological investigation was conducted between 28 February to 26 March 2018 to determine the etiologies and risk factors associated with the outbreak. A total of 275 samples were collected from 18 health facilities reporting AJS cases. Blood samples were collected from all patients fulfilling the study specific case definition and inclusion criteria, and tested for antibody responses using enzyme-linked immunosorbent assay (ELISA). Out of the 275 samples, 206 were positive for one of the agents tested. The laboratory results confirmed multiple etiologies including 154 (56%) samples tested positive for hepatitis A, 1 (0.4%) positive for hepatitis E, 36 (13%) positive for hepatitis B, 25 (9%) positive for hepatitis C, and 14 (5%) positive for leptospirosis. Among all specimens tested 24 (9%) showed evidence of co-infections with multiple etiologies. Hepatitis A and E are commonly found in refugee camps and have similar clinical presentations. In the absence of robust testing capacity when the epidemic was identified through syndromic reporting, a particular concern was that of a hepatitis E outbreak, for which immunity tends to be limited, and which may be particularly severe among pregnant women. This report highlights the challenges of identifying causative agents in such settings and the resources required to do so. Results from the month-long enhanced investigation did not point out widespread hepatitis E virus (HEV) transmission, but instead strongly suggested a large-scale hepatitis A outbreak of milder consequences, and highlighted a number of other concomitant causes of AJS (acute hepatitis B, hepatitis C, Leptospirosis), albeit most likely at sporadic level. Results strengthen the need for further water and sanitation interventions and are a stark reminder of the risk of other epidemics transmitted through similar routes in such settings, particularly dysentery and cholera. It also highlights the need to ensure clinical management capacity for potentially chronic conditions in this vulnerable population.

Hepatitis A virus strains identified in jogaejeot associated with outbreaks in Seoul, South Korea.

Jogaejeot, seasoned Venerupis philippinarum, is a traditional Korean fermented food, and hepatitis A virus (HAV) can be transmitted through contaminated food, especially bivalve shellfish, causing acute gastroenteritis worldwide. Here, we carried out a phylogenetic analysis to identify and characterize HAV strains in jogaejeot samples associated with hepatitis A (HA) outbreaks in Seoul, South Korea, in 2019. The HAV strains were identified using blast and molecular analysis of the amplified HAV VP1-P2B genome region. The HAV strains identified in the five jogaejeot samples shared at least 99% sequence identity, were all classified as genotype IA and were most closely related to strains that are widespread in East Asia. These results support a link between the consumption of jogaejeot and the HA outbreaks observed in 2019 in Seoul. In addition, they indicate a need for more stringent enforcement of food safety regulations for the shellfish industry, especially against HAV, and the value of widespread vaccination.

Virus-specific memory T cell responses unmasked by immune checkpoint blockade cause hepatitis.

Treatment of advanced melanoma with combined PD-1/CTLA-4 blockade commonly causes serious immune-mediated complications. Here, we identify a subset of patients predisposed to immune checkpoint blockade-related hepatitis who are distinguished by chronic expansion of effector memory CD4+ T cells (TEM cells). Pre-therapy CD4+ TEM cell expansion occurs primarily during autumn or winter in patients with metastatic disease and high cytomegalovirus (CMV)-specific serum antibody titres. These clinical features implicate metastasis-dependent, compartmentalised CMV reactivation as the cause of CD4+ TEM expansion. Pre-therapy CD4+ TEM expansion predicts hepatitis in CMV-seropositive patients, opening possibilities for avoidance or prevention. 3 of 4 patients with pre-treatment CD4+ TEM expansion who received αPD-1 monotherapy instead of αPD-1/αCTLA-4 therapy remained hepatitis-free. 4 of 4 patients with baseline CD4+ TEM expansion given prophylactic valganciclovir and αPD-1/αCTLA-4 therapy remained hepatitis-free. Our findings exemplify how pathogen exposure can shape clinical reactions after cancer therapy and how this insight leads to therapeutic innovations.

Male-Dominant Hepatitis A Outbreak Observed among Non-HIV-Infected Persons in the Northern Part of Tokyo, Japan.

Recently, we experienced an outbreak of acute hepatitis A virus (HAV) infection between 2018 and 2020. Herein, we describe this male-dominant HAV infection outbreak observed among non-human immunodeficiency virus (HIV)-infected persons in the northern part of Tokyo, Japan. Clinical information was collected from patient interviews and from medical record descriptions. In the present study, 21 patients were retrospectively analyzed. A total of 90.4 and 33.3% of patients were males, and men who have sex with men (MSM), respectively. The total bilirubin levels and platelet counts tended to be lower in the MSM group than in the non-MSM group. C-reactive protein (CRP) levels tended to be higher in acute liver failure (ALF) patients than in non-ALF patients. Prolonged cholestasis was observed in one patient (4.8%). We also found that 18 HAV isolates belonged to HAV subgenotype IA/subgroup 13 (S13), which clustered with the HAV isolate (KX151459) that was derived from an outbreak of HAV infection among MSM in Taiwan in 2015. Our results suggest that the application of antivirals against HAV, as well as HAV vaccines, would be useful for the treatment and prevention of severe HAV infection.