Hepatitis E in Italy: a long-term prospective study.

BACKGROUND & AIMS: In developed countries, hepatitis E is usually associated with travelling to endemic areas, but a growing number of sporadic cases are also seen in patients with no travel history. The aim of this study was to assess the impact and the molecular epidemiology of hepatitis E in Italy. METHODS: Between January 1994 and October 2009, we analyzed 651 patients with acute non-A-C hepatitis. Diagnosis of hepatitis E was based on the presence of IgM anti-HEV and/or the detection of HEV RNA by RT-PCR. Viral isolates were sequenced and phylogenetically characterized. RESULTS: A total of 134 out of 651 (20.6%) patients tested had acute hepatitis E. All were anti-HEV IgM and IgG positive and 96 (71.6%) were also positive for HEV RNA. Moreover, 39 (6%) patients were anti-HEV IgG positive but negative for both IgM anti-HEV and HEV RNA. A total of 109 (81.3%) patients developed hepatitis E travelling to endemic areas, 3 (2.3%) acquired intra-familial infection from relatives who developed travel-related disease, while 22 (16.4%) patients denied having travelled abroad. In all patients, acute disease had a self-limited course with ALT normalization within 3-6 weeks. Phylogenetic analysis of 39 isolates from patients with a travel-related disease showed that they belonged to genotype 1, while sequences from five patients with autochthonous hepatitis E belonged to genotype 3. CONCLUSIONS: In Italy, most cases of hepatitis E are travel related, caused by viral genotype 1, while autochthonous cases are caused by genotype 3. The prevalence of genotype 3 among pigs and boars suggests that HEV infection may have zoonotic origins in non-endemic countries.

Hepatitis A epidemic in men who have sex with men (MSM) in Milan, Italy.

BACKGROUND AND AIM OF THE WORK: Hepatitis A is an infectious disease characterized by fecal-oral transmission; however, a rise in sexually-transmitted cases has been observed, particularly among "men who have sex with men". In Europe, a Hepatitis A epidemic occurred among men who have sex with men between 2016 and 2018. The aim of this study is to describe this Hepatitis A epidemic in the city of Milan and to analyze the incidence of Sexually Transmitted Diseases co-infection among Hepatitis A cases. METHODS: Hepatitis A cases were traced and identified. Epidemiological data were collected and Hepatitis A vaccination was investigated. Cases were georeferenced, calculating incidence rates for each Milan Municipality. Viral genotypic analysis was carried out. RESULTS: 353 cases were reported in Milan. Incidence rates resulted significantly higher in males (RR 18.1 CI9 5% 11.5 - 28.4). 70 cases reported foreign travel. 172 cases reported "Men  who have Sex with Men" behaviour. Genotypic analysis revealed correlation with strains of the European "Men who have Sex with Men" epidemic. Georeferencing showed asymmetric case distribution. Only 12 cases reported Hepatitis A vaccination. The Relative Risk for syphilis infection among Hepatitis A cases was 133.9 (95% CI 81.7 - 219.7) and 29.7 (95%CI 9.5 - 92.7) for gonorrhea. CONCLUSIONS: Most genotyped cases (93.7%) correlated to the European Hepatitis A epidemic among Men who have Sex with Men. Georeferencing showed a greater incidence of Hepatitis A cases in areas characterized by the homosexual community. The higher incidence of Sexually Transmitted Diseases co-infection in Hepatitis A cases correlated to clusters responsible for the European Hepatitis A epidemic, suggests increased sexual promiscuity among Men who have Sex with Men. These data support the need for Hepatitis A vaccination programs and sensitization of Men who have Sex with Men to the adoption of safe sexual practices.

Molecular Characterization and Phylogenetic Analysis of Enteroviruses and Hepatitis A Viruses in Sewage Samples, Northern Italy, 2016.

Enteroviruses (EVs) and Hepatitis A Viruses (HAVs) are human pathogens with a wide spectrum of clinical manifestations. The monitoring of sewage samples enables to monitor the EVs and HAVs in circulation among the general population and recognize possible outbreaks. This study focused on the molecular characterization and phylogenetic analysis of the EVs and HAVs identified in 33 sewage samples collected every 15 days at the influent of a wastewater treatment plant located in Northern Italy from March to October 2016. According to the results of the molecular characterization, the most frequently identified viruses were Echovirus 6 (E-6), E-11 and HAV-IA. The phylogenetic analyses indicated the rapid genetic evolution of E-6 and E-1; noteworthy, most E-11 strains clustered with a strain isolated from a clinical sample collected in the same geographical area over the same period by our laboratory. Most of the HAV strains detected clustered with epidemic HAV-IA strains identified during the European hepatitis A outbreak that occurred in 2016-2017 affecting men who have sex with men (MSM). The detection of environmental HAV strains before and at the beginning of its spread amongst humans demonstrated that this outbreak could have been predicted by monitoring sewage samples. Moreover, conducting a genetic comparison between the HAV and EV strains identified in sewage and clinical samples may improve knowledge of viral epidemiology. EV and HAV molecular environmental surveillance may prove useful for identifying viral circulation and for issuing early warning alerts on possible outbreaks among the human population.

Persistence of immunity 18-19 years after vaccination against hepatitis B in 2 cohorts of vaccinees primed as infants or as adolescents in Italy.

This study was aimed at assessing the anti-HBs persistence and immune memory 18-19 y after vaccination against hepatitis B in healthy individuals primed as infants or adolescents. We enrolled 405 teenagers (Group A) vaccinated as infants, and 409 young adults (Group B) vaccinated as adolescents. All vaccinees were tested for anti-HBs and anti-HBc antibodies; those found anti-HBc positive were further tested for HBsAg and HBV DNA. Eight individuals belonging to Group B were positive for anti-HBc alone, and were excluded from analysis. Individuals with anti-HBs concentration ≥ 10 mIU/ml were considered protected while those with anti-HBs concentration <10 mIU/ml were offered a booster dose and re-tested 2 weeks later. Overall, 67.9% individuals showed anti-HBs concentrations ≥ 10 mIU/ml (48.9% in Group A vs 87.0% in Group B, p < 0.001). The antibody geometric mean concentration (GMC) was higher in Group B than in Group A (102.5 mIU/ml vs 6.9 mIU/ml; p < 0.001). When boosted, 94.2% of vaccinees with anti-HBs <10 mIU/ml belonging to Group A and 94.7% to Group B showed an anamnestic response. Post-booster GMCs were similar in both groups (477.9 mIU/ml for Group A vs 710.0 mIU/ml for Group B, p = n.s.). Strong immunological memory persists for at least 18-19 y after immunization of infants or adolescents with a primary course of vaccination. Thus, booster doses are not needed at this time, but additional follow up is required to assess the long-life longevity of protection.

Phylogeography and phylodynamics of European genotype 3 hepatitis E virus.

Hepatitis E virus is classified into four genotypes that have different geographical and host distributions. The main cause of sporadic autochthonous type E acute hepatitis in developed countries is genotype 3, which has a worldwide distribution and widely infects pigs. The aim of this study was to make hypotheses concerning the origin and global dispersion routes of this genotype by reconstructing the spatial and temporal dynamics of 208 HEV genotype 3 ORF-2 sequences (retrieved from public databases) isolated in different geographical areas. The evolutionary rates, time of the most recent common ancestors (tMRCAs), epidemic growth and phylogeography of HEV-3 were co-estimated using a MCMC Bayesian method. The maximum clade credibility tree showed the existence of two distinct main clades: clade A, which consists of only European subtypes (HEV-3e and 3f), and clade B, which consists of European subtype 3c and all of the Asian subtypes (3a, 3b and 3d) sharing a common ancestor, which most probably existed in Asia in 1920s. All of the North American isolates belonged to Asian subtype 3a. On the basis of our time-scaled phylogeographical reconstruction, we hypothesise that after originating in the early 1800s in Europe, HEV reached Asia in the first decades of 1900, and then moved to America probably in the 1970s-1980s. Analysis of the skyline plot showed a sharp increase of the number of infections between the 1980s and 2005, thus suggesting the intervention of new and highly efficient routes of transmission possibly related to changes in the pig industry.

The changing face of the epidemiology of type A, B, and D viral hepatitis in Italy, following the implementation of vaccination.

The morbidity and mortality rates of viral hepatitis A, B and Delta have dramatically dropped in Italy during the last decades. Thanks to the general improvements in hygiene and sanitation, hepatitis A has shifted from a high to an intermediate/low endemicity status. Vaccination against hepatitis A is recommended to people at increased risk, including travellers to endemic areas, military personnel and individuals at occupational risk. The implementation of universal anti-hepatitis B vaccination of infants and adolescents has resulted in a dramatic decline in disease burden and in the carrier rate. An additional benefit of hepatitis B vaccination is that hepatitis Delta has also substantially declined.