Hepatitis A occurrence and outbreaks in Europe over the past two decades: A systematic review

Hepatitis A (HA) is a vaccine‐preventable liver disease with >170 million new cases occurring yearly. In recent outbreaks in the USA, hospitalization and case‐fatality ratios were >60% and ~1%, respectively. In Europe, endemicity persists and outbreaks continue to occur. We performed a systematic literature review to understand the changes in HA occurrence in Europe over the past two decades. PubMed and Embase were systematically searched for peer‐reviewed articles published between 1 January 2001 and 14 April 2021 using terms covering HA, 11 selected European countries, outbreaks, outcomes and HA virus circulation. Here, we focus on HA occurrence and outbreaks in the five countries with the largest population and the most comprehensive vaccination recommendations: France, Germany, Italy, Spain and the UK; 118 reports included data for these five European countries. Notification rates (≤9.7/100,000 population) and percentages of men among cases (≤83.0%) peaked in 2017. The number of person‐to‐person‐transmitted cases and outbreaks decreased in children but increased in other risk groups, such as men who have sex with men (MSM). Sexually transmitted outbreaks in MSM clustered around 2017. Travel‐related outbreaks were few; the proportion of travel‐related cases decreased during the past two decades, while the number of domestic cases increased. Despite the existing risk‐based vaccination recommendations, HA transmission shifted in proportions from travelers and children to other risk groups, such as MSM and older age groups. Because a substantial proportion of the European population is susceptible to HA, adherence to existing recommendations should be monitored more closely, and enhanced vaccination strategies should be considered.


| INTRODUC TI ON
Hepatitis A (HA) is a vaccine-preventable liver disease caused by a single-stranded ribonucleic acid virus (HAV). Infection may result in severe outcomes, especially at increasing ages and in older adults.
HAV is resistant to low pH as well as heat and freezing temperatures and is mainly transmitted in common-source outbreaks (i.e. consumption of contaminated frozen food or water) or through close person-to-person contact via the fecal-oral route. 1  showed that in a series of HAV outbreaks ongoing since 2016, the case-fatality ratio was much higher, at nearly 1%. In addition, 61% of the >43,000 infected persons were hospitalized. 3 These outbreaks also led to an increase in the HA notification rate by 294% between the 2013-2015 and 2016-2018 periods in the United States. 4 Hepatitis A transmission is evolving worldwide, including in Europe, where endemicity persists and outbreaks continue to be reported. 5 Traditionally, HAV transmission had been mostly attributable to travelers, who were at increased risk of exposure and infection when visiting higher endemic regions. However, during the Coronavirus disease 2019 (COVID-19) lockdown in Switzerland, when borders were closed and travel was at a standstill, the HA incidence decreased only by 5%, illustrating that a major proportion of cases is autochthonous (domestic) now. 6 Recent outbreaks or increased infection rates in low-endemic settings have been associated with men who have sex with men (MSM), consumption of HAV-contaminated food (grown with contaminated water), drug use or homelessness. 4 Water can be contaminated with feces from infected humans to spread HAV directly or indirectly. Contamination, especially of private wells, may result from sewage clogging/overflow or polluted stormwater runoff. 7 We performed a systematic literature review to gain detailed insight over the published data on the occurrence, transmission patterns, severity and outcomes of HA in Europe in the past two decades. Considering endemicity, propensity of movement of people-including travelers, mass gatherings and immigrationsurveillance systems and notification systems in place (see details in the Supplement S1), we selected 11 European countries for inclusion in this review. Here, we focus on disease occurrence data and the trends in transmission shift observed in five of these countries with the largest population size and the most comprehensive vaccination recommendations: France, Germany, Italy, Spain and the United Kingdom (UK). Because more rigorous HA prevention strategies could aid to achieve WHO's goal to eliminate viral hepatitis as a public health threat by 2030, 8 we also discuss current and potential vaccination strategies of HA in Europe.
A plain language summary contextualizing the relevance, the results and the impact of our study is described in Figure S1.

| MATERIAL S AND ME THODS
PubMed was systematically searched for relevant peer-reviewed articles published in any language between 1 January 2001 and 14 April 2021. Search terms covered the disease (HA), the 11 selected countries, the term "outbreaks" and its synonyms, outcomes and terms for HAV circulation. A similar, complementary search was also performed in Embase for the same period. Additional details are presented in the Supplement S1.
The relevant articles retrieved from PubMed and Embase were selected using a three-step selection procedure. In the first step, titles and abstracts were screened by two researchers. Nonpertinent publication types (e.g. letters to the editor, editorials or comments) as well as seroprevalence and risk factor studies and studies in other than the selected countries were excluded. The full texts of articles meeting the inclusion criteria (relevant for the objectives, all ages, selected countries, prevalence of HAV in food/water/soil etc.) were subsequently screened. Additionally, full texts were also screened for articles for which title or abstract screening was inconclusive. In the data extraction phase, additional articles were excluded. If two or more articles presented similar results from identical datasets, only the most recent and complete was included. Articles about the same outbreak but different outcomes were combined in one row of the data extraction sheet. Reports on multi-country outbreaks were considered if any of the included countries had reported cases in the respective outbreak. Measures implemented to ensure quality control and reproducibility are detailed in the Supplement S1. For all selected countries, notification of HA cases is passive, and for all except the UK, it is mandatory. Figure 1 and Table S1 de- This review includes data on HA endemicity and outbreaks and focuses on the five largest European countries. Data for the remaining six selected countries included in the search are presented in the Supplement S1. Severity and outcomes of the disease in Europe in the past two decades will be summarized in a separate article.

| Search results
In PubMed and Embase, 134 peer-reviewed articles were found eli-

| Notification rates
Across the five largest European countries, <5 HA cases were notified per 100,000 population in most years between 2001 and 2020 ( Figure 3A). Two peaks were observed concomitantly in several European countries, one in 2008-2009 and a higher one in 2017, the latter of which was more pronounced in Spain, Italy and France.
The respective notification rates were 9.7, 6.2 and 5.1 per 100,000 population.
In 2017, a clearly distinguishable peak was also observed for the percentage of men among HA cases ( Figure 3B The risk of HA in human immunodeficiency-infected (HIV+) patients was evaluated in two reports from France. In the first one, the estimated percentages of individuals who became infected with HAV during a half-year follow-up were 2.0%-3.8% among HIV+ MSM and 2.7%-3.0% among MSM pre-exposure prophylaxis users during a half-year follow-up. 11 In the second report, this percentage was 3.2% in HIV+ MSM or bisexual men during a one-year follow-up. 12

| Outbreak reports
The time periods, impacted populations, numbers/ages of cases, proportions of males and routes of transmission in outbreaks published for the five European countries are summarized in Table 1 and   Tables S2-S6. Across outbreak reports limited to France, Germany, Italy, Spain or the UK, the main suspected transmission routes were close person-to-person contact (n = 18) and sexual transmission (MSM, n = 17), followed by consumption of contaminated food (n = 13), mixed (at least two transmission routes: person-to-person contact, sexual contact, food, travel and parenteral pathway; n = 13) and travel (n = 3) ( Figure 4, Table 1). The transmission route was unclear or unknown for two outbreaks. 13

| Foodborne outbreaks
The first foodborne outbreak in the period covered by our review was reported in Spain in 1999, 15 where two other outbreaks were reported in 2005/2006 and 2017. 16,17 Root causes were Coquina clams and razor shells. In Italy, the first of three was a F I G U R E 1 Hepatitis A notification systems and case definitions. The index case was not reported in any of these sexually transmitted outbreaks.

| Mixed transmission outbreaks
Outbreaks with mixed transmission that occurred before the 2017 European outbreak that mostly affected MSM were reported in 1998/1999 63

| Surveillance studies-transmission routes and risk factors
Aside from the outbreak reports described in the previous sec- One report describes travel-related cases that occurred in multiple European countries between 2009 and 2015. 106 In France and Germany, respectively, 43.1% and 37.1% of these occurred in persons <15 years. 106

| HAV circulation in water/sewage
In France, no HAV was found in water samples collected in the Seine through Paris between 2013 and 2014, 107 but almost all wastewater samples in an urban area in Central France were positive for HAV. 108 In Germany, the two studies from the early 2000s showed that HAV was circulating in water samples. 109,110 In Greece, HAV was found in untreated sewage in Patras between November 2007 and July 2009, 111 and once in a harbor in June 2013. 112 Other samples did not contain HAV. 112,113 In two of the seven studies from Italy, no HAV was found in water/wells. 114,115 In the other five studies, positive samples were found, 116

| DISCUSS ION
Hepatitis  Common risk groups include chronic liver disease patients and MSM, but additional risk groups are not harmonized and differ across these countries ( Figure 5)

ACK N OWLED G M ENTS
The authors thank Akkodis Belgium for medical writing services, design support, editorial assistance and publication coordination, on behalf of GSK. Medical writing services were provided by Alpár Pöllnitz (Akkodis Belgium on behalf of GSK). This work was supported by GlaxoSmithKline Biologicals SA in all stages of the study conduct and analysis. GlaxoSmithKline Biologicals SA also took responsibility for all costs associated with the development and publishing of the present manuscript. The authors did not receive any payment for their collaboration.

CO N FLI C T O F I NTE R E S T S TATE M E NT
AA and PM are employees of GSK, declare financial and nonfinancial relationships and activities, and hold shares as part of their employee remuneration. The institution of EB and JE received grants and payment from GSK for developing this study. EB and JE also report grants from GSK for other projects. PVD declares that the University of Antwerp obtains grants from vaccine manufacturers (including GSK) for the conduct of vaccine trials. RS, GK and KM declare no conflicts of interest relating to the subject presented here.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing is not applicable to this article as no new data were created or analyzed in this study.

R E FE R E N C E S
F I G U R E 5 Vaccination recommendations in France, Germany, Italy, Spain and the UK. UK, United Kingdom.