Epidemiology and clinical course of hepatitis A in Cantabria before and after the epidemic outbreak of June 2016

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Rev Clin Esp. 2019;xxx(xx):xxx---xxx

Revista Clínica Española www.elsevier.es/rce

ORIGINAL ARTICLE

Epidemiology and clinical course of hepatitis A in Cantabria before and after the epidemic outbreak of June 2016夽 J.I. Fortea a,b,∗ , M. Fernandez González a , L. Samaniego Vega a , Á. Puente a,b , A Cuadrado a,b , J Cabezas a,b , S. Llerena a,b , A. Sáez López c , J. Crespo a,b , E. Fábrega a,b a

Servicio de Aparato Digestivo, Hospital Universitario Marqu´ es de Valdecilla, Santander, Spain Instituto de Investigación Sanitaria Marqués de Valdecilla (IDIVAL), Santander, Spain c Servicio de Microbiología, Hospital Universitario Marqu´ es de Valdecilla, Santander, Spain b

Received 21 June 2019; accepted 27 August 2019

KEYWORDS Hepatitis A; Epidemic outbreak; Men who have sex with men; Sexually transmitted diseases; Prevention measures

Abstract Background and objectives: Since June 2016, there have been outbreaks of hepatitis A in various European countries, mainly affecting men who have sex with men (MSM). The aim of this study was to assess their clinical and epidemiological impact in Cantabria, Spain. Material and methods: We retrospectively collected all cases of hepatitis A diagnosed in Cantabria between January 2013 and September 2018. We compared 2 periods: January 2013---May 2016 and June 2016---September 2018. Results: A total of 156 cases were diagnosed, observing an increase in the incidence starting in October 2016. With regard to 2013---2016, we observed a higher proportion of men (50.0% vs. 84.5%; p = .012) with a predominance of the homosexual orientation (80.6%) and a higher rate of sexual transmission (0% vs. 48.3%; p = .061) for the patients in the 2016---2018 period. From the clinical standpoint, all cases of severe hepatitis occurred during this latter period. Conclusions: Our results reaffirm the high clinical and epidemiological impact of the epidemic outbreak in Cantabria and emphasises the need for optimising the current prevention measures against hepatitis A. © 2019 Elsevier Espa˜ na, S.L.U. and Sociedad Espa˜ nola de Medicina Interna (SEMI). All rights reserved.

夽 Please cite this article as: Fortea JI, Fernandez González M, Samaniego Vega L, Puente Á, Cuadrado A, Cabezas J, et al. Epidemiología y curso clínico de la hepatitis A en Cantabria antes y después del brote epidémico de junio 2016. Rev Clin Esp. 2019. https://doi.org/10.1016/j.rce.2019.08.005 ∗ Corresponding author. E-mail address: [email protected] (J.I. Fortea).

2254-8874/© 2019 Elsevier Espa˜ na, S.L.U. and Sociedad Espa˜ nola de Medicina Interna (SEMI). All rights reserved.

RCENG-1727; No. of Pages 9

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PALABRAS CLAVE Hepatitis A; Brote epidémico; Hombres que tienen sexo con Hombres; Enfermedades de transmisión sexual; Medidas de prevención

Epidemiología y curso clínico de la hepatitis A en Cantabria antes y después del brote epidémico de junio 2016 Resumen Antecedentes y objetivos: : Desde junio de 2016 se han producido brotes de hepatitis A en diversos países europeos, afectando principalmente a hombres que tienen sexo con hombres (HSH). El objetivo del presente trabajo fue valorar su impacto clínico y epidemiológico en Cantabria. Materiales y métodos: Se recogieron retrospectivamente todos los casos de hepatitis A diagnosticados en Cantabria entre enero de 2013 y septiembre de 2018. Se compararon dos periodos (enero 2013-mayo 2016 y junio 2016-septiembre 2018). Resultados: Se diagnosticaron un total de 156 casos, objetivándose un aumento de la incidencia a partir de octubre de 2016. Con respecto al periodo 2013-2016, se observó una mayor proporción de varones (50,0 vs. 84,5%; p = 0,012) con una predominancia de la orientación sexual homosexual (80,6%) y una mayor frecuencia de transmisión sexual (0 vs. 48,3%; p = 0,061) en los pacientes del periodo 2016-2018. Desde el punto de vista clínico destacó que todos los casos de hepatitis grave ocurrieron en este último periodo. Conclusiones: Nuestros resultados reafirman el elevado impacto clínico y epidemiológico del brote epidémico en Cantabria y ponen de relieve la necesaria optimización de las actuales medidas de prevención contra la hepatitis A. © 2019 Elsevier Espa˜ na, S.L.U. y Sociedad Espa˜ nola de Medicina Interna (SEMI). Todos los derechos reservados.

Background The hepatitis A virus (HAV) is an RNA virus belonging to the genus Hepadnavirus, within the Picornaviridae family. The virus is mainly transmitted through the fecal-oral pathway, either through person-person contact or by ingestion of contaminated water or food.1 HAV has a worldwide distribution and is one of the most common causes of acute hepatitis globally. The uneven incidence among countries is related to their healthcare development level, with high prevalence in those countries with poor health conditions.2 HAV produces self-limiting acute hepatitis that rarely results in acute hepatic failure (0.35%) and never progresses to chronicity. The likelihood that the hepatitis is symptomatic and/or severe increases with age and in individuals with prior liver disease. The diagnosis is based on detecting IgM or HAV-RNA antibodies in blood. The treatment is symptomatic due to the lack of a specific treatment.1,2 Unlike developing countries with high endemicity where most individuals are infected during childhood presenting asymptomatic or subclinical hepatitis, developed countries have good sewage and hygiene systems maintained over decades, resulting in a significant reduction in viral circulation, which has led to low endemicity. In these populations, individuals reach adolescence and adulthood without immunity, which favors the onset of disease outbreaks in which the clinical course of hepatitis is more often symptomatic and severe.2---4 These outbreaks usually affect certain risk groups for whom the World Health Organization recommends systematic vaccination5 : populations with low socioeconomic levels, travelers to endemic areas, injecting drug users, recipients of blood products, staff of pediatric daycare cen-

ters, relatives and caregivers in direct contact with patients with hepatitis A, laboratory staff in contact with HAV and men who have sex with men (MSM). This last risk population was involved in the epidemic outbreak of hepatitis A that has mainly occurred in Europe6---14 but that has also affected other parts of the world since June 2016.15---18 According to the latest report by the European Centre for Disease Prevention and Control, 22 European countries reported 4475 confirmed cases of hepatitis A associated with this outbreak between June 2016 and August 2018, reaching its peak in March 2017. Compared with the same period between 2012 and 2015, these figures represent a more than 2-fold increase in the incidence.19 In Spain, data published to date in Asturias,11 Catalonia,10 , Andalusia20 and the Community of Valencia21 confirm the impact of the HAV epidemic outbreak in these autonomous communities. The aim of this study is to study the epidemiology and clinical course of hepatitis A in Cantabria during the last 5 years.

Materials and methods Study population We conducted an observational retrospective study that included all patients diagnosed with hepatitis A from the 1st of January 2013 to the 19th of September 2018 in Cantabria. To assess the epidemiological and clinical impact of the HAV disease outbreaks in Europe since June 2016, we differentiated 2 periods: the first from January 1, 2013 to May 31, 2016 and the second from June 1, 2016 to September 19, 2018.

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Epidemiology and clinical course of hepatitis A in Cantabria

Definitions of hepatitis a, severe acute hepatitis and acute hepatic failure The diagnosis of hepatitis A was based on ALT levels more than 10-fold higher than the upper limit of normality and on positive anti-HAV IgM. The definition of acute hepatitis as severe was established when the prothrombin activity was <50% and/or the INR was >1.5 (after the administration of vitamin K if the patient had associated hyperbilirubinemia), and the definition of acute hepatic failure was defined as hepatic encephalopathy with a prothrombin activity <50% and/or INR >1.5.23

Statistical analysis The quantitative variables are expressed as mean and standard deviation or median and interquartile range, depending on whether their distribution was normal, as assessed by the Kolmogorov-Smirnov test. The qualitative variables are expressed as absolute values and proportions. We compared the groups using an unpaired Student’s t-test or Fisher’s exact test. The adjusted association with the onset of severe acute hepatitis was assessed using a logistic regression analysis with backward elimination, in which we inserted variables related to its development (p < .1) in a univariate analysis. The maximum number of variables included in the multivariate analysis was 1 for every 5 events (i.e., severe acute hepatitis). The strength of the association of each variable was estimated using the odds ratio (OR) and its 95% confidence interval (CI). We performed the statistical analysis with the IBM SPSS Statistics package v22.0 for Mac (IBM Corp., Armonk, NY).

Spanish mean

Total Men

Women

Incidence rate (per 100.000 individuals/year)

25

M/W ratio 25

20

20

15

15

10

10

5

5

2013

2014

2015

2016

2017

Men/women ratio

We recorded epidemiological variables (age, sex, race, country of birth, travel to endemic areas in the past 6 weeks, sexual orientation, transmission method and focus of infection), clinical variables (extrahepatic manifestations, other previous or concomitant sexually transmitted diseases [STDs], previous chronic liver disease, death, need for hospitalization and time to hepatic profile normalization), laboratory variables (including the highest readings for alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, gamma glutamyl transpeptidase [GGT], bilirubin, hemoglobin, total leukocytes and creatinine and the lowest levels of prothrombin activity, international normalized ratio [INR], albumin, platelets and glomerular filtration) and radiological variables (ascites, collateral coronary circulation or thrombosis of the splanchnic axis). The figures for the Cantabria population for the calculation of the annual incidence of hepatitis A were obtained from the Spanish National Institute of Statistics (https://www.ine.es).22 The study protocol was approved by the Ethics Committee of Cantabria. We followed the provisions of Good Clinical Practices and the international conventions on the protection of individuals in clinical research (Declaration of Helsinki and subsequent updates). Given the retrospective nature of the study, informed consent was not requested from the included patients.

3

2018

Year 2013 2014 2015 2016 2017 2018 1.3 1.2 2.8 0.68 0.34 1.89 11.2 12.41 Male incidence, Cantabria 0.35 0.70 0.35 3.53 19.16 21.66 Female incidence, Cantabria 0.33 0.66 0.33 0.33 3.69 3.68 Men/women ratio 0.49 0.98 9.84 5.32 6.14 1.3 Overall incidence, Spain Overall incidence, Cantabria 0.34

Figure 1 Number of cases of hepatitis A per 100,000 personyears (total number and by sex) in Cantabria from January 1, 2013 to September 19, 2018. The red line reflects the incidence rate corresponding to the mean Spanish rate to 2016 due to the lack of official data beyond this date. The bars reflect the malefemale ratio in each year in Cantabria. In 2013, the ratio could not be calculated due to the lack of cases in women older than 15 years (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).

Results Incidence of hepatitis A From January 1, 2013 to September 19, 2018, 156 cases of hepatitis A were diagnosed in Cantabria. Of these 156 patients, 8 were diagnosed during the first study period (January 2013-May 2016); the remaining 148 were diagnosed in the second period (June 2016-September 2018). As shown in Fig. 1, this increase in the incidence rate in the second period was accompanied by an increase in the malefemale ratio. The maximum peak in the incidence occurred in February 2018, with 2 other peaks of lesser intensity in February and June 2017 (Fig. 2).

Clinical and epidemiological characteristics of hepatitis A Table 1 shows the clinical and epidemiological characteristics of the population for each study period. None of the patients developed extrahepatic manifestations or subsequent autoimmune hepatitis, ascites, collateral coronary circulation or splanchnic axis thrombosis in the ultrasound.

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24

Women

Men

21

No. of cases

18 15 12 9 6

2016

2017

Sep

Jul

Aug

Jun

Apr

May

Mar

Jan

Feb

Dec

Oct

Nov

Sep

Jul

Aug

Jun

Apr

May

Mar

Jan

Feb

Dec

Oct

Nov

3

2018

Figure 2 Number of cases of hepatitis A per month (total and by sex) during the second period (June 2016- September 2018). From June to September 2016, there were no cases.

For January 2013---May 2016, we observed a higher proportion of men (50.0% vs. 84.5%; p = .012) and a higher tendency to develop severe acute hepatitis (0% vs. 12.9%, p = .598) in the patients in the second period. The mechanism of transmission and sexual orientation were incompletely recorded, because these variables were not shown in all the medical records. For those patients for whom these variables were available, we observed that sexual transmission (0% vs. 48.3%; p = .061) and a homosexual orientation (0% vs. 73.8%; p = .008) were more common in the patients in the second period. Homosexual men represented 80.6% of the men during the epidemic expansion. Transmission through contact with an infected individual was the most common form in the first period and was also highly present in the second (75.0% vs. 48.3%; p = .612). Of the patients infected by the sexual pathway, 12 (42.9%) and 26 (96.3%) had had a previous or concomitant STD and were homosexual men, respectively. In the remaining 19 patients with previous or concomitant STD, the transmission pathway was not recorded in the medical history. Eighteen patients (11.5%), all from the second period, developed severe hepatitis A. None of these patients progressed to acute hepatic failure, death or liver transplantation. The need for hospitalization was greater in the second period, although this difference did not reach statistical significance (12.5% vs. 22.4%; p = .686). There were no clinically relevant differences between the patients in the two periods in any of the assessed laboratory parameters (Table 2). The median time for normalization of the hepatic profile was longer in the second period but did not reach statistical significance (12.6 vs. 20.0 weeks; p = .843).

Predictors of hepatitis A severity Table 3 shows the clinical, laboratory and epidemiological characteristics of the cases of hepatitis A according to their severity. Compared with the patients with non-severe hepatitis, those with severe hepatitis were older and showed higher bilirubin and transaminase levels and lower albumin and alkaline phosphatase levels. In the multivariate analysis, the only variables that predicted severity were AST (OR,

1.001; 95% CI 1.001---1.002; p < .001), albumin (OR, 0.14; 95% CI 0.03---0.77; p = .024) and bilirubin (OR, 1.41; 95% CI 1.08---1.85; p = .012).

Discussion The present study evaluated the epidemiology and clinical characteristics of hepatitis A in Cantabria between 2013 and 2018 and analyzed the impact on Cantabria of the epidemic hepatitis A outbreak that has taken place in Europe and other parts of the world since June 2016.19 The results confirm a significant increase in the incidence of hepatitis A since June 2016, which translates into the international character of this phenomenon, clearly distinguishing 2 periods that differ not only in the number of cases but also in their clinical characteristics. Thus, the cases in the second period appear to involve mainly MSM and are frequently more severe and/or require hospital admission. These data reaffirm the high impact of the epidemic outbreak in Spain and emphasize the need for optimizing the current prevention measures against HAV. As with data from other European countries6---9,12---14 and autonomous Spanish communities,10,11,20,21 our data suggest that the group most affected during June 2016---September 2018 was MSM. The high male-female ratio (a surrogate marker of MSM), the predominance of the homosexual orientation in the men, the frequent sexual transmission and the high prevalence of previous or concomitant STD in these patients support this assertion. From the clinical standpoint, our data demonstrate a greater healthcare impact of hepatitis A during the epidemic expansion. Thus, the hospital admission rate was virtually double that of the previous period (22.4% vs. 12.5%), and all cases of severe acute hepatitis occurred during the latter period. Consistent with these results, the scarce epidemiological studies that have also assessed the clinical profile of the disease outbreaks have confirmed this higher incidence of severe acute hepatitis and the need for hospitalization.10---12,20 Their underlying causes for the outbreaks are unclear. Although the phylogenetic analysis confirmed that the epidemic cases are secondary to 3 strains of the IA subgenotype,19 hepatitis A

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Epidemiology and clinical course of hepatitis A in Cantabria Table 1 Variables

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Clinical and epidemiological characteristics of cases of hepatitis A. a

Age Sex (male) [0,1---4] Race White Latin American Arab [0,1---4] Country Spain Morocco Bulgaria Peru Ukraine [0,1---4] Chronic liver disease [0,1---4] Transmission mechanism (N4/N58)b Sexual Water and food Infected contact [0,1---4] IDU Travel to endemic areas [0,1---4] Sexual orientation (N4/N42)b Heterosexual Homosexual [0,1---4] HCV (N8/N147)c Previous or concomitant STD [0,1---4] HBV (N8/N147)c No Vaccinated Past Active [0,1---4] HIV infection (N8/N147)c [0,1---4] Syphilis (N8/N147)c Previous Concomitant [0,1---4] Chlamydia (N8/N147)c Previous Concomitant [0,1---4] Gonococcus (N8/N147)c Previous Concomitant [0,1---4] Clinical presentation (N7/N147)c Anicteric Icteric [0,1---4]

January 2013-May 2016 (n = 8)

June 2016-September 2018 (n = 148)

p

28.5 (13.7---41.2) 4 (50.0)

33.0 (24.6---42.0) 125 (84.5)

.405 .031

7 (87.5) 0 (0) 1 (12.5)

145 (98) 1 (0.7) 2 (1.4)

7 1 0 0 0

143 (96.6) 2 (1.4) 1 (0.7) 1 (0.7) 1 (0.7)

.080

.274 (87.5) (12.5) (0) (0) (0)

0 (0)

2 (1.4)

1

0 (0) 1 (25.0) 3 (75.0)

28 (48.3) 1 (1.7) 28 (48.3)

.032 .120 .126 .612

0 (0) 0 (0)

1 (1.7) 1 (0.7)

1 1

4 (100) 0 (0)

11 (26.2) 31 (73.8)

0 (0) 0 (0)

0 (0) 31 (20.9)

6 2 0 0

107 (72.8) 26 (17.7) 13 (8.8) 1 (0.7)

.008

1 .358 .803

(75.0) (25.0) (0) (0)

0 (0)

15 (10.2)

0 (0) 0 (0)

16 (10.9) 5 (3.4)

0 (0) 0 (0)

1 (0.7) 1 (0.7)

0 (0) 0 (0)

2 (1.4) 0 (0)

1 (14.3) 6 (85.7)

22 (15.0) 125 (85.0)

1 .516

.946

1

1

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J.I. Fortea et al. Table 1 (Continued) Variablesa c

Recurrent course (N8/N147) Extrahepatic manifestations Subsequent autoimmune hepatitis Emergency department care (N8/N147)c Ward admission (N8/N147)c [0,1---4] Severity (N7/N140)c Not severe Severe [0,1---4] Imaging tests

January 2013-May 2016 (n = 8)

June 2016-September 2018 (n = 148)

p

0 0 0 2 1

4 (2.7) 0 (0) 0 (0) 25 (21.9) 33 (22.4)

1 1 1 .652 .686

(0) (0) (0) (28.6) (12.5)

.598 7 (100) 0 (0)

122 (87.1) 18 (12.9)

5 (62.5)

115 (77.7)

.387

Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IDU, injecting drug users; STD, sexually transmitted disease. The bolded values indicate the variables with statistically significant differences between the 2 groups. a The qualitative variables are shown as absolute numbers and percentages, while the quantitative variables are shown as medians and interquartile ranges. b The review of the medical history prevented the complete collection of these variables for all patients, and none of the patients in the first period. Comparisons could not therefore be made. c Represents the number of patients with each variable available within each group. If not available in all patients, it is not specified.

Table 2

Biochemical profile of cases of hepatitis A.

Variablesa

January 2013---May 2016 (n = 8) June 2016---September 2018 (n = 148) p

Leukocytes, ×10 /␮L Hemoglobin, g/dL Platelets, ×103 /␮L Prothrombin activity, % (N7/N140)b INR (N6/138)b Creatinine, mg/dL (N8/142)b ALT, U/L AST, U/L GGT, U/L (N8/N146)b Phosphatase alkaline, U/L (N8/142)b Bilirubin, mg/dL (N7/N147)b Albumin, g/dL (N8/132)b Hepatic profile normalization time, weeks (N8/85)b 3

5.0 (4.1---8.1) 14.4 (12.7---16.0) 219.0 (147---358) 76.0 (13.03) 1.2 (1.1---1.4) 0.6 (0.4---0.8) 3453.0 (2343---4030) 2111.0 (1033---2907) 245.0 (178---387) 262.0 (211---610) 5.5 (2.0) 4.1 (0.4) 12.6 (4.2---36.7)

5.4 (4.4---6.7) 14.9 (14.2---15.8) 188.5 (153---228) 71.5 (15.7) 1.3 (1.2---1.4) 0.8 (0.7---0.9) 2587.0 (1721---3951) 1496.5 (681---2359) 264.0 (159---411) 195.5 (144---261) 5.6 (3.0) 3.9 (0.4) 20.0 (9.2---32.5)

.743 .292 .049 .665 .492 .003 .955 .614 .623 <.001 .669 .250 .843

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma glutamyl transpeptidase; INR, international normalized ratio. The bolded values indicate the variables with statistically significant differences between the 2 groups. a The quantitative variables are expressed as mean and standard deviation or median and interquartile range. b Represents the number of patients with each variable available within each group. If not available in all patients, it is not specified.

severity has classically been associated with age and the previous presence of chronic liver disease and not to the viral genotype or subgenotype.2 In our cohort, the only variables that predicted severity were AST, albumin and bilirubin. The lack of an association between the 2 previous variables is probably due to the relatively young population and the virtual absence of patients with chronic liver disease in our study. All these data highlight the enormous healthcare costs directly and indirectly (e.g., work leave) associated with hepatitis A and the need to intensify the vaccination and health education programs in risk populations such as MSM. Thus, a low prevalence of immunity against HAV (39%, even lower in young populations) has been observed in MSM in

countries with low endemicity, such as Spain.24 The implementation of a vaccination program during an HAV epidemic outbreak in MSM and HIV-positive men resulted in a significant reduction in the incidence of new cases with the achievement of immunity levels of at least 65%.25 Our study design prevented us from addressing factors related to the prior non-vaccination of the patients who contracted the disease. Previous studies have identified factors such as young age, immigrant status, low educational level, barriers to accessing the healthcare system for certain risk groups (such as injecting drug users) and poor collaboration among the medical community in implementing vaccination programs.2,26,27 Thus, for example, in the epidemic outbreak that occurred in Catalonia, only 2 of the 11 cases of hepatitis

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Epidemiology and clinical course of hepatitis A in Cantabria Table 3 Variables

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Epidemiological, clinical and laboratory characteristics of the cases of hepatitis A according to its severity. a

Age Sex (male) [0,1---4] Race White Latin American Arab [0,1---4] Country Spain Morocco Bulgaria Peru Ukraine [0,1---4] Previous or concomitant STD Active HBV HIV infection Previous or concomitant syphilis Previous or concomitant chlamydia [0,1---4] Symptoms Anicteric Icteric [0,1---4] Remitting No Yes [0,1---4] Transmission (N46/N10)b Sexual Water and food Infected contact IDU [0,1---4] Sexual orientation (N34/N11)b Heterosexual Homosexual [0,1---4] Chronic liver disease [0,1---4] Period 2013---2016 2016---2018 [0,1---4] Leukocytes, ×103 /␮L Hemoglobin, g/dL Platelets, ×103 /␮L Prothrombin activity, % INR (N126/N18)b Creatinine, mg/dL (N127/17)b

Not severe (n = 129)

Severe (n = 18)

p

32.9 (24.8---41.2) 108 (83.7)

41.8 (29.9---46.2) 15 (83.3)

.029 1

126 (97.7) 1 (0.8) 2 (1.6)

18 (100) 0 (0) 0 (0)

125 (96.9) 2 (1.6) 1 (0.8) 1 (0.8) 0 (0)

17 (94.4) 0 (0) 0 (0) 0 (0) 1 (0.8)

26 (20.2) 0 (0) 15 (11.6) 17 (13.2) 1 (0.8)

5 1 0 4 1

19 (14.7) 110 (85.3)

1 (5.6) 17 (94.4)

127 (98.4) 2 (1.6)

17 (94.4) 1 (5.6)

20 (43.5) 2 (4.3) 23 (50.0) 1 (2.2)

8 0 2 0

11 (32.4) 23 (67.6)

3 (27.3) 8 (72.7)

1 (0.8)

1 (5.6)

7 (5.4) 122 (94.6)

0 (0) 18 (100)

5.3 (4.4---6.8) 14.9 (1.6) 189.0 (158---231) 74.0 (11.7) 1.2 (0.14) 0.8 (0.2)

5.6 (4.5---6.6) 15.3 (1.6) 175.5 (133---212) 43.5 (8.4) 1.8 (0.4) 0.8 (0.1)

.808

.102

(27.8) (5.6) (0) (22.2) (5.6)

.537 .122 .217 .292 .231 .469

.326

.212 (80.0) (0) (20.0) (0) 1

.231 .598

.666 .546 .079 <.001 <.001 .588

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J.I. Fortea et al. Table 3 (Continued) Variablesa

Not severe (n = 129)

Severe (n = 18)

p

ALT, U/L AST, U/L GGT, U/L (N128/18)b Phosphatase alkaline, U/L (N126/N18)b Bilirubin, mg/dL Albumin, g/dL (N118/17)b Hepatic profile normalization time, weeks (N78/N12)b

2575.0 (1748---3651) 1431.0 (642---2096) 275.0 (189) 201.5 (157---282) 5.6 (3.4---7.3) 3.9 (0.4) 17.9 (9.1---30.1)

5679.0 (3380---7919) 3900.0 (2522---5307) 324.5 (164---423) 165.0 (138---213) 7.5 (4.2---9.2) 3.4 (0.6) 23.4 (15.3---39.7)

<.001 <.001 .858 <.001 .023 .006 .218

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; HBV, hepatitis b virus; HIV, human immunodeficiency virus; INR, international normalized ratio; IDU, injecting drug users; STD, sexually transmitted disease. The bolded values indicate the variables with statistically significant differences between the 2 groups. a The qualitative variables are shown as absolute numbers and percentages, while the quantitative variables are shown as mean and standard deviation or median and interquartile range. b Represents the number of patients with each variable available within each group. If not available in all patients, it is not specified.

A in patients younger than 30 years (a population who, due to their age, are protected by the universal vaccination in this community) did not originate in Catalonia.10 The inclusion of the HAV vaccine in the vaccination calendar,28 as occurs only in Catalonia, Ceuta and Melilla,29 could be the best strategy for preventing not only the expansion of the outbreak in MSM but also in the general population, who are also at risk of infection during outbreaks. Thus, the involvement of other groups beyond MSM is shown in our study by the frequent transmission by contact with an infected individual. Nevertheless, the protection of the general population and groups such as MSM through universal vaccination would take decades to achieve. This measure should therefore be implemented along with others that more immediately seek to increase the vaccination rates in risk groups such as MSM. The identification of programs that provide services to MSM to administer the HAV vaccine and improve the reach of sexual education campaigns are, in our opinion, the most important measures.30 Our study had a number of limitations. Firstly, the study’s retrospective nature prevented us from fully collecting important variables such as the transmission method and the previously mentioned factors related to previous nonvaccination for HAV. Secondly, the absence of a phylogenetic analysis of the virus prevents us from verifying the connection between the increased incidence of hepatitis A in Cantabria and the outbreaks that occurred in various European countries. Lastly, an analysis of the financial cost associated with hepatitis A might have provided valuable data for assessing the cost-effectiveness of implementing the universal vaccination against HAV in our community.

Conclusions As with other regions of Europe and the United States, there has been an increase in cases of hepatitis A in Cantabria since October 2016, which appears to predominantly affect MSM and are frequently severe and/or require hospital admission. These results demonstrate the need to reconsider and intensify the current vaccination and health education programs.

Funding Jose Ignacio Fortea received a grant from the Marqués of Valdecilla Healthcare Research Institute (NVAL17/07).

Conflicts of interest Javier Crespo has received grants and fees for consulting and conferences from AbbVie, Gilead Sciences, Bristol-Myers Squibb, Janssen and MSD. The other authors declare that they have no conflicts of interest.

References 1. Nainan OV, Xia G, Vaughan G, Margolis HS. Diagnosis of hepatitis a virus infection: a molecular approach. Clin Microbiol Rev. 2006;19(1):63---79, doi:10.1128/cmr.19.1.63-79.2006. 2. Lemon SM, Ott JJ, Van Damme P, Shouval D. Type A viral hepatitis: A summary and update on the molecular virology, epidemiology, pathogenesis and prevention. J Hepatol. 2017, doi:10.1016/j.jhep.2017.08.034. 3. Collier MG, Tong X, Xu F. Hepatitis A hospitalizations in the United States, 2002-2011. Hepatology. 2015;61(2):481---5, doi:10.1002/hep.27537. 4. Ly KN, Klevens RM. Trends in disease and complications of hepatitis A virus infection in the United States, 1999---2011: a new concern for adults. J Infect Dis. 2015;212(2):176---82, doi:10.1093/infdis/jiu834. 5. WHO position paper on hepatitis A vaccines: June 2012recommendations. Vaccine. 2013;31(2):285---6, doi:10.1016/j. vaccine.2012.10.102. 6. Beebeejaun K, Degala S, Balogun K, Simms I, Woodhall SC, Heinsbroek E, et al. Outbreak of hepatitis A associated with men who have sex with men (MSM), England, July 2016 to January 2017. Euro Surveill. 2017;22(5), doi:10.2807/ 1560-7917.es.2017.22.5.30454. 7. Werber D, Michaelis K, Hausner M, Sissolak D, Wenzel J, Bitzegeio J, et al. Ongoing outbreaks of hepatitis A among men who have sex with men (MSM), Berlin, November 2016 to January 2017 - linked to other German cities and European countries. Euro Surveill. 2017;22(5), doi:10.2807/ 1560-7917.es.2017.22.5.30457. 8. Charre C, Ramiere C, Roque-Afonso AM, Chidiac C, Zoulim F, Godinot M, et al. Hepatitis A outbreak in HIV-infected MSM and in PrEP-using MSM despite a high level of immunity, Lyon,

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France, January to June 2017. Euro Surveill. 2017;22(48), doi:10.2807/1560-7917.es.2017.22.48.17-00742. Lanini S, Minosse C, Vairo F, Garbuglia A, Di Bari V, Agresta A, et al. A large ongoing outbreak of hepatitis A predominantly affecting young males in Lazio, Italy; August 2016 March 2017. PLoS One. 2017;12(11):e0185428, doi:10.1371/ journal.pone.0185428. Rodriguez-Tajes S, Perpinan E, Caballol B, Lens S, Marino Z, Costa J, et al. Hepatitis A outbreak in Barcelona among men who have sex with men (MSM), January-June 2017: a hospital perspective. Liver Int. 2018;38(4):588---93, doi:10.1111/liv.13606. Fraile M, Barreiro Alonso E, de la Vega J, Rodriguez M, Garcia-Lopez R, Rodriguez M. Acute hepatitis due to hepatitis A virus during the 2017 epidemic expansion in Asturias, Spain. Med Clin (Barc). 2019;152(10):391---4, doi:10.1016/ j.medcli.2018.07.009. Boucher A, Meybeck A, Alidjinou K, Huleux T, Viget N, Baclet V, et al. Clinical and virological features of acute hepatitis A during an ongoing outbreak among men who have sex with men in the North of France. Sex Transm Infect. 2019;95(1):75---7, doi:10.1136/sextrans-2017-053395. Alberts CJ, Boyd A, Bruisten SM, Heijman T, Hogewoning A, Rooijen MV, et al. Hepatitis A incidence, seroprevalence, and vaccination decision among MSM in Amsterdam, the Netherlands. Vaccine. 2019;37(21):2849---56, doi:10.1016/ j.vaccine.2019.03.048. Bradley-Stewart A, Smith-Palmer A, Hawkins G, Gunson R. Hepatitis A-2017 an unusual year in Scotland. J Clin Virol. 2019;115:1---4, doi:10.1016/j.jcv.2019.03.011. Chen GJ, Lin KY, Hung CC, Chang SC. Hepatitis A outbreak among men who have sex with men in a country of low endemicity of hepatitis A infection. J Infect Dis. 2017;215(8):1339---40, doi:10.1093/infdis/jix123. Rivas V, Barrera A, Pino K, Nunez R, Caceres CJ, LopezLastra M, et al. Hepatitis A outbreak since November 2016 affecting men who have sex with men (MSM) in Chile connected to the current outbreak in MSM in Europe, situation up to October 2017. Euro Surveill. 2018;23(9), doi:10.2807/1560-7917.es.2018.23.9.18-00060. Gozlan Y, Bar-Or I, Rakovsky A, Savion M, Amitai Z, Sheffer R, et al. Ongoing hepatitis A among men who have sex with men (MSM) linked to outbreaks in Europe in Tel Aviv area, Israel, December 2016 - June 2017. Euro Surveill. 2017;22(29), doi:10.2807/1560-7917.es.2017.22.29.30575. Foster MA, Hofmeister MG, Kupronis BA, Lin Y, Xia GL, Yin S, et al. Increase in Hepatitis A Virus Infections - United States, 2013-2018. MMWR Morb Mortal Wkly Rep. 2019;68(18):413---5, doi:10.15585/mmwr.mm6818a2.

19. European Centre for Disease Prevention and Control. Epidemiological update: Hepatitis A outbreak in the EU/EEA mostly affecting men who have sex with men. 14 September 2018. 20. Garcia Ferreira AJ, Ortega Alonso A, Cobos Rodriguez J, Bardon de Tena P, Calderon Cid M, Garcia Garcia AM, et al. Outbreak of acute hepatitis A in the health area served by the Hospital Universitario Virgen de la Victoria (HUVV): a change in epidemiology. Rev Esp Enferm Dig. 2018;110(6):380---5, doi:10.17235/reed.2018.5207/2017. 21. Alventosa Mateu C, Urquijo Ponce JJ, Diago Madrid M. An outbreak of acute hepatitis due to the hepatitis A virus in 2017: are we witnessing a change in contagion risk factors? Rev Esp Enferm Dig. 2018;110:675---6, doi:10.17235/reed.2018.5633/2018. 22. Instituto Nacional de Estadística. 2019 [consultada 17/3/2019]. 23. Wendon J, Cordoba J, Dhawan A, Larsen FS, Manns M, Samuel D, et al. EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure. J Hepatol. 2017;66(5):1047---81, doi:10.1016/j.jhep.2016.12.003. 24. Weerakoon AP, Chen MY, Read TR, Bradshaw C, Fairley CK. Immunity to hepatitis A when outbreaks of infection in men who have sex with men (MSM) are rare. Vaccine. 2012;30(23):3430---4, doi:10.1016/j.vaccine.2012.03.024. 25. Chen GJ, Lin KY, Sun HY, Sheng WH, Hsieh SM, Huang YC, et al. Incidence of acute hepatitis A among HIV-positive patients during an outbreak among MSM in Taiwan: Impact of HAV vaccination. Liver Int. 2018;38(4):594---601, doi:10.1111/liv.13468. 26. Kourkounti S, Paparizos V, Leuow K, Paparizou E, Antoniou C. Adherence to hepatitis A virus vaccination in HIV-infected men who have sex with men. Int J STD AIDS. 2015;26(12):852---6, doi:10.1177/0956462414560274. 27. Winnock M, Bani-Sadr F, Pambrun E, Loko MA, Lascoux-Combe C, Garipuy D, et al. Prevalence of immunity to hepatitis viruses A and B in a large cohort of HIV/HCV-coinfected patients, and factors associated with HAV and HBV vaccination. Vaccine. 2011;29(47):8656---60, doi:10.1016/j.vaccine.2011.08.125. 28. Sharp A, Coles S, Pegorie M, Harwood C, Ngui SL, Welfare W, et al. Vaccination strategies for control of community outbreaks of hepatitis A: A comparison of two outbreaks in England. Vaccine. 2019;37(11):1521---7, doi:10.1016/j.vaccine.2019.01.026. 29. Generalitat de Catalu˜ na. Nota informativa sobre la normalització de l’ús de la vacuna contra l’hepatitis A en adults (HA). http://salutpublica.gencat.cat/web/.content/minisite/aspcat /promocio salut/vacunacions/03prioritzacions us/hepatitis ha.pdf. 30. Puoti M, Rossotti R, Merli M. Hepatitis A virus in men who have sex with men: Need for awareness and vaccination. Liver Int. 2018;38(4):581---4, doi:10.1111/liv.13702.

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