Hepatitis A and E: surveillance and epidemiological situation in the Russian Federation.

Mikhail Mikhaylov

Mechnikov Research Institute for Vaccines and Sera, Russian Medical Academy of Continuous Professional Education,

October 25 2018 State Sanitary and Epidemiological Surveillance of Hepatitis A in

The purpose of surveillance: assessment of the epidemiological situation and trends in the development of the epidemic process and the timely adoption of effective management decisions with the development and implementation of adequate sanitary and anti-epidemic (preventive) measures to prevent the occurrence and spread of CAA. Tasks of hepatitis A surveillance: - constant and objective assessment of the extent and nature of the prevalence, and socio- economic significance of the infection; - Identification of the trends in the epidemic process; - identification of territories and institutions with a high incidence and risk of infection; - identification of the contingents most at risk of developing the disease; - identifying the causes and conditions that determine the level and structure of HAV incidence in the territory; - monitoring and evaluating the effectiveness of ongoing preventive and anti-epidemic measures for its optimization; - development of epidemiological forecasts Hepatitis A incidence rates in Russian Federation in 1977-2016 300 283.8

250

204.3 200

,000 population ,000 150 150 123.3

100 120.6 100 110.2 79.5

50 30.1 30.8 7.26 7.3 4.4 Incidence perIncidence 0

Factors contributing to decrease in hepatitis A incidence: • Socio-economic changes since 1990s (↓birthrate, ↓ number of pioneer / sports camps, ↓ preschool institutions, ↓ student construction brigades) • Improving sanitary and hygienic living conditions (consumption of bottled water, etc.) Hepatitis A: shift in epidemiology

Increase in the Increase number in the number of susceptible of non immune teenagers and adults Decrease of young adults HAV circulation in children

Increase in the number of Improving symptomatic and severe hygiene cases of hepatitis A and sanitation

Van Herck & Van Damme, Expert Rev Vaccines 2005; 4: 459–71. WHO, Hepatitis A, WHO/CDS/CSR/EDC/2000.7 Hepatitis A outbreaks in Russian Federation

In 2017 the number of hepatitis A outbreaks increased from 22 Outbreaks associated with in 2015-2016 to 28, with 19,8% increase in total number of HAV genotype IA affected persons Outbreaks associated with HAV genotype IIIA Ca. 3000 cases Ca.800 cases

Kaliningrad, 2009 Severodvinsk, 2006

Rzhev,2005 , 2006

Moscow, 2010

Nizhniy Novgorog, 2005 Raduzhny, 2008 Neryungri, 2007

Ryazan region, 2009 Ekaterinburg, 2006, 2010 г. Ужур, с. Тургужан 2009 Sakhalin region, 2006, 2007 Ufa, 2009

Makhachkala, 2008

Kemerovo region, 2006 Republic of Tyva, 2008, 2010 Chulanov V., 2018 Hepatitis A incidence in different age groups in Russian Federation in 2009-2017

100% >60 лет 90% 50-59 80% 40-49 44% 70% 30-39 60% 61% 20-29 50% 15-19 40% 11-14

30% 7-10 51% 20% 3-6

10% 28% 1-2 года

0% <1 года 2009 2011 2013 2015 2017

The proportion of children under 17 years among all reported cases of hepatitis A has decreased in the last 6 years from 46.9% to 25,0% Distribution of subjects of the Russian Federation by the incidence rates of hepatitis A, per 100 thousand population

State report "On the state of sanitary and epidemiological welfare of the population in the Russian Federation in 2017" Hepatitis A incidence rates (per 100,000 population) and

vaccination coverage

Incidence, Incidence, per 100,000 Number of vaccinated persons Number ofvaccinated

Number of vaccinated Incidence, total population Incidence, children <17 y.o. State report "On the state of sanitary and epidemiological welfare of the population in the Russian Federation in 2017" Incidence of hepatitis A in Tyva Republic before (2012) and after implementation of vaccination in children (2013 - 2016)

300 Coverage rate in children of 3 - 8 y.o. by 31.12.2012 : 87.4% 250 241.7

(about 40,000 children) population

200

,000 Total population There was a 43-fold decrease in the incidence of hepatitis A 100 Children < 14 among the entire population of 150 the Republic and a 75-fold decrease among children in 2014 97.4 compared to 2012 (before 100 vaccination).

50

7.5 Hepatitis A incidence, incidence, A Hepatitis per 3.2 2.3 3.2 0.6 1 0 0 0 0 0 2012 2013 2014 2015 2016 2017 Hepatitis A outbreak in USA in 2017-2018 (lesson for the world and the Russian Federation) •As of October 1, 2018, the US Centers for Disease Control and Prevention (CDC) reports on increase in hepatitis A incidence since August 2018 in the states of Kentucky and West Virginia among homeless and drug users. •About 50 new cases each week. On September 28, 2018 total 1851 cases were registered in Kentucky and 1,395 cases in West Virginia. In addition, the increase in incidence was registered in the states of California (San Diego), Utah, Colorado and Wyoming.

• Despite vaccination against hepatitis A in the US, the risk of outbreaks remains; • Homeless and drug users are at increased risk of HAV infection; • The analysis of hepatitis A outbreaks in the suggests the possibility of such situations in the Russian Federation, which determines the need for universal (mass) vaccination against hepatitis A among the population of the Russian Federation and especially in risk groups, including homeless; • Interdisciplinary research is needed to study the spread of hepatitis A in various population groups. Mikhail Surenovich Balayan 12 August 1981: oral selfinfection with a combined extract containing stool samples from 9 patients with a second episode of hepatitis Hepatitis E incidence in Russia Notifiable disease in RF since 2013

2017 158 0.11 0/0000 in RF 0.26 0/0000 in CFO 2016 113

2015 96

2014 110

2013 92

0 20 40 60 80 100 120 140 160 180

Hepatitis E, number of cases Hepatitis E incidence, per 100,000 per E incidence, Hepatitis RF CFO NWFO SFO NCFO PFO UFO SFO FEFO 2015 2016 2017 Incidence rates of hepatitis A and hepatitis E in Belgorod region in 2010-2017

7

5.9 hepatitis A hepatitis E 6 5.2 5 4.3 3.94

4 ,000 ,000 population 3 3 2.5 2.2 2.2 2 1.8 1.3 1.1 1 0.6 0.7 0.4 0.52

Incidence, 100 perIncidence, 0.2 0 2010 2011 2012 2013 2014 2015 2016 2017 Anti-HEV IgG prevalence in general population in Russian Federation

30 28.2 < 20 20-60 > 60 25.3 25

, % , 20 IgG 15.5

15

HEV HEV -

11.3 Anti 10 8.3 7.5 8.1 5.7 4,4 5 3.6 3.8 1.6 1.9 2.3 0.6 0.4 1 0.8 0 Moscow region Rostov region Sverdlovsk region Yakutia Tyva Khabarovsk region

n = ca. 6000 persons Sources and routes of transmission of hepatitis E Hepatitis E outbreak in Kovrov (Vladimir region) in 2009

Branches highlighted in red have confidence >90% 4173ekat.1 4357ekat.3 4172ekat.1 4352ekat.3 4178ekat.1 HEV prevalence in pigs 4198ekat.2 4199ekat.2 4156ekat.1 100 4191ekat.1 4410sar.1 100 4591sar.3 4196ekat.2 78 4194ekat.2 90 97 5512arch.3 5525arch.3 100 5435arch.3 5320arch.1 80 5353arch.2 100 5376arch.2 70 100 5354arch.2 98 5374arch.2 60.5% 4192ekat.2 60 100 4131ekat.1 91 4313ekat.3 AF455784 H.3g 4952khab.3 50 AF336296 3f AY323506 3f 98 AF332620 3f 40

AY032758 3f HEVRNA, % 100 AY032757 3f 28.4% 98 AY362357 H.3e 30 AF503512 3e 20.4% AB094231 3e AB073911 3e 100 20 4835khab.1 12.8% 12.9% 4892khab.1 8.8% 5107kalin.1 10 5151kalin.2 100 5109kalin.1 5130kalin.2 3990vlad 0 98 3950vlad Vladimir Sverdlovsk Saratov region Kaliningrad Khabarovsk 3951vlad 100 3968vlad region region region region region 3974vlad 3973vlad 87 3948vlad AB105903 S.3a AP003430 H.3b AF296167 H.3d Age-specific HEV RNA prevalence in pigs 100 AY115488 S.3j 80% 80 4586sar.2 100 4631sar.3 69,5% 87 4610sar.3 4677sar.3 70% 95 4539sar.2 4863khab.1 100 4502sar.2 60% 4579sar.2 50,0% 100 FJ998010 3i FJ998012 3i 50% AF336293 3c AF336290 S.3c AF336298 3c 40% 100 AF336297 3c AB097811 Japan HEV type IV M74506 HEV2 Mexico 30%

100 DQ450072 HEV type IV HEVRNA, % AY723745 India HEV type IV 18,0% AY594199 China HEV type IV 20% 15,8% 76 M73218 Burma H. E virus type I 90 D10330 Burma HEVNE8L type I 98 AF051830 Nepal HEV TK15/92 type I 10% X99441 India HEV type I X98292 India hev037 type I 0,0% 0,0% 100 M80581 Pakistan HEV type I 0% D11093 China HEV type I 100 88 L25547 China HEV type I M94177 China HEV type I 1 2 3 4 5 >5

0.10 0.08 0.06 0.04 0.02 0.00 Age, months Phylogenetic tree for HEV sequences isolated in Belgorod region from pigs, patients and the sewage from pig farms

Sequences from sewage are indicated in red, sequences from patients in green, sequences from swine in blue. Branches highlighted in red have confidence >90% Stable circulation of a single HEV strain in the pig farm in 2012-2016 Case of hepatitis E caused by HEV GT4 in patient who traveled to Corsica

The patient F (23 years old), lived and worked in Moscow. From June to August 2012, he periodically lived in Corsica (10-14 days a month), where the family rented a house for the summer by the sea. Moscow He ate a variety of food, including tasting meat products (smoked and blood sausages) in various private village shops. He ate not only homemade food, but also in small restaurants, ate poorly roasted meat, seafood, including oysters, sushi and rolls. Drank mostly bottled water. Until June 2012, did not leave Moscow for a year.

No operations, donation, parenteral Corsica manipulations in anamnesis, did not visit the dentist for more than 6 months. Had no contact with feverish, icteric patients. All family members were healthy. HEV GT4 detection in humans HEV GT4 detection in pigs Importation of HEV GT 4 in cynomolgus monkeys (Macaca fascicularis) from Vietnam

Total 79 cynomolgus monkeys were imported to Adler primate research center from Vietnam in 2017. Anti-HEV IgM: 43.2%; anti-HEV IgG: 56.8% animals. HEV RNA in feces had 7 (8.9%) animals. State sanitary and epidemiological surveillance of hepatitis E in the Russian Federation (the period of formation)

• The purpose of surveillance: assessment of the epidemiological situation and trends in the epidemic process and the timely adoption of effective management decisions with the development and implementation of adequate sanitary and anti-epidemic (preventive) measures to prevent the occurrence and spread of HEV.

Distinctive features of the sanitary and epidemiological surveillance of hepatitis E, compared to hepatitis A, are :

• Low public awareness of the significance and the threat of hepatitis E; • Lack of vaccine against this infection; • Interventions for disruption of HEV transmission routes associated with infected pigs as the main source of the virus. Thank you for your attention