hev superinfection in chronic hepatitis b...

HEV superinfection in chronic hepatitis

B Patients

Jun Zhang

May 26, 2019

School of Public Health, Xiamen University

Source: R. Purcell 2008

Hepatitis E virus (HEV) is a leading cause of

acute viral hepatitis globally

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⚫ Every year, there are an estimated 20 million HEV infections

worldwide, leading to an estimated 3.3 million symptomatic

cases of hepatitis E, and 56,600 hepatitis E-related deaths,

7,000 still-births

The Global Outbreaks of HE

cases

deaths

1955-1956 ,New Delhi, India,97000 cases.

2004 ,Darfur, Sudan, 2621 cases, 45 deaths. 2014 ,Sudan, 712 cases, 3 deaths.

2013.6~2014.1 , Napak, Uganda, 656 cases，19deaths2007-2009, Kitgum , Uganda,10196 cases ,160 deaths.

1988-1989 Lower reaches of Shebelle River, Somalia , 11413 cases, 346 deaths.

1976-1977, Mandalay City, Burma, 20000 cases.

2014.4-, Morang District, Nepal, 7000 cases, 14 deaths1973-1974, Kathmandu Valley, Nepal, 10000 cases, 30 deaths were pregnant.

1955-1956 ,Kyrgyz Republic, Former USSR, 10812 cases.

1978-1982,Kashmir,India,

52000 cases, 1700 deaths.

1990-1991,Kanpur,India, 79091 cases, 48 deaths.

2012.08-2013.09, South Sudan, 12386 cases , 225 deaths. 1986-1988 Xinjiang, China, 119,280

cases, 707 deaths(414 pregnant).

In highly endemic area, big outbreak with thousands cases appears periodically.

2004 ,Chad, 1442cases, 46 deaths. 2016-2017, Chad, 1697cases,18 deaths

2017 ,Niger 3530 cases, 60 deaths.

2017 ,Nigeria 696 cases, 4 deaths.

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http://doctorswithoutborders.org/podcast/episode.cfm?id=4048&cat=podcast&ref=footer-features

Hakim et al, Liver International 2017

The Epidemic history of large HEV outbreak in India with > 1000 suspected cases since 1955

Global distribution by “Endemicity”

Source: CDC 2011

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Central Africa Republic2002:7152004-2005:4112018.9.10---：187（1）

Congo2006:341(13)

Ethiopia2014:367(13)

Sudan2004:2621(45)2010-2011:39(11)2014:712(3)South Sudan2012-2013: 12386(225)

2018.1.3---：198（2）

Chad2004:1442(46)2016-2017:1874 (23)

Uganda 2007-2009: 10356(160)2013-2014:656(19)

Kenya 2012:349(10)

Niger2017：2078 (39)

<1000

1000-5000

5000-10000

10000-15000

Notes：numbers in brackets represent the deaths; different colors represent different levels of epidemic situations

Nigeria 2017-2018：1651 (8)

*Namibia

2017.9.8---：5014（42）

Recent outbreaks of hepatitis e in Africa (updated to May.5, 2019)

分子疫苗学和分子诊断学国家重点实验室 (厦门大学)

➢ The incidence of hepatitis E is higher than hepatitis A in consecutive 7 years;

➢ The mortality of hepatitis E is higher than hepatitis A

Annual reported Hepatitis E and hepatitis A cases in China

Resource：http://www.nhc.gov.cn/zhuz/index.shtml，全国法定传染病疫情概况

http://www.nhfpc.gov.cn/zhuz/index.shtml

In China, recorded HE cases increased with the sales of HEV IgM diagnostic reagents.

Zhao, J Gastroenterol (2013) 48:159–168

HEV: lesson from India of Chronic Liver Disease patients

Kumar Acharya et al. J Hepatol 2007

The mortality in HEV super-infected decompensated chronic liver disease patients are higher than HEV non-infected

mortality = 30%

mortality = 70%


World journal of gastroenterology 2016; 22(47): 10388-97.


➢ HEV-CHB increase the incidence of hepatic failure

➢ HEV-CHB increase the mortality

Incidence of hepatic failure MortalityJia F et al. JMV 88:1003–1009 (2016); Zhang X et al. Hepatol Int (2010) 4:615–620Cheng S et al. World J Gastroenterol (2013) 19(35): 5904-5909Chen C et al. World J Gastroenterol (2016) 22(47): 10388-10397张国顺等，中华肝脏病杂志 2006

Previous studies of hepatitis E superinfection in CHB patients


The prognosis of CHB-HEV patients in China: a Meta-analysis

➢ Objects: Evaluate the prevalence and prognosis of hepatitis E virus (HEV)

superinfection in hospitalized patients with chronic hepatitis B (CHB)

➢ Literature Resources:

Pubmed, CNKI, and Wanfang; references of the relevant articles.

➢ Jan 2008- Mar 2019

➢ Index words:

English: hepatitis E, hepatitis E virus, HEV, hepatitis B, hepatitis B virus,

HBV, China, Chinese.

Chinese:戊肝，戊型肝炎，戊型肝炎病毒，戊肝病毒，乙肝，乙型肝炎，乙型肝炎病毒，乙肝病毒，



➢ Inclusion criteria⚫ Research population should be CHB patients: liver necrosis or

inflammation with disease course longer than 6 months caused byHBV infection.

⚫ The diagnosis of Hepatitis E: with symptom of acute hepatitis(ALThigher than 2.5 times of upper limitation of normal) , following anyone pathogenic indicator of HEV infection, including seroconversionof HEV IgM or IgG, 4 times rise of IgG antibody titers, or positiveresult of HEV-RNA.

⚫ Provide the original data of any outcome of the research, includingthe prevalence of CHB-HEV, the incidence of hepatic failure or themortality of CHB-HEV superinfection.



➢ Exclusion criteria⚫ The research population was superinfected with HIV;⚫ The research population had high risk of HIV infection(including men

who have sex with men(MSM), female sex works(FSWs) etc.);⚫ The research population was transplant patients.


➢ Article screeningdiagram




Proportion of hepatic failure，%(95%CI)

Fatality，%（95%CI)

CHB-HEV 34.7 (29.6, 40.1) 13.8(10.3, 17.8)

CHB 6.1 (3.7, 8.9) 1.5(0.3, 3.4)

CHB-HAV 16.3(10.9, 22.5) 0.9(0, 2.8)

Hepatitis E 6.8(4.3, 9.8) 1.8(0.6, 3.6)

➢ Main findings:



➢ Main findings: CHB patients with HEV superinfection have a higher likelihood of having hepatic failure which often leading to death

Control group OR of hepatic failure, %(95%CI) OR of death, %(95%CI)

Combined control group 5.6(4.5, 7.0) 6.1(4.4, 8.5)

CHB 10.9(6.8, 17.4) 8.5(4.0, 18.3)

CHB-HAV 3.8(2.4, 6.2) 14.4(4.8, 42.9)

Hepatitis E 5.1(3.8, 6.8) 4.4(3.0, 6.4)

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CHB-HEV重叠感染患者与不同对照组相比肝衰竭发生风险的Meta分析

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CHB-HEV重叠感染患者与不同对照组相比肝衰竭发生风险的Meta分析


⚫ One study reported that the rate of HEV superinfection in hospitalized CHB

patients was 13.6% (95% CI: 12.5~14.9)

⚫ The pooled incidence of hepatic failure in CHB-HEV superinfection patients was

34.7% (95% CI:29.6~40.1), which was 10.9 times (95%CI: 6.8~17.4) comparing

with CHB patients, 3.8 times (95% CI: 2.4~6.2) comparing with HAV superinfected

CHB patients.

⚫ The pooled mortality of CHB-HEV superinfection patients was 13.8%

(95%CI:10.3~17.8), which was 8.5 times (95%CI: 4.0~18.3) comparing with CHB

patients, 14.4 times (95%CI: 4.8~42.9) comparing with HAV superinfected CHB

patients.


➢ Conclusion:

1998

2003

2004-2006

2007-2009

2012

. HEV vaccine program initiated by NIDVD

• Pre-clinical study finished and IND submitted

• Ph1 & Ph2 CT

• Ph3 CT

• Launched in China

2017

2019

New Drug Certificate

GMP Certificate

CT in Bangladesh

CT in US

Hecolin® -- World's Only Vaccine against Hepatitis E

• The vaccine efficacy against clinical HE was 100.0%(72.1-100.0).

• Two doses vaccination is protective for at least 5 months, with the efficacy of

100.0%(9.1-100.0).

(Zhu et al., Lancet 2010)

Vaccine efficacy – 19 months follow-up, for registration

• Up to 4.5 years, the long-term efficacy against clinical HE was 93% (95%CI, 79-98)

• The vaccine efficacy remained highly for at least 4.5 yrs.

(Zhang et al., N Engl J Med 2015)Long-term efficacy – up to 4.5 yrs


• 309 HBsAg (+) and 5258 HBsAg (-) participants received three vaccine doses and donated their blood samples at month 7 according to the protocol (Immunogenicity Analysis Set).

• The safety and immunogenicity of Hecolin® for HBsAg (+) adults is very similar to that for the general population.

Hepatitis E vaccination in healthy HBsAg (+) adults

Wu T, et al. Human vaccines & immunotherapeutics 2013; 9(11): 2474-9.

ITEMS CONTENTS

Title of the Trial An Open, Pared Trial of Hecolin® in the Chronic Hepatitis B Patients on the Clinical Stability .

Design Open-label study (ClinicalTrials.gov ID: NCT02964910)

participants The chronic Hepatitis B patients and healthy adult aged over 30 years old

Vaccination

Two arms,

1. Experimental: the chronic Hepatitis B patients

• >30yr, receive three doses of Hecolin® at 0,1,6 month

2. Active Comparator: the healthy volunteer

• >18yr, receive three doses of Hecolin® at 0,1,6 month

Sample size 475

Collaborators: Shandong CDC, China

Clinical Trial in the Chronic Hepatitis B Patients

Clinical Trial in the Chronic Hepatitis B Patients


EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection:“Testing for antibodies against hepatitis A virus

(anti-HAV)should be performed, and patients with

negative anti-HAV

should be advised to be vaccinated against HAV.”

Centres for Disease Control andPrevention(US)“Persons who have chronic liver disease. Persons with chronic liver disease who have never had hepatitis A should be vaccinated, as they have a higher likelihood of having fulminant hepatitis A (i.e., rapid onset of liver failure, often leading to death). Persons who are either awaiting or have received liver transplants also should be vaccinated.”

EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection[J]. J Hepatol, 2017,67(2):370-398.

https://www.cdc.gov/hepatitis/hav/havfaq.htm

Recommendation: Hepatitis A vaccination


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CHB -Hong Kong CHB -US and Europe CHC -US and Europe CLD(CHB CHC) -Taiwan other CLD -US and Europe

Lee S. Hepatitis A vaccination in patients with chronic liver disease in Taiwan. Journal of viral hepatitis 2000; 7 Suppl 1: 19-21.Tsang SW, Sung JJ. Inactivated hepatitis A vaccine in Chinese patients with chronic hepatitis B infection. Aliment Pharmacol Ther 1999; 13(11): 1445-9.Keeffe EB, Iwarson S, McMahon BJ, et al. Safety and immunogenicity of hepatitis A vaccine in patients with chronic liver disease. Hepatology 1998; 27(3): 881-6.

Hepatitis A vaccine was well tolerated and induced asatisfactory immune response in patients with chronic hepatitis B, chronic hepatitis C, and miscellaneous CLD.

Hepatitis A vaccination in CLD patients


➢ 65 HBV-infected patients (30 carriers, 22 chronic hepatitis, 13 cirrhosis)

➢ Patients with chronic HBV infection were recruited from the Hepatitis Clinic at the

Prince of Wales Hospital between July 1997 and June 1998.

Hepatitis A vaccination in HBV-infected patients

Tsang SW, Sung JJ. Inactivated hepatitis A vaccine in Chinese patients with chronichepatitis B infection. Aliment Pharmacol Ther 1999; 13(11): 1445-9.


Summary

➢ Increasing evidences had indicated that CHB patients with HEV superinfection

have a higher likelihood of having hepatic failure which often leading to death;

➢ The high-quality, multiple-center, large size epidemiological study to disclose

the additional disease burden in CHB patient caused by HEV superinfection is

very limited;

➢ The guidance for CHB patients to prevent the HEV superinfection is missing;

➢ More studies are urgently needed to evaluated the safety and effectiveness of

hepatitis E vaccine on CHB patients of different clinical status.


Thank you

hev superinfection in chronic hepatitis b...

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