Case finding for HBV in the UK

1. Case finding for HBV in the UK Stuart McPherson Consultant Hepatologist Liver Unit, Freeman Hospital, Newcastle upon Tyne and Institute of Cellular Medicine, Newcastle University.

2. 350 million HBV-infected individuals worldwide 15-40% will develop serious complications related to cHBV Worldwide there are an estimated 620,000 deaths HBV-related deaths/year 50-55% of all liver HCCs in Europe are due to HBV Prevalence varies significantly across the world Overall the UK is a low prevalence area (~0.3% of population HBsAg pos) Background Cooke, BMJ 2010; Lok, Hepatology 2009; DOH 2002

3. Geographic Distribution of Chronic HBV Infection UK 0.3% HBsAg Prevalence (%)  8: High 2-7: Intermediate <2: Low Centers for Disease Control. Dec 23 2005/Vol 54/No RR-16. Web site: Available at http://www.cdc.gov/nip/vacsafe/concerns/hepB/genHepb.htm. CHMP Guidelines on the Clinical Evaluation of Medicinal Products Intended for Treatment of Chronic Hepatitis B. Feb 2006.

4. HBV can be treated and prevented • Several effective treatment for HBV • Tenofovir • Entecavir • PEG-IFN • Treatment have been shown to: • Reduce hepatic inflammation and reverse fibrosis • prevent progression to cirrhosis • reduce risk of HCC • Reduce liver related mortality in those with advanced disease • There is a highly effective vaccine for HBV Lok Hepatology 2009; Liaw NEJM 2004; Zhang Virol J 2011

5. Effective treatment of HBV in the “real world” - Tenofovir 302 NA-naive patients with median baseline viraemia of 5.9 log IU/mL (1.6–>9). Baseline characteristics (n=302 naïve patients) • Median age: 55 (19–80) years • Cirrhosis: 35% • Concomitant diseases: 43% • HBeAg(-)ve: 80% HBeAg(-)ve HBeAg(+)ve 100 100 93% 92% 92% 89% 85% 80 75% 80 71% 71% 70% 69% 60 57% 60 Patients % Patients % 40 40 26% 20 20 0 0 21 18 9 12 15 6 21 9 12 15 18 6 Months Months Patients on f-up Patients on f-up 53 51 51 43 28 34 211 205 194 166 116 143 Lampertico P, et al. EASL 2011. Poster 731.

6. Effective treatment of HBV in the “real world” - Entecavir HBeAg(-)ve HBeAg(+)ve Baseline characteristics (n=418): 100% 96% 100 95% 100 86% 93% 90% 82% • Median age (range): 58 (18–82) • Cirrhosis: 49% • Concomitant diseases: 56% • HBeAg(–)ve: 83.1% 73% 80 80 65% 60 60 Patients % Patients % 37% 40 40 20 20 0% 0% 0 0 30 24 6 12 18 Baseline 30 24 6 12 18 Baseline Months Months Patients on f-up 71 67 62 51 21 35 Patients on f-up 347 332 315 283 137 220 Adapted from Lampertico P, et al. AASLD 2010. Abstract 391.

7. sAg seroconversion with treatment HBsAg-seroconversion in HBeAg neg 25 18% 20 15 Percentage of patients (%) 10 3% 2% 5 0% 0 B n=43 C n=63 D n=55 A n=11 Hadziyannis, 2005

8. Rationale for the promotion of case-finding for viral hepatitis • Surveys by the ELPA suggest that up to 90% of HBV infected individuals in the EU are unaware of their condition • In the UK the majority of HBV is imported from endemic areas, so at risk groups could be targeted • There is no universal screening or vaccination program for HBV in the UK • The ELPA has called for targeted screening or case finding in risk groups for viral hepatitis to facilitate early diagnosis and if appropriate treatment • In the US the CDC and AASLD recommend screening for all subjects born in Countries with HBsAg prevalence of >2% Piorkowsky N. J Hepatol 2009: 51; 1068-1073

9. • Persons with elevated liver enzymes and/or clinical sign of hepatitis • Patients with liver cirrhosis or fibrosis • Patients with hepatocellular carcinoma • People who share or have ever shared needles (injecting drug users) • People with long-term imprisonment history • People who are undergoing or have undertaken hemodialysis • Men who have sex with men or heterosexual persons with multiple sex partners • People with HIV or HCV infection • Families and household members or sexual partners of persons infected with HBV • Pregnant women and newborns of HBV-infected mothers • Patients before or during immunosuppressive treatment or chemotherapy • Migrants from countries with high prevalence of Hepatitis B • Unvaccinated healthcare workers and public safety workers who undertake exposure-prone procedures. High risk groups for Hepatitis B Piorkowsky N. J Hepatol 2009: 51; 1068-1073

10. NICEHepatitis B and C: ways to promote and offer testingKey Questions • Which interventions are effective and cost effective in encouraging people from high-risk groups to use services that currently (or potentially could) offer hepatitis B or C testing? • What prevents people in high-risk groups from seeking and accepting a hepatitis B or hepatitis C test? How do these factors differ for each group – and what factors increase the likelihood that they will seek and accept a test? • Which interventions are effective and cost effective at overcoming the barriers to hepatitis B or C testing faced by high-risk groups and professionals? • What type of services and activities need to be commissioned to encourage people who have tested positive to continue to seek support?

11. Geographic Distribution of Chronic HBV Infection HBsAg Prevalence (%)  8: High 2-7: Intermediate <2: Low Centers for Disease Control. Dec 23 2005/Vol 54/No RR-16. Web site: Available at http://www.cdc.gov/nip/vacsafe/concerns/hepB/genHepb.htm. CHMP Guidelines on the Clinical Evaluation of Medicinal Products Intended for Treatment of Chronic Hepatitis B. Feb 2006.

12. Chinese Hepatitis Awareness, Surveillance and Education – B • The British-Chinese community is the largest in Europe and the fastest growing non-European ethnic group in the UK. • It is estimated that in 2007 there were 430,000 British-Chinese people in the UK. • Case finding was undertaken in collaboration with the Newcastle Chinese Healthy Living Centre (NCHLC) based in Newcastle’s Chinatown. hase B Supported by Gilead Fellowship 2010

13. CHASE-B - “Awareness-raising among at-risk groups” hase B Supported by Gilead Fellowship 2010

14. CHASE-B- “Education among at-risk groups” hase B Supported by Gilead Fellowship 2010

15. CHASE-B – testing for HBV Dried blood spot testing hase B Supported by Gilead Fellowship 2010

16. CHASE-B – “reducing the barriers to hepatitis B testing” hase B Supported by Gilead Fellowship 2010

17. CHASE-B – “reducing the barriers to hepatitis B testing” hase B Supported by Gilead Fellowship 2010

18. CHASE-B methods • Case finding undertaken at 4 sites in the NE of England • Newcastle Chinese healthy living centre • True Jesus Church in Newcastle • True Jesus Church in Sunderland • Tees Valley Chinese centre in Middlesbrough • Testing session advertised in the local Chinese press and at testing locations • A presentation in English and Chinese at each session • All attendees were given written information in English and Chinese and those wanting to be tested had dry blood spot testing for HBV • Result of the test was communicated to the subjects in English and Chinese • GPs were advised of subjects with positive HBsAg tests and repeat testing was recommended • Specialist referral was recommended for all confirmed HBsAg pos tests Supported by Gilead Fellowship 2010

19. CHASE-B – results of case finding • 606 subjects were screened in 11 sessions at the 4 sites. • Mean age was 49 ± 17 years (range 16-94) • 61% were female. • 53 subjects (8.7%) were HBsAg positive (48% female) indicating chronic HBV • 10 reported being previously diagnosed with HBV, but were not under follow up. • When previously diagnosed individuals were excluded the prevalence of HBsAg positivity was 7.2%. Country of birth of screened subjects Supported by Gilead Fellowship 2010

20. CHASE-B – results of case finding Prevalence of HBV infection by country of birth Prevalence of past HBV infection by country of birth 80 (14%) subjects were HBsAg –ve & HBcAb +ve indicating past HBV infection. Supported by Gilead Fellowship 2010

21. CHASE-B – results of case finding • Only 12% of subjects reported previous vaccination against HBV. • 31 HBsAg pos subjects have been reviewed in the NUTH viral hepatitis clinic • 1 eAg pos and 30 eAg neg CHB • 3 (10%) had active eAg neg CHB (bloods +biopsy) • 1 immunotolerant eAg pos • 20 inactive CHB (ALT<40 and HBV DNA <2000 and LSM <8KPa) • 7 currently indeterminate activity (ALT > 40 and DNA <2000 or ALT<40 and DNA >2000) • No cases of HCV, HIV or delta co-infection • One incidental RCC on ultrasound – had nephrectomy

22. CHASE-B conclusions • Undiagnosed chronic HBV is highly prevalent in British-Chinese in NE England, including subjects born in the UK. • If the our results were applied to the entire UK British-Chinese population targeted case finding should lead to approximately 32,250 newly diagnosed cases of chronic HBV • The frequency of previous HBV vaccination was low in this high risk group. Supported by Gilead Fellowship 2010

23. Case finding in migrants from countries with intermediate prevalence of HBV • The UK’s South Asian population is the largest minority ethnic group at approximately 4% of the total population (2.3 million). The term ‘south Asian’ refers to anyone of Indian, Bangladeshi, Pakistani or Sri Lankan origin. • Within the British Asian community, the largest ethnic minority is people of Indian descent (1.8%), followed by those of Pakistani origin (1.3%). • It is estimated that there are approximately 50 million people affected with chronic HBV in India and 7-9 million in Pakistan, whilst the prevalence of HBsAg in Bangladesh has been reported to be 5.5%. Datta S. Virology journal. 2008;5:156. Ali M et al. Virology journal. 2011;8:102. Mahtab MA et al. Hepatobiliary Pancreat Dis Int. 2008;7:595.

24. SHADE-B – case finding in the British South Asian community • Conducted Case finding in South Asian Community of the NE of England • 7 sessions at Mosques in Newcastle, Sunderland and Middlesbrough and Bangladeshi community centre in Sunderland • Dry blood spot testing for HBsAg, anti-HBcAb and HCV Ab • Otherwise methods similar to CHASE-B study Supported by Gilead Fellowship 2010

25. SHADE-B results • 520 subjects screened in 7 sessions to date at 4 locations in NE of England • Mean age 43 ± 16 years (range 6-83) • 76% males • 9 subjects (1.7%) were HBsAg pos • 9 subjects had evidence of past HBV (HBcAb pos and HBsAg neg) • 4 subjects (0.8%) were HCV Ab pos

26. SHADE-B results Serological evidence of past infection by country of birth HBsAg prevalence by country of birth

27. SHADE-B Other results • All 4 HCV Ab pos subjects were from Pakistan • 1.8% prevalence in the Pakistani community • 1 Patient previous HCV with SVR following treatment • 3 HCV G3 – undergoing workup for treatment • Only 5% reported vaccination against HBV

28. SHADE-B conclusions • Undiagnosed cHBV is prevalent in the Pakistani community of NE England, although the prevalence was lower than in the local British-Chinese community. • The prevalence of cHBV in subjects born in Pakistan was above the 2% threshold for screening suggested by the AASLD and ELPA, which provides evidence for targeted case finding in this population.

29. Other studies from the UK in South Asian population • A total of 4998 people attending community centres were screened for viral hepatitis using oral fluid testing. • London, Birmingham and Bradford • For chronic HBV infection, the prevalence was similar in migrants from Pakistan and Bangladesh, where the prevalence was in line with WHO estimates, but the prevalence was lower in people from India. J Viral Hep. 2010;17:327

30. Cost effectiveness of case finding or screening • No clinical trials of screening for HBV or HCV • One recent study that used Markov modelling showed that • Screening and treatment with Lamivudine or PEG-IFN is cost effective at HBV prevalence of only 0.3% • If high cost low resistance drugs are used screening is cost effective at recommended level of screening of >2% ($43000 per QALY) • NICE economic evaluation • A ‘one-off’ HCV case finding intervention in prevalence areas of 2% or more, that achieves levels of testing of at least 17.5%, is likely to be cost effective at a willingness to pay for an additional QALY of £20,000 if it costs between £50-75 per person invited for a test. • The base case ICER for HBV case finding was estimated to be approximately £21,000 when similar assumptions were made (intervention effect of 17.5%, £20 per person invited for a test and a 2% prevalence level). • Uptake of “screening” in populations • A study in New Zealand found uptake of 27% to targeted Radio advertisements and opportunistic letters and phone calls from primary care • UK colorectal cancer screening uptake is 50-55% (only 20-30% in South Asian Ethnic minorities) Robinson NZ Med J 2005, Whynes D Public Health 2003; Miners NICE 2012

31. Vaccination • No universal vaccination program in the UK • Taiwan started a Nationwide universal vaccination program in 1984 • All infants given vaccinations at birth and those born to HBeAg pos mothers also had HBIG • There coverage >96% to 3 dose program • Reduction of HBsAg prevalence from 10% pre-vaccination to 0.9% post vaccination • The majority (86%) of subjects who were HBsAg pos despite vaccination are believed to have acquired it in utero • Reduction in incidence of paediatric HCC Yen-Hsuan N el al. J Hepatol 2012

32. Conclusions • Finger prick dry blood spot testing in community settings is an effective method for targeted case finding for blood borne viruses. • Undiagnosed cHBV was prevalent in the British Chinese and Pakistani communities of the NE of England • These results provide evidence for a targeted case finding or screening program in those populations • The optimum method of screening or case finding remains to be determined

33. HPA Dr Manoj Valappil Dr Samuel Moses Gary Eltringham Freeman Hospital Dr Mark Hudson Prof Maggie Bassendine Carolyn Miller Kerry Baxter Sunderland Dr Kamran Shafiq Gateshead Dr Athar Saaed NCHLC Amanda Chan Annie Ho Gilead LIVErNORTH NCHLC Acknowledgments