10/12/2018 Disclosures Research: Abbvie, Gilead, Janssen, Merck, - - PDF document

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10/12/2018 1

Viral hepatitis in migrants?

Jordan J. Feld MD MPH

Toronto Centre for Liver Disease Sandra Rotman Centre for Global Health University of Toronto

Disclosures

• Research: Abbvie, Gilead, Janssen, Merck, Wako
• Speaking: None

Outline

• Scope of the problem

– HBV & HCV by the numbers – HBV & HCV – commonalities and differences

• Situation in migrants

– To screen or not to screen

• When, where and how?
• Screening tools
• Beyond screening

– Linkage to care & treatment

Should the “Big 3” be the “Big 4”?

Deaths (millions) in 2015

Viral hepatitis HIV/AIDS Tuberculosis Malaria 0.5 1 1.5 1.34 1.06 1.37 0.44

HCV (30%) HBV (66%) A & E (4%)

WHO Global Hepatitis Report, 2017.

HCV is a MAJOR global public health problem

‐ ~71 million people infected ‐ No vaccine ‐ Leading indication for liver transplant

WHO

HBV: Some sobering facts

• 250 Million people chronically infected
• 2 billion with evidence of “past” infection
• 600,000-1 million deaths annually (same as malaria!)

Toronto

WHO

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Health Adjusted Life Years (HALYs) 2000 4000 6000 8000 1000 Years of Life Lost Year-equivalents of reduced functioning

Kwong PLoS One 2012

Hepatitis is a MAJOR health problem in Canada

Human papilloma virus

• E. Coli

HIV/AIDS Staphylococcus aureus

• C. Dificile

Rhinovirus Group B Strep Group A Strep Legionella Chlamydia Adenovirus Gonorrhea Tuberculosis Influenza Hepatitis B virus Hepatitis C virus Parainfluenza virus Streptococcal pneumonia Haemophilus influenza Respiratory syncytial virus

0% 20% 40% 60% 80% 100% IFN IFN IFN/R IFN/R PegIFN PegIFN/R Sustained Virological Response

• ie. Cure

16% 55% 6% 34% 42% 39%

6 mo 12 mo 6 mo 12 mo 12 mo

1991 1995 1998 2002 2001

Ribavirin Peginterferon Standard Interferon

6-12 mo

75% 2011

PR + PI

PR/PI 12 mo 3 mo

90% 2013

PR + NI

PR/SOF 3 mo

95-99% 2014

DAAs

DAAs

Dramatic improvement in HCV therapy

Trend in 3rd dose of vaccine coverage in infants global coverage

Africa SE Asia Americas Eastern Mediterranean

• Increasing but plateauing global coverage  79% in 2012 and 82% in 2014
• Only 38% coverage of birth‐dose (reduces risk by 8‐fold)

WHO,

The first cancer vaccine – highly effective!

HBsAg Positivity (%) 1984 No vaccine 1989 Vaccine<5 yo 1994 1999 2004 Age (years) Africa SE Asia Americas Western Pacific Eastern Mediterranean European Global coverage 79% in 2012 Ni Gastro 2007, WHO 2017

WHO takes the lead

Vision: “A world where viral hepatitis transmission is halted and everyone living with viral hepatitis has access to safe, affordable and effective prevention, care and treatment services” WHO Global Health Sector Strategy 2016‐2021

• Eliminate viral hepatitis as a public health problem
• Although called ‘Elimination’ – given the targets…maybe this is really ‘Control’
• Whatever we call it ‐ very ambitious!

WHO Elimination Targets

WHO

WHO Elimination Targets

WHO

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Treatment uptake more important than cure rate

SVR in individuals SVR in the population

Thomas Nat Medicine 2010

Improved therapy of no benefit unless treatment rates increase

• Curing the individual is now easy
• Curing the population will take a lot more work…

The cascade of care…not just treatment

Yehia PLoS One 2014

But won’t this all get better with IFN-free therapy?

Diagnosis Access Treated SVR

Modeled data for non-VA US population

An elimination strategy

Anti‐HCV Positive N=715 RNA Tested N=488 RNA Positive N=388 Initiated Treatment N=223 Completed Treatment N=201 Achieved SVR N=180

68% 80% 57% 90% 90%

(46% RNA+)

Percentage Reminder in EPR  92,012 visits  16,772 (18%) tested  715 Ab + (4.2%)

Even with effective treatment, major gaps in cascade of care!

Mera MMWR 2016 DAAs only help here

Left side of the cascade actually more important

Why are treatment rates so low?

Patients

• Unaware of infection  feel perfectly well until advanced disease
• May have little interaction with the healthcare system
• Screening and active case finding required

Doctors

• Poor awareness – late diagnosis and referral
• Treatment capacity – few hepatologists, GIs, IDs

– PCPs/addiction medicine…just starting to enter the field – Outdated models of care – based on the interferon days

• Treatment access often limited – fibrosis stage, specialists
• Improved access, increased provider base and new models of

care required

What about HBV?

Tenofovir vs Tenofvir/emtricitabine in LAM‐R HBV

Long‐term therapy with potent oral nucleos(t)ide analogues leads to suppression in almost all patients (even after resistance)

Chang Hepatology 2010, Fung J Hep 2017

Long‐term entecavir in eAg +ve HBV

% suppressed HBV DNA % suppressed HBV DNA

Highly effective therapy

• Current therapy taken long-term

– Suppresses HBV DNA – Normalizes ALT – Prevents fibrosis progression – Promotes fibrosis regression – even in cirrhosis – Prevents and even reverses hepatic decompensation – Reduces, but does not eliminate, the risk of HCC

Lim Gastro 2014, Papaetheodoridis J Hep 2015, Zoutendijk Gut 2013, Marcelllin Lancet 2013, Chang Hepatology 2010

Highly effective BUT not curative

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HBsAg loss is the real goal of therapy

7% 1.1% 1.7% ~1% 3% 1%

0% 10% 20% 30%

PegIFN Lamivudine Adefovir Entecavir Tenofovir Placebo HBsAg Loss after 1 year of therapy

Implication: Once you start…usually very long-term therapy!

Summary data from multiple trials – not head‐to‐head

HBV ≠ HCV: Some key differences

• Transmission

– HBV: At birth, (sexual)

• HCV: Throughout life – medical, IDU
• Epidemiology

– Some overlap but some key differences – HBV: Asia, SS Africa

• HCV: S. Asia, Egypt, Eastern Europe
• Natural History

– HBV: Dynamic, unpredictable

• HCV: Slowly progressive
• Treatment

– HBV: Complicated decisions, long-term/indefinite  specialty care – HCV: Simple, finite, curative  primary care

Outline

• Scope of the problem

– HBV & HCV by the numbers – HBV & HCV – commonalities and differences

• Situation in migrants

– To screen or not to screen

• When, where and how?
• Screening tools
• Beyond screening

– linkage to care & treatment

Benefits of screening for viral hepatitis

Individual

• Access to treatment – prevent complications of

the disease

• Prevent additional harms to health – alcohol,
• besity (even if no treatment)
• Vaccination for HBV – personal & contacts

Societal

• Harm reduction – reduce transmission
• Assess burden in the population – plan for the

future

Potential ‘harms’ of screening

Individual

• Diagnosis in asymptomatic individuals

– Give a well person a ‘disease’ – Potentially stigmatizing – may affect employment, immigration

• Potentially ‘harmful’ unless

– Linkage to care – minimum – information, harm reduction – Access to treatment – this is really the key

• Very frustrating to be told:
• ‘No treatment available’, ‘No doctors available’ or ‘You’re not sick enough

for treatment’ or ‘No treatment for you unless you stop using drugs/EtOH’

Societal

• Cost of screening
• Cost of treatment  cost effective is not cost saving – huge

budget impact…opportunity cost!

Screening Approaches

 Risk-based

 Identify and test only those with

risk factors

 Pros:

 High yield  Cheaper

 Cons:

 Contact with HC system  Must know & discuss risk factors  Test may be stigmatized  Miss those without RFs

 Population-based

 Test a segment of the population

• eg. baby boomers, newcomers

 Pros:

 High coverage rate  Easy to implement

 Cons:

 Need to choose the population  Low yield, expensive  May be stigmatizing to population –

• eg. migrants

Not mutually exclusive

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Should migrants be screened?

• Probably – in most settings
• But need data to determine optimal approach

– All migrants or only certain countries? – All migrants or only certain types e.g. refugees vs immigrants vs other? – Part of population-based screening or separate program? – Where, when and how should migrants be screened?

Collecting the data…

• Rarely available for given migrant population in a particular country
• Estimate:

Migrant population (census) x prevalence in country of origin – Caveats: Undocumented migrants missed Quality of country-specific prevalence data variable HCV antibody vs HCV RNA HBsAg vs anti-HBc (exposure)

Migrants: Multiple studies…multiple meta-analyses

Increase with age Higher in refugees Greenaway PLoS One 2015

Not always as ‘expected’

20 15 10 5 Percent

Poland

12

Somalia Pakistan

2.9 1.5 0.7 2.4 0.8

India

2.3‐6.3 0.8 Prevalence home country Prevalence in migrants

• Lower prevalence than expected…common pattern in Sub‐Saharan Africa and South Asia
• Led authors to question whether screening should be done based on ‘country

prevalence’…difficult question Prenatal HBV screening in 5,840 migrant women in Bristol, UK Cochrane J Clin Virol 2015

Prevalence in migrants vs home country

HCV HBV

Lower in migrants from high endemic countries Egypt, Pakistan Likely a ‘healthy’ migrant effect – mostly younger! Lower in migrants from many countries – South Asia, Africa Likely a ‘healthy’ migrant effect – vaccine effect Ahmad BMC ID 2018, Falla BMC ID 2018, Crawshaw BMC Med 2018

Does the type of migrant matter?

Region HBV Prevalence Overall Immigrants 5.1% Refugees 9.6% East Asia Immigrants 8.6% Refugees 13.2% Sub‐Saharan Africa Immigrants 9.9 % Refugees 10.5 % Eastern Europe/ Central Asia Immigrants 5.9 % Refugees 5.9 % South Asia Immigrants 2.4% Refugees 6.5% Americas/Middle East Immigrants 1.4% Refugees 2.6‐3.0% Rossi PLoS One 2012 Less relevant SS Africa & Eastern Eur/Central Asia Most relevant S. Asia (poor vaccine coverage) (vaccine coverage varies)

On balance refugees greater burden ‐ more true for HBV than HCV…but variable

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Situation worst for undocumented

Wendland BMC Public Health 2016 100 80 60 40 20 Percent tested 60

HIV

58 43

HBV Syphilis

Prenatal testing in Denmark 100 80 60 40 20 Percent tested >99

HIV

>99 >99

HBV Syphilis

• Standardized prevalence ratio 2.4 (1.1-5.3) for HBV
• Major issues with access even beyond testing for undocumented

Undocumented migrants (n=219) General population – including documented migrants

Should migrants be ‘targeted’ for testing?

Estimated relative contribution of migrants to total HCV cases High HCV prevalence Few migrants Low HCV prevalence Many migrants/low pop’n Variable foreign‐born, but most from HCV endemic country Proportion of foreign‐born (blue), from HCV endemic (green)

• Where migrants account for a high % of HCV  screen migrants (France, Germany, Netherlands, UK)
• In countries with high baseline prevalence  screen everyone (e.g. Bulgaria, Poland, Romania)

Screen migrants Screen everyone Falla BMC ID 2018

Same question for HBV?

Estimated relative contribution of migrants to total HCV cases High HBV prevalence Few migrants Low HBV prevalence Many migrants/low pop’n Variable foreign‐born, but most from HBV endemic country Proportion of foreign‐born (blue), from HBV endemic (green) Screen migrants Screen everyone Ahmad BMC ID 2018

• Similar conclusions – screen migrants vs whole population but…easier to target
• Migrants account for 25% of HBV in Europe ‐ ~50% from 10 counties

Is testing being done when recommended?

From high prevalence (>2%) 5 10 15 20 Tested + M F 5 12 11 3 N=82,561 N=410,897 From low prevalence (<2%) 9 Tested + 0.29 9 Tested + 0.53 From unknown country N=194,025 Percent HBV screening uptake & yield in UK according to NICE guidelines (>2%) Low awareness of guidelines, concerns about cost & workload by GPs Evlampidou Br J Gen Practice 2016

Where do you get these data?

HEPscreen – a very useful resource (for Europe)

Data by country + information for providers, policy‐makers and affected population

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And in North America?

High burden of HBV in migrants to US Leads to estimates of much higher HBV prevalence Kowdley Hepatology 2012, Greenaway PLoS One 2015

• CDC increasing efforts to improve surveillance
• Efforts underway to collect more robust data

Outline

• Scope of the problem

– HBV & HCV by the numbers – HBV & HCV – commonalities and differences

• Situation in migrants

– To screen or not to screen

• When, where and how?
• Screening tools
• Beyond screening

– Linkage to care & treatment

What happens after a diagnosis is made?

Mera MMWR 2016

Linkage to care is critical!

Anti‐HCV Positive N=715 RNA Tested N=488 RNA Positive N=388 Initiated Treatment N=223 Completed Treatment N=201 Achieved SVR N=180

68% 80% 57% 90% 90%

(46% RNA+)

Percentage Biggest ‘drops’

• 1. HCV RNA
• 2. First Visit

Diagnosis needs simplification

Step 1 See the doctor Step 2 To the lab for HCV Ab Step 3 See the doctor for result Step 4 To the lab for HCV RNA Step 5 See the doctor for result Step 6 Start DAA therapy (may be additional steps: fibrosis assessment, approvals etc) Loss to F/U Loss to F/U Loss to F/U Loss to F/U Loss to F/U

Lots of places to ‘get lost’…particularly if HCV not a priority

Reflex HCV RNA testing

95

20 40 60 80 100 120

MAY JUN JUL AUG SEP OCT NOV DEC JAN FEB MAR APR MAY JUN JUL AUG SEP OCT NOV DEC JAN FEB MAR APR MAY JUN JUL AUG SEP OCT NOV DEC JAN FEB MAR APR MAY 2013 2014 2015 2016

Percent w/ 30d follow‐up among Ab+

RNA follow‐up testing within 30 days of Ab+ result LabCorp – continues requirement for second specimen 33 Total tested: Quest 415,000; LabCorps 319,000 J Ward – CDC – unpublished data Quest changes policy and tests all anti‐HCV+ specimens

Improving diagnostics

Dried Blood Spot Saliva or blood rapid antibody test Point‐of‐care PCR test

• Some improvements but variable quality (few WHO pre‐qualified)
• Very variable cost – sometimes more than therapy!
• Ideally – finger prick, treatment, finger prick…it can be that easy!

Grebely.Feld Exp Rev Mol Diag 2017

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Barriers to treatment: Restrictions

• Restrictions based on alcohol and/or drug use
• Restrictions based on fibrosis
• Restrictions based on coverage – major issue for migrants
• Restrictions based on provider type
• No evidence for any of this!

Barua Ann Int Med 2015

Access should be the only barrier…It does not get much easier

99 98 99 100 100 97 100 20 40 60 80 100 SVR12 (%)

618 624 206 210 117 118 104 104 116 116 34 35 41 41

Total 1a 1b 2 4 5 6 Genotype

SOF + Velpatasvir (NS5A) x 12 wks in G1, 2, 4, 5, 6 – Naïve/Experienced +/‐ cirrhosis

Feld NEJM 2015, Foster NEJM 2015 SVR12 (%) 100 80 60 40 97

191/ 197

91

73/ 80

G3: SOF/RBV x 24 vs SOF/VEL x 12

F0‐3 F4

1‐3 pills, once a day for 8 to 12 weeks  >95% cure all populations

No reason for HCV to be treated in specialty care!

Treatment equally or more effective by nurse or family doctor than specialist

Kattakhuzy Annals Int Med 2017 Randomized to receive care from primary care practitioner vs specialist

Nurse Practitioner Primary Care Physician Specialist Total

Improving linkage to care – get help!

Primary Care MDs Nurses Other care providers Harm reduction Project ECHO ‐ Linking PCPs to specialists ‐ Facilitates linkage to care ‐ Allows people to be treated by people and in settings they know & trust Arora NEJM 2011

The elephant in the room…cost!

$142,710 $104,723 $96,404 $87,632 $84,281 $76,757 $68,280 $65,616 $50,059 $47,972 $37,729 $33,800 $29,361 $5540 $9,906 $84 $78 $47 $0 $20,000 $40,000 $60,000 $80,000 $100,000 $120,000 $140,000 $160,000 Price of a 12‐week course in USD

• Even at high costs…still cost‐effective – especially with cirrhosis & PWID (prevention benefit)
• But high quality generics available (<$50 per course) – excellent experience with Buyers Clubs – SVR>90%

Andrew Hill, World Hepatitis Summit, Sao Paulo 2017

Linkage can work well

>50% clearance! But treatment suboptimal: ‐ 2/31 (6.5%) cirrhosis – DAAs & SVR ‐ 6 others ‘high risk of progression’ – treated IFN ‐ 12 others no treatment! 4% + Strengths: ‐ Testing well accepted ‐ Good f/u – 100% Ab+, RNA tested ‐ Multidisciplinary care – culture & language Sagnelli Ann Hepatol 2018 HCV screening offered to 2,032 immigrants to Southern Italy

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Have your ducks in order…before you start

• Key elements for successful screening & linkage for migrants
• Involve patients in design and delivery of care
• Screening – peer screeners
• Peer navigators
• Communication
• Language ‐ interpreter facilities
• Culture sensitivity – address & discuss stigma
• Confidentiality
• Avoid loss to follow‐up
• Ensure screening leads to diagnosis – e.g. HCV Ab followed by HCV RNA
• Strategies for linkage and treatment (ideally same place) before screening
• Assistance for access to therapy – navigating the bureaucracy

Make sure you’re ready….

Seedat Lancet ID 2018

Even more complicated for HBV…

5-30 years months-years

Infection

Immunotolerance Immune Clearance E Negative Chronic HBV (precore mutant) HBeAg+ HBeAg- HBeAb+

months-years

ALT HBV DNA

Treatment Treatment Treatment? Immunosuppression (Chemo/HIV/BMT) Treatment Dynamic disease…not everyone needs therapy…therapy may be long‐term/indefinite

Treatment challenges

HCV

• Access
• Simple diagnosis
• Everyone needs treatment
• Treatment is near 100% effective
• Minimal or no monitoring required

HBV

• Complicated serology
• Determining if and when to start

therapy

• And if and when to stop therapy
• Long-term monitoring
• Long-term coverage
• Liver cancer surveillance
• Drugs are well tolerated & generic

So, how are we doing?

CDA 2017: Polaris Observatory (http://centerforda.com/polaris/)

• On Track: Iceland, Qatar, Netherlands, Georgia, Australia, France, Germany, Japan, Egypt
• Getting to elimination will mean better addressing viral hepatitis in migrants

HCV Elimination Targets

Summary

• Viral hepatitis is a major global public health problem
• Migrants shoulder a disproportionate burden of disease

– Lack of access to prevention (vaccination) – Unsafe or no healthcare (HBV, HCV)

• Screening strategies need to be country-specific depending on the local

epidemiology and the migrant population (type & origin)

• Screening is just the beginning…linkage to care is critical
• For HCV  treatment can and should be delivered in primary care
• For HBV  a bit more complicated but can be done in primary care
• Need to address the entire cascade with a focus on migrants if we have a

hope of reaching WHO 2030 elimination targets