10/12/2018

1

Viral hepatitis in migrants?

Jordan J. Feld MD MPH

Toronto Centre for Liver DiseaseSandra 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”?D

eath

s (m

illio

ns)

in

201

5

Viral hepatitis HIV/AIDS Tuberculosis Malaria0

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

10/12/2018

2

Health Adjusted Life Years (HALYs)

0 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. ColiHIV/AIDS

Staphylococcus aureus

C. DificileRhinovirus

Group B Strep

Group A Strep

LegionellaChlamydia

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 VirologicalR

esponse 

ie. C

ure

16%

55%

6%

34%42% 39%

6 mo 12 mo 6 mo 12 mo 12 mo

19911995

1998

20022001

Ribavirin

Peginterferon

Standard Interferon

6-12 mo

75%

2011PR + PI

PR/PI12 mo 3 mo

90%2013

PR + NI

PR/SOF3 mo

95-99%2014

DAAs

DAAsDramatic improvement in HCV therapy

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

Africa

SE Asia

Americas

EasternMediterranean

• 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 Po

sitivity (%)

1984 No vaccine

1989 Vaccine<5 yo

1994 1999

2004

Age (years)

Africa

SE Asia

Americas

Western Pacific

EasternMediterranean

European

Global coverage 79% in 2012

Ni Gastro 2007, WHO 2017

WHO takes the leadVision: “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

10/12/2018

3

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?

DiagnosisAccess

TreatedSVR

Modeled data for non-VA US population

An elimination strategy

Anti‐HCVPositiveN=715

RNATestedN=488

RNAPositiveN=388

InitiatedTreatmentN=223

CompletedTreatmentN=201

AchievedSVR

N=180

68%

80%

57% 90%

90%(46% RNA+)Pe

rcentage

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 hereLeft 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, MarcelllinLancet 2013, Chang Hepatology 2010

Highly effective BUT not curative

10/12/2018

4

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

HB

sA

g L

oss

aft

er

1 ye

ar o

f th

erap

y

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 hepatitisIndividual

• Access to treatment – prevent complications of the disease

• Prevent additional harms to health – alcohol, obesity (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 screeningIndividual• 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

10/12/2018

5

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

0

Per

cen

t

Poland

12

Somalia Pakistan

2.91.5

0.72.4

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 countryHCV HBV

Lower in migrants from high endemic countries Egypt, PakistanLikely a ‘healthy’ migrant effect –mostly younger!

Lower in migrants from many countries – South Asia, AfricaLikely 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‐SaharanAfrica 

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/MiddleEast

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

10/12/2018

6

Situation worst for undocumented

Wendland BMC Public Health 2016

100

80

60

40

20

0

Per

cen

t te

sted

60

HIV

58

43

HBV Syphilis

Prenatal testing in Denmark

100

80

60

40

20

0

Per

cen

t te

sted

>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 prevalenceFew migrants

Low HCV prevalenceMany 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 prevalenceFew migrants

Low HBV prevalenceMany 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%)

0

5

10

15

20

Tested + M F

5

1211

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

10/12/2018

7

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‐HCVPositiveN=715

RNATestedN=488

RNAPositiveN=388

InitiatedTreatmentN=223

CompletedTreatmentN=201

AchievedSVR

N=180

68%

80%

57% 90%

90%(46% RNA+)Pe

rcentage Biggest ‘drops’

1. HCV RNA2. First Visit

Diagnosis needs simplificationStep 1

See the doctorStep 2

To the labfor HCV Ab

Step 3See the doctor

for result

Step 4To the lab

for HCV RNA

Step 5See the doctor

for result

Step 6Start 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

0

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

Percen

t w/ 30d follo

w‐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 SpotSaliva or blood 

rapid antibody test

Point‐of‐carePCR 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

10/12/2018

8

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

0

20

40

60

80

100

SVR12 (%)

618624

206210

117118

104104

116116

3435

4141

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

SV

R12

(%

)

100

80

60

40

0

97

191/197

91

73/80

G3: SOF/RBV x 24vs 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

NursePractitioner

Primary CarePhysician

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

 

$96,40

4 

$87,63

2 

$84,28

1 

$76,75

7 

$68,28

0 

$65,61

6 

$50,05

9 

$47,97

2 

$37,72

9 

$33,80

0 

$29,36

1 

$554

0

$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‐wee

k 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

10/12/2018

9

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

ImmunotoleranceImmune Clearance

E Negative Chronic HBV

(precore mutant)

HBeAg+ HBeAg- HBeAb+

months-years

ALT

HBV DNA

TreatmentTreatment

Treatment?Immunosuppression(Chemo/HIV/BMT)

Treatment

Dynamic disease…not everyone needs therapy…therapy may be long‐term/indefinite

Treatment challengesHCV

• 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