63rd 3-coi slides zimmer v10.1 revised

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Faculty/Presenter Disclosure

• Faculty/Presenter: Dr. Rudy Zimmer

• Relationships with commercial interests:

Grants/Research Support: Not Applicable

Speakers Bureau/Honoraria: Not Applicable

Consulting Fees: Not applicable

Other: This presentation has received support from the Alberta College of Family Physicians in the form of a speaker fee and/or expenses.

Travel Hepatitis Vaccines

ACFP 63rd ASADisclosure of Commercial Support

This program has received financial support in the form of sponsorship from:

• Potential for conflict(s) of interest: Those speakers/faculty who have made COI disclosure are noted in the 63rd ASA Program and on the Salon A/B slide scroll.


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Mitigating Potential Bias• ACFP:

The ACFP’s Sponsorship Guidelines apply to ASA Sponsorship. The ACFP abides by the College of Family Physicians of Canada’s Understanding Mainpro+ Certification Guidelines, the Canadian Medical Association’s Policy Guidelines for Physicians in Interactions With Industry and the Innovative Medicines Canada Code of Ethical Practices (2016). As a non‐profit organization, the ACFP complies with Canada Revenue Agency regulations. When deliberating acceptance of sponsorship, the ACFP considers and accepts sponsorship only from those whose products, services, policies, and values align with the ACFP vision, values, goals, and strategies priorities.

• ASA Planning Committee: Consideration was given by the 63rd ASA Planning Committee to identify when Planning

Committee members’ and speakers’ personal or professional interests may compete with or have actual, potential, or apparent influence over program content.

Material/Learning Objectives and/or session description were developed and reviewed by a Planning Committee composed of experts/family physicians responsible for overseeing the program’s needs assessment and subsequent content development to ensure accuracy and fair balance.

The 63rd ASA Planning Committee reviewed Sponsorship Agreements to identify any actual, potential or apparent influence over the program.

Information/recommendations in the program are evidence‐ and/or guidelines‐based, and opinions of the independent speakers will be identified as such.


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Odyssey Travel + Tropical Medicine ClinicTravel Medicine Consultant, AHS Calgary Zone

Clinical Assistant ProfessorDepartment of Community Health Services

The University of Calgary

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Non‐responders and hypo‐responders to Hepatitis B: usually older persons, and VFR immigrant travellers.

New indications for Hepatitis A vaccine for children between 6 and 12‐months‐of‐age.

Effect of direct‐to‐consumer advertising (DTCA) on physician behaviour providing combination Hepatitis A + B vaccine (e.g., revaccinating teens already vaccinated with Hepatitis B vaccine through school programs – and not checking Netcare or hard copy records)


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7Travel Hepatitis Vaccines

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HAV is positive‐sense, single‐stranded linear RNA virus (only 1 serotype)

Fecal‐oral transmission, incubation 14‐45 days, illness 1‐6 weeks

Approximately 1.4 million infections annually, no chronic carriage

No effective antiviral treatment, but highly effective vaccines

HAV can cause fulminant hepatitis (e.g., age > 50‐years, liver disease)

Travel‐related cases regularly occur in unimmunized (e.g., food‐handlers)

Reference: http://www.who.int/mediacentre/factsheets/fs328/en/

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resolved


14‐45 days

Incubation

1‐6 weeks

Illness

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HBV is mostly double‐stranded DNA virus with a lipid bilayer envelope

Blood & body fluid transmission, incubation 30‐180 days, rarely acute

About 257 million people living with HBV infection (HBsAg positive)

Suppressive treatment for chronic infection, generally effective vaccines

10% chronic infection, more than 800,000 deaths (e.g., cirrhosis, HCC)

Travel‐related cases regularly reported (e.g., iatrogenic, STI, BBFE, VFR)


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Incubation 1‐6 m

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HCV is a flavivirus (like Dengue) with positive‐sense single‐strand RNA

Blood transmission, incubation 2 weeks to 6 months, < 20% acute S&S

About 71 million people with chronic infection, 60‐80% of new infections

Chronic infection can be cured with treatment, but no vaccine

60‐80% chronic infection, cirrhosis risk 15‐30% within 20 years

Travel‐related cases rarely reported (e.g., tattooing, IDU, MSM)


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HDV is single‐stranded circular RNA virus requiring HBsAg for replication

Blood & body fluid transmission, with acute or chronic HBV infection

Approximately 15 million people chronically coinfected (HDV + HBV)

No effective antiviral treatment, but HBV vaccination prevents spread

Most commonly associated with high‐risk groups (e.g., IDU)

Travel‐related cases rarely reported, but not routinely tested

Reference: http://www.who.int/mediacentre/factsheets/hepatitis‐d/en/

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HEV is positive‐sense, single‐stranded RNA virus (at least 4 genotypes)

Fecal‐oral transmission, incubation 15‐50 days, illness 1‐6 weeks

At least 20 million infections, 3.3 million symptomatic, > 50,000 deaths

No effective antiviral treatment or currently approved vaccine

Rare fulminant hepatitis with 25% (e.g., third trimester of pregnancy)

Travel‐related cases uncommon (e.g., backpackers, VFRs and expatriates)


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Figure 1 ‐ Current estimates on vaccine‐preventable disease incidence among Western travelers to tropical and subtropical destinationsReference: J Travel Med. 2014;22(1):1‐12. doi:10.1111/jtm.12171

Hepatitis B

Hepatitis A

Typhoid

Antibiotics

Influenza


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Not recommended unless one has not had a completed vaccine series …

… or a lab confirmed case of Hepatitis A infection in the past history.

Targets for testing:

Immigrantswith no previous test positive (e.g., look on Netcare).

History of jaundice with no documented test positive (also HBV).

Unreliable or undocumented HAV vaccine series in past.

Additional reading: https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/hepa.pdf

Reference: https://www.canada.ca/en/public‐health/services/publications/healthy‐living/canadian‐immunization‐guide‐part‐4‐active‐vaccines/page‐6‐hepatitis‐a‐vaccine.html


Extremely rare occurrence with few well‐documented published cases.

In 16 years, I have had only two cases in tens of thousands of travellers.

Several cases of “IgM” false non‐responders sent by family doctors:

anti‐HAV IgM positive = recent infection with HAV

anti‐HAV IgG positive = past infection or vaccine seroconversion

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To avoid testing errors, use the Provincial Laboratory virology requisition.

Do not order non‐specific panels, but specifically order “anti‐HAV IgG”.

If anti‐HAV IgG positive, no need for future testing – “immune for life”.

If anti‐HAV IgG negative, complete vaccine series (2 doses q6m or greater).

Retesting after immunization not needed, as non‐response very rare.


Current HBV vaccines are less immunogenic compared with HAV vaccines.

Targets for testing:

Immigrants at risk for chronic HBV infection with no previous testing.

Age‐related risk of non‐response (i.e., immunosenescence) > 40 years.

Risk of vaccine escape mutant infections (e.g., childhood infections).

Incomplete or undocumented HBV vaccine series in the past.

Avoid testing persons with documented HBV vaccines in distant past.(unless boosting the patient first and testing 1‐2 m afterward)

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Vaccineantigen

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‐ Exposure to natural HBV infection‐ Does not infer chronic infection‐ Does not appear post‐vaccine

Reference: https://www.cdc.gov/hepatitis/hbv/pdfs/serologicchartv8.pdf

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unimmunized noninfected person, or undetectable waning HBV vaccine immunity*

*if documented distant vaccine series – boost then check anamnestic response 1‐4 months later

true non‐responder to recent HBV vaccine****if documented completed HBV immunization series)

* In context of no acute symptoms

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fully HBV immunized uninfected person

no evidence of chronic HBV infection


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immunity to future HBV infection

from natural exposure to past infection


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chronic HBV infection needing confirmation

evidence of natural exposure to past infection


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detection of recent vaccine antigen

testing within 4 weeks of administration


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Four possibilities: false positive core test recovery from asymptomatic acute infection distant cleared infection with waning immunity chronic infection with undetectable HBsAg*

* Use alternate testing (HBeAg, anti‐HBe, HBV DNA detection)


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Rare encounter: false positive test(s) HBs antigen escape mutant infections vaccine response in chronically HBV infected*

* Reason to test all three markers initially


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A positive immunity test is measured arbitrarily ≥ 10 ml/mL of anti‐HBs.

This is a surrogate marker for protection against future HBV infection.

This measurement is only meaningful done 1‐2 months after provocation*

* Following a full primary series (e.g., 0, 1 and 6 ‐12 months)* Following a booster shot in a person with a distant primary series* Following exposure to HBV infection in an immunized person

Prevention of Hepatitis B Virus Infection in the United States: Recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2018 Jan 12; 67(1): 1–31. Available: https://www.cdc.gov/mmwr/volumes/67/rr/rr6701a1.htm

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Testing if done several years after a primary HBV series or infection:

Only helpful if anti‐HBs titres are still ≥ 10 ml/ml (slow waning)

Meaningless if < 10 ml/ml due to normal waning antibodies with time

If testing distant vaccine series, boost first and test 1‐2 month later

Routine testing of anti‐HBs is not recommended, if an individual has had a confirmed completed vaccine series

Vaccine immunity is considered to last > 30 years or “life time”, regardless of waning antibodies in an otherwise healthy person.

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Standard series

Rapid series

anti

-HBs

test

ing:

1-2

mon

ths

afte

r pri

mar

y se

ries

anti

-HBs

test

ing:

1-2

mon

ths

afte

r pro

voca

tion

10 mIU/ml threshold

First booster dose

Exposure to HBV infection

Time in months and years

an

ti-H

Bs le

vels

Further booster dose

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Standard series

Rapid series

Double doseboosters:

hypo-responder,moderate

primaryresponse

Normal dosebooster:

normal waningantibodies,anamnestic

response

Normal dosebooster:

fast waningantibodies,anamnestic

response

Normal dosebooster:

fast waningantibodies,anamnestic

response

Normal doseboosters:

non-responder,no anamnestic

response

Possible non-responder immunity profile:R/O chronic infection: HBsAg, anti-HBc True non-responder immunity profile

anti

-HBs

test

ing:

1-2

mon

ths

afte

r pri

mar

y se

ries

an

ti-H

Bs le

vels

10 mIU/ml threshold

First booster dose

Time in months and years

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Do not routinely test children receiving publicly‐funded or travel vaccines

95% seroconversion in newborns (at birth) with full primary series

99% seroconversion in school‐aged (5‐15 y) children with full primary series

Age‐related immunosenescence (> 30‐40 y), especially elderly

Chronic diseases: diabetes mellitus (70‐80%), renal failure (60‐70%) and chronic liver disease (60‐70%), and well as immunosuppressed.

Reference: https://www.canada.ca/en/public‐health/services/publications/healthy‐living/canadian‐immunization‐guide‐part‐4‐active‐vaccines/page‐7‐hepatitis‐b‐vaccine.html#a4

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Reference: Van Der Meeren O, Crasta P, et al. Characterization of an age‐response relationship to GSK's recombinant hepatitis B vaccine in healthy adults: An integrated analysis. Hum Vaccin Immunother. 2015;11(7):1726‐9. Available:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4514334/ (accessed 2018 Feb 04).

80% seroconversion at 60 years old

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There is no clear guidance on this issue with great variance of opinions.

NACI recommends a second full normal dose series, 50‐70% will respond. NACI then recommends “giving up” and assuming non‐response – we disagree.

The problem with non‐response is lack of antigen “noise”, thus our experience over 16 years is more doses of normal “noise” does not work, we crank the noise.

We recommend only using 20ug anti‐HBs vaccine (Engerix®‐B) for adults.

If there is no‐low response to primary series, then boost 20ug x 2 as a trial, but test anti‐HBs with HBsAg and anti‐HBc 1‐2 m later, if not done already.

Recombivax HB®‐Adult dialysis (40ug) is not usually available in community, whereas Recombivax HB® only contains 10ug which is insufficient > 30‐40 years.


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Medical literature also suggests other approaches, some still experimental:

Twinrix® (combined HAV + HBV) vaccine using HAV as adjuvant – we disagree

Our experience with Twinrix® is similar to Engerix® regarding vaccine failures

Intradermal HBV vaccine administration shows promise in other travel clinics

It requires expertise in ID administration and could lead to vaccine waste

Formulated vaccine adjuvants added to the monovalent HBV vaccine

There are no currently licensed adjuvanted HBV vaccines in Canada

Reference: Leroux‐Roels G. Old and new adjuvants for hepatitis B vaccines. Med Microbiol Immunol. 2015 Feb;204(1):69‐78.


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Studies estimate 44 ‐ 55% of reported HA cases in Canada are linked to travel.

Low‐budget travellers, volunteer humanitarian workers, and Canadian‐born children of new Canadians returning to their country of origin to visit friends and relatives, may be at increased risk.

The risk of HA for susceptible travellers to developing countries is estimated to range from 0.1/1,000 to 1/1,000 per month.

Update on the Recommended use of Hepatitis A Vaccine. An Advisory Committee Statement (ACS) National Advisory Committee on Immunization (NACI). May 2016. Available: https://www.canada.ca/en/public‐health/services/publications/healthy‐living/update‐recommended‐use‐hepatitis‐vaccine.html


Canada has several licensed HAV‐containing vaccines, all with similar safety and protective efficacy:

AVAXIM® (adult formulation) and AVAXIM®‐Pediatric (paediatric formulation) (inactivated hepatitis A vaccine), Sanofi Pasteur SA (manufacturer), Sanofi Pasteur Ltd. (distributor) (HA)

HAVRIX® 1440 (adult formulation) and HAVRIX® 720 Junior (paediatric formulation) (inactivated hepatitis A vaccine), GlaxoSmithKline Inc. (HA)

TWINRIX® (adult formulation) and TWINRIX® Junior (paediatric formulation) (combined hepatitis A and hepatitis B [HB ] vaccine), GlaxoSmithKline Inc.

VAQTA® (inactivated hepatitis A vaccine), Merck Canada Inc. (HA )

ViVAXIM® (combined purified Vi polysaccharide typhoid and inactivated hepatitis A vaccine), Sanofi Pasteur Ltd. (distributor) (HA‐Typh‐I)

Hepatitis A Vaccine. Canadian Immunization Guide: Part 4 ‐ Active Vaccines (evergreen). Available: https://www.canada.ca/en/public‐health/services/publications/healthy‐living/canadian‐immunization‐guide‐part‐4‐active‐vaccines/page‐6‐hepatitis‐a‐vaccine.html

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Recommendation 1: HA vaccine may be provided, beginning at six months of age, to infants who are at increased risk of infection or severe HA. (NACI recommendation Grade B)

Canadian‐born infants travelling to HA endemic countries, including children of new Canadians returning to their country of origin to visit friends and relatives


AHS Hepatitis A Vaccine Biological Page. Revised February 2017. Available: https://www.albertahealthservices.ca/assets/info/hp/cdc/if‐hp‐cdc‐hep‐a‐vac‐bio‐pg‐07‐230.pdf

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Recommendation 3: For post‐exposure prophylaxis, unless contraindicated or unavailable, HA vaccine is recommended in preference to Ig for healthy individuals six months of age and older. (NACI recommendation Grade B)

There are a total of six new recommendations available on‐line:


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Heywood P, Cutler J, Burrows K, et al. A community outbreak of travel‐acquired hepatitis A transmitted by an infected food handler. Can Commun Dis Rep. 2007 Nov 1;33(11):16‐22. Available:

https://www.canada.ca/content/dam/phac‐aspc/migration/phac‐aspc/publicat/ccdr‐rmtc/07pdf/cdr3312.pdf


One recurrent observation over 15 years is the provision of a single normal dose of the combined HAV + HBV vaccine in last minute travellers.

The combined vaccine contains ½ the normal antigen dose of HAV, which increases the risk of HAV vaccine non‐response.

A single normal antigen dose of HBV does not induce protective immunity in a majority of health individuals.

Focus on administering a full monovalent HAV vaccine dose, and consider separately starting a HBV series to be completed after the trip.

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Another recurrent observation over 15 years is the provision of a rapid series of the combined HAV + HBV vaccine in non‐last minute travellers.

A standard (0, 1 and 6 months) and rapid (0, 7 and 21 days) series will provide equivalent protection against HBV within 60 days, when needed *.

At 6 months, anti‐HBs was higher in a standard series (3 doses).

A rapid series needs boosting at 12 months to ensure long‐term immunity.

A rapid series simply provides a shorter window to prime (< 1 month).

* Jin H, Tan Z, Zhang X, et al. Comparison of Accelerated and Standard Hepatitis B Vaccination Schedules in High‐Risk Healthy Adults: A Meta‐Analysis of Randomized Controlled Trials. PLoS One. 2015 Jul 21;10(7):e0133464. Available:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4510064/


For older children, 2 adult doses given 6‐12 month apart provides similar long‐term response compared to a standard 3 child dose series.

Limiting factor is pain due to larger injection volumes in smaller children.

Though licensed 1‐15 years, practice experience limits administration to larger‐sized children (e.g., 6 years and older – case‐by‐case).

Useful in extremely needle‐phobic children and/or anxious parents.

Data on long‐term antibody persistence or protection among adolescents for 2‐dose schedules are lacking*.

* Prevention of Hepatitis B Virus Infection in the United States: Recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2018 Jan 12; 67(1): 1–31

Available: https://www.cdc.gov/mmwr/volumes/67/rr/rr6701a1.htm.

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https://www.youtube.com/watch?v=zYpuuLLKQx4


https://www.youtube.com/watch?v=‐MDXN7rXHt4

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The availability heuristic is a mental shortcut that relies on immediate examples that come to a given person's mind when evaluating a specific topic, concept, method or decision (e.g., “off the top of my head”).

Availability is a heuristic whereby people make judgments about the likelihood of an event based on how easily an example, instance, or case comes to mind.

Branding and marketing create new customers or patients,where there may be none and no medical necessity for a particular product.

Brown JL. Physician Exposure to Direct‐to‐Consumer Pharmaceutical Marketing: Potential for Creating Prescribing Bias. Am J Med. 2017 Jun;130(6):e247‐e248.


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Pondé RA. Atypical serological profiles in hepatitis B virus infection. Eur J Clin Microbiol Infect Dis. 2013 Apr;32(4):461‐76. doi: 10.1007/s10096‐012‐1781‐9.

Prevention of Hepatitis B Virus Infection in the United States: Recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2018 Jan 12; 67(1): 1–31Available: https://www.cdc.gov/mmwr/volumes/67/rr/rr6701a1.htm

Update on the Recommended use of Hepatitis B Vaccine. An Advisory Committee Statement (ACS) National Advisory Committee on Immunization (NACI). February 2017. Available: https://www.canada.ca/en/public‐health/services/publications/healthy‐living/update‐recommended‐use‐hepatitis‐b‐vaccine.html

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Rudy Zimmer, MD, FCFP, FRCPC, CTropMed®Office Address:#142, 3715‐51 Street SWCalgary, AB T3E 6V2

Office Ph: 403‐229‐2273 or 403‐210‐4770Office Fx: 403‐246‐9688

Office Email: [email protected]

63rd 3-coi slides zimmer v10.1 revised

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