National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention

HEPLISAV-B: Considerations and Proposed Recommendations, VoteSarah Schillie, MD, MPH, MBA

Hepatitis Work Group, Advisory Committee on Immunization Practices

February 21, 2018

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Hepatitis B An infection of the liver caused by Hepatitis B Virus (HBV) Transmitted through percutaneous or mucosal exposure to blood or

body fluid––

–

Viable on environmental surfaces for at least 7 daysTransmitted in the absence of visible blood

Symptoms include anorexia, malaise, abdominal pain, nausea, vomiting, and jaundice

Extra-hepatic manifestations (e.g., skin rashes, arthralgias) may occur

Bond et al., Lancet 1981;317:550-551.Trepo et al., Lancet 2014;384:2053-2063.

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Acute and fulminant Hepatitis B

Acute infection symptomatic in 30%-50% of adults–

–

Fatality rate <1.5%; higher in adults ≥55 years

Fulminant infection uncommon (<1%) Often results in death or liver failure necessitating transplantation

Surveillance for Viral Hepatitis – United States, 2015 (https://www.cdc.gov/hepatitis/statistics/2015surveillance) McMahon et al., JID 1985;151:599-603.Trepo et al., Lancet 2014;384:2053-2063.

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Chronic Hepatitis B Chronic infection develops in:

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90% of persons infected during infancy<1-12% of persons infected during adulthood

• More frequent among immunosuppressed, persons with diabetes

Persons with chronic Hepatitis B have 15-25% risk for premature death from cirrhosis or liver cancer

850,000-2.2 million persons estimated to be living with HBV infection in the U.S.

Hyams, CID 1995;20:992-1000.Surveillance for Viral Hepatitis – United States, 2015 (https://www.cdc.gov/hepatitis/statistics/2015surveillance) Roberts et al., Hepatol 2016;63:388-397.Wasley et al., JID 2010;202:192-201.Kowdley et al., Hepatol 2012;56:422-23.

National Notifiable Diseases Reporting SystemSurveillance for Viral Hepatitis – United States, 2015 (https://www.cdc.gov/hepatitis/statistics/2015surveillance)

0

1,000

2,000

3,000

4,000

5,000

6,000

7,000

8,000

9,000

Num

ber o

f cas

es

Year

Increase associated with concomitant rise in injection-drug use

Reported number of acute Hepatitis B cases –United States, 2000-2015

0

1

2

3

4

5

6

Repo

rted

cas

es/1

00,0

00 p

opul

atio

n

Year

0-19 yrs

20-29 yrs

30-39 yrs

40-49 yrs

50-59 yrs

60+ yrs

Incidence of acute Hepatitis B by age group –United States, 2000-2015

National Notifiable Diseases Reporting SystemSurveillance for Viral Hepatitis – United States, 2015 (https://www.cdc.gov/hepatitis/statistics/2015surveillance)

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Hepatitis B vaccines Vaccine available in U.S. since 1981 (plasma)

–

–

–

Recombinant vaccine available since 1986

Safe, immunogenic, effectiveAnaphylaxis in yeast-sensitive individuals: 1.1 per million doses administered (95% CI, 0.1-3.9)

Generally administered as a 3-dose series* Protection lasts ≥30 years

Booster doses not routinely recommended

*Recombivax® licensed for 2-dose schedule for adolescents aged 11-15 years; 4-dose series available (e.g., when using combination vaccine, compressed schedule for travel, dialysis)

Stratton et al., National Academies Press 2012;435-503. Bohlke et al., Pediatr 2003;112:815-820.Bruce et al., JID 2016;214:16-22.Schillie et al., MMWR 2018;67:1-31.

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Currently-recommended Hepatitis B vaccines

Monovalent formulations (all ages)––

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Engerix®Recombivax®

Combination formulationsPediarix® (6 wks through 6 yrs)

• Hepatitis B, diphtheria, tetanus, pertussis, polio

Twinrix® (≥18 yrs) • Hepatitis A, Hepatitis B

Schillie et al., MMWR 2018;67:1-31.

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Persons recommended for Hepatitis B vaccination

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All infants and children aged <19 years Persons at risk for infection by sexual exposure

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–

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e.g., sex partners of HBV-infected persons, persons with multiple sex partners, men who have sex with men

Persons at risk for infection by percutaneous or mucosal exposure to blood e.g., injection-drug users, household contacts of HBV-infected persons, healthcare and public safety workers, persons with end-stage renal disease and dialysis patients, adults with diabetes

Others e.g., international travelers to regions with high or intermediate HBV endemicity, persons with Hepatitis C Virus (HCV) and chronic liver disease, persons with HIV infection, incarcerated persons

All persons seeking protection from HBV infection

Schillie et al., MMWR 2018;67:1-31.

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Assessment of serologic evidence of protection

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Antibody to hepatitis B surface antigen (anti-HBs) ≥10mIU/mL measured 1-2 months after vaccine series completion corresponds to vaccine-induced protection

Anti-HBs ≥10 mIU/mL in healthy adults aged <40 years:–––

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After 1 dose: 30%-55%After 2 doses: 75%After 3 doses: ≥90%

Lower 3-dose seroprotection associated with advanced age, diabetes, renal disease/dialysis, obesity, chronic illness, smoking

Diabetes: 31.3%-94.4%Dialysis: 10%-83.5%

Sit et al., World J Hepatol 2015;7:761-768.Asan et al., Int Urol Nephrol 2017;49:1845-1850. Leuridan et al., CID 2011;53:68-75.Jack et al., JID 1999;179:489-492.Schillie et al., Diab Care 2012;35:2690-2697.

Hepatitis B vaccine coverage (≥3 doses) among adults aged ≥19 years ─ United States, 2016

National Health Interview Survey*Had traveled outside the United States to countries other than countries in Europe, Japan, Australia, New Zealand, or Canada since 1995

0102030405060708090

100

Adultsoverall

Traveler* Chronic liverconditions

Diabetes(19-59 yrs)

Diabetes(60 yrs and

older)

Healthcarepersonnel

Cove

rage

(%)

Completion of Hepatitis B vaccine series among adult Vaccine Safety Datalink enrollees (n=88,711)

Nelson et al., Am J Public Hlth 2009;99:S389-397.

Completed 3-dose series Did not complete 3-dose series

Completed 3-dose series within 1 year of 1st dose

Completed 3-dose series 1-2 years after 1st dose

Completed 3-dose series >2 years after 1st dose

Received 1 dose

Received 2 doses

41.4-62.2% 2.8-4.9% 2.0-4.6% 15.1-25.7% 12.5-21.2%

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HEPLISAV-B

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HEPLISAV-B FDA licensed November 9, 2017 Indicated for active immunization against infection caused by all known

subtypes of HBV in persons aged ≥18 years Series of 2 doses, separated by 1 month Uses 1018 adjuvant (immunostimulatory cytidine-phosphate-guanosine

[CpG] motifs), which binds Toll-like receptor 9 to stimulate directed immune response to hepatitis B surface antigen (HBsAg)

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Immunogenicity

Studies demonstrate high rates of seroprotection:– 90.0%-100.0% of subjects receiving HEPLISAV-B vs. 70.5%-90.2% of

subjects in the comparison group • Type 2 diabetes mellitus: 90.0% (HEPLISAV-B) vs. 65.1% (comparator) • Chronic kidney disease: 89.9% (HEPLISAV-B, 3 doses) vs. 81.1%

(comparator, 4 double doses)

Halperin et al., Vaccine 2006;24:20-26.Halperin et al., Vaccine 2012;30:2556-2563.Heyward et al., Vaccine 2013; 31:53005305.Jackson et al., Vaccine 2018;36:668-674.Janssen et al. Vaccine 2013;31:5306-5313.HEPLISAV-B package insert 11/2017

Proportion of subjects with anti-HBs ≥10 mIU/mL following HEPLISAV-B or comparison vaccine

Halperin et al., Vaccine 2012;30:2556-2563.Heyward et al., Vaccine 2013; 31:53005305.

Healthy adults aged 18-55 years; n=1548-1557 (Heplisav-B);

531-533 (comparator)

Healthy adults aged 40-70 years; n=1101-1123 (Heplisav-B);

353-359 (comparator)

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HEPLISAV-B for Non-Responders

Anti-HBs ≥10 mIU/mL among non-responders to 3 previous doses:–

–

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52.6% (HEPLISAV-B, n=19) vs. 37.5% (comparator, n=16), not-significant

Anti-HBs ≥10 mIU/mL among non-responders to 4-6 previous doses:63.6% (HEPLISAV-B, n=11) vs. 58.3% (comparator, n=12), not-significant

Anti-HBs ≥100 mIU/mL among non-responders to 4-6 previous doses:54.5% (HEPLISAV-B, n=11) vs. 8.3% (comparator, n=12), p=0.027

Halperin et al., Hum Vacc Immunotherap 2013;9:1438-1444.

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Safety and reactogenicity Mild and serious adverse events similar*

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Mild: 45.6% (HEPLISAV-B) vs. 45.7% (comparator) Serious: 5.4% (HEPLISAV-B) vs. 6.3% (comparator)

Cardiovascular events: 0.27% (HEPLISAV-B) vs. 0.14% (comparator) Potentially immune-mediated adverse events**

0.1%-0.2% (HEPLISAV-B) vs. 0.0%-0.7% (comparator) Safety to be further assessed through post-marketing studies*Herpes zoster: 0.68% (HEPLISAV-B) vs. 0.32% (comparator) (RR=2.1, 95% CI=1.0-4.0)**e.g., granulomatosis with polyangiitis, Tolosa-Hunt Syndrome, autoimmune thyroiditis, vitiligo

Halperin et al., Vaccine 2006;24:20-26.Halperin et al., Vaccine 2012;30:2556-2563.Heyward et al., Vaccine 2013; 31:53005305.Jackson et al., Vaccine 2018;36:668-674.Janssen et al. Vaccine 2013;31:5306-5313.HEPLISAV-B package insert 11/2017U.S. FDA, HEPLISAV-B (https://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm584752.htm)

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GRADE Summary

Evidence type––

Benefits: 2*Harms: 1**

*Evidence from randomized controlled trials with important limitations, or exceptionally strong evidence from observational studies**Evidence from randomized controlled trials, or overwhelming evidence from observational studies

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Work Group Considerations

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Work Group considerations Interchangeability

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Vaccine series initiated with Hepatitis B dose(s) from another manufacturer and completed with HEPLISAV-BMinimum dosing intervals

Postvaccination serologic testing following HEPLISAV-B series and revaccination for non-responders using HEPLISAV-B

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Work Group considerations: Interchangeability ACIP recommendations

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When feasible, doses from the same manufacturer should be used to complete the seriesHowever, vaccination should not be deferred because a previously used manufacturer’s dose is not availableMinimum intervals (4-day grace period):

• Dose 1-2: 4 weeks• Dose 2-3: 8 weeks• Dose 1-3: 16 weeks

Doses administered at less than the minimum interval should be repeatedNo maximum interval

Kroger et al., General Best Practice Guidelines for Immunization. Accessed 2/16/18.Schillie et al., MMWR 2018;67:1-31.

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Work Group considerations: Interchangeability, cont. Proposed recommendations

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The 2-dose series only applies when all doses in the series consist of HEPLISAV-B When a vaccine series initiated with one dose of a vaccine from a different manufacturer must be completed with HEPLISAV-B, 3 total Hepatitis B vaccine doses should be administeredMinimum intervals should be heeded (Exception: A series containing two doses of HEPLISAV-B administered at least 4 weeks apart is valid, even if the patient received a single earlier dose from another manufacturer.)

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Work Group considerations: Postvaccination serologic testing and revaccination with HEPLISAV-B ACIP recommendations

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Postvaccination serologic testing (anti-HBs) is recommended for hemodialysis patients, HIV-positive and other immunocompromised persons, healthcare personnel, sex partners of HBV-infected persons, and infants born to HBV-infected mothers*)Persons with anti-HBs <10 mIU/mL should be revaccinated

• 1 more dose → anti-HBs → if anti-HBs <10 mIU/mL: 2 more doses → anti-HBs • 3 more doses → anti-HBs

Administration of more than 2 complete Hepatitis B vaccine series (i.e., 6 doses) is generally not recommended, except for hemodialysis patients and other immunocompromised persons

*Postvaccination serologic testing for infants born to HBsAg-positive mothers consists of anti-HBs and HBsAg

Schillie et al., MMWR 2018;67:1-31.

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Work Group considerations: Postvaccination serologic testing and revaccination with HEPLISAV-B, cont.

Proposed recommendations–

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HEPLISAV-B may be used for revaccination following an initial Hepatitis B vaccine series that consisted of doses of HEPLISAV-B or doses from a different manufacturer (including healthcare personnel)Postvaccination serologic testing and revaccination guidance remains unchanged

• Administration of more than 2 complete Hepatitis B vaccine series is generally not recommended, except for hemodialysis patients and other immunocompromised persons

• Note: 2 HEPLISAV-B series = 4 doses

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Work Group summary HEPLISAV-B likely to improve Hepatitis B vaccine series completion and result in

earlier protection (2 doses over 1 month)–

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Especially beneficial in persons with anticipated low adherence (e.g., injection drug users)

Improved immunogenicity in populations with typically poor vaccine response e.g., elderly, diabetes, dialysis

Post-marketing surveillance studies and additional data, including safety, pertaining to the use of HEPLISAV-B will be reviewed by ACIP as they become available, and recommendations will be updated as needed

Prior to preferential consideration

Future economic analyses may inform cost-effectiveness considerations of HEPLISAV-B, including its use among persons at an increased risk for vaccine non-response

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AcknowledgementsNCHHSTP/Division of Viral Hepatitis

• John Ward• Noele Nelson• Aaron Harris

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ACIP Vote

Non-preferential recommendation

Vote language: HEPLISAV-B is a Hepatitis B vaccine that may be used to vaccinate

persons aged 18 years and older against infection caused by all known subtypes of HBV.