Hepatitis B Immunization : Choosing the        Most Effective Schedule          Dr Gaurav Gupta, MD          Charak Clinic...
Conflict of Interest• Received grants from various vaccine manufacturers  including   •   - Sanofi Pasteur   •   - GSK   •...
Scope• The hepatitis burden- Worldwide & India• Hepatitis B – disease profile• What is an ideal vaccination schedule?• Why...
Global Burden—Hepatitis B Virus Infection  • 2 billion people infected with HBV  • > 350 million have chronic HBV infectio...
Leading Causes of Infectious Disease                 Deaths WorldwideDisease                                       Est. De...
Dr. Gaurav   6
Geographic distribution of chronic hepatitis B virus     (HBV) infection — worldwide, 2006*                               ...
Three distinct levels of Hepatitis B endemicity     Hepatitis B seroprevalence (Hadler& Margolis)Endemicity Area       HBs...
9
10
11
12
13
Risk of acquiring HBV from a needlestickSource-HBs Ag positive, HBe Ag negative—1-6%Source-HBs Ag positive, HBe Ag positiv...
Vertical Transmission           Hepatitis BTHE BEST PREVENTIVE METHOD IS    VACCINATION                                15
HBV Vaccination – Fast Facts1. Plasma derived vaccines – 19822. Yeast derived vaccines – 19863. First Mass immunization pr...
Success of Hepatitis B vaccine    • The vaccine has an outstanding record of safety and       effectiveness.    • Vaccinat...
Questions needed to be asked regarding Ideal        Schedule for Hep B vaccine?1. Has it been used for extensive period of...
Hepatitis B immunizationBirth dose and interval between the doses are extremelyimportant :    • not only for the robustnes...
Importance of vaccination schedule at 0-1-6 mo/o   vs 2-4-6 mo/o. Results: Anti-HBs Post-dose 3                           ...
Ab titres (ShanvacB) with 0-1-2 &0-1-6 schedules                  7000                                                    ...
GMT in infant vaccinated against Hepatitis B by       different vaccination schedules                                     ...
WHO targets hepatitis B control in WesternPacific Region  An universal vaccination program was launched in Taiwan in  1984...
Estimation of annual incidence of HBs Ag chronic carrier               due to vertical transmission  What is the «cost» o...
25
The Rationale1st Dose – At birth - Prevents vertical transmission2nd Dose – Min 4 wk later – Limited number of seroconvers...
AAP recommendations - hepatitis B, 2012• Administer Monovalent HepB to all newborns before hospital discharge• The second ...
Comparision of vaccination schedule in         different countries throughout world   Country                             ...
International SchedulesMajority of schedules begin at birthMany vaccination schedules end at 6 months age or moreGap of at...
Key Points• The GMTs with 0, 1, and 6 months schedule are upto 10  times higher than 0, 1, and 2 months schedule.• Infants...
IAP recommendationsHep B vaccine may be given in any of the following schedules:(i) Birth, 1 and 6 months(ii) Birth, 6 and...
0, 1 & 6 months• Gold standard,• Protects high risk infants,• Enough evidence regarding long term efficacy (at least 25yea...
0, 6 & 14 weeks•Not enough evidence regarding long term effectiveness•Protects High risk infants,•Can be piggy backed to e...
6,10 & 14 weeks•Does NOT protect against vertical transmission•Can be piggybacked to EPI,IAPCOI – Only recommended for mis...
Birth, 6,10 & 14 weeks•Protects against vertical transmission•Can be piggybacked to EPI,•Increases overall cost of vaccina...
Birth 6 weeks & 6 monthsSimilar to the classic schedule of 0 1 & 6 monthsCan be partially piggybacked to EPI,IAP recommend...
Interesting facts – IAPCOI recommendations•Catch-up vaccination schedule - 0,1 & 6 months for ALLchildren to prevent horiz...
Importance of a 6 month visit: pediatricians perspective• 24 wk (6 mo) visit introduces a potential visit between  14 week...
FAQWhen should double dose be given?In elderly, immunocompromised and chronic renal  failure patients– 4 doses at 0,1,2 an...
FAQWhat antibody titres signify a response?Antibody levels more than 10 mIu/ml signify a responseWhat should be done in No...
FAQIs booster dose required ?• Routine boosters are NOT needed in healthy children and   adults• Individuals who respond t...
FAQWhat the accelerated schedules for HBV vaccine?• 0, 1, 2 & 12 months• 0, 7 days, 21 days and 12 monthsWhat are the reco...
Longer needle length for Hep-B vaccination of          macrosomic neonates• Use of a longer (1 in.) rather than a standard...
44
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Hepatitis B Vaccine revisited - Ideal Schedule & recommendations

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Presented in SAVE Sanofi Aventis program for Pediatricians from Western India in Goa in May 2012

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  • I am sure that most of you sitting in this room are already convinced that HB is a major public health problem But just in case there is someone who isn't, and because this is the first talk on this meeting, let's review the tremendous burden of this disease. An estimated 2 billion people have been infected with HBV More than 350 million have chronic HBV infection Approximately 88% of the world's population live in areas where the prevalence of chronic HBV infection is high or moderate (as defined by the prevalence of HB surface antigen) There were ~ 600,000 HBV-related deaths in 2002 Approximately 93% of these deaths were the result of chronic infection
  • Hepatitis B Vaccine revisited - Ideal Schedule & recommendations

    1. 1. Hepatitis B Immunization : Choosing the Most Effective Schedule Dr Gaurav Gupta, MD Charak Clinics, Mohali. MAAP, MIAP 1
    2. 2. Conflict of Interest• Received grants from various vaccine manufacturers including • - Sanofi Pasteur • - GSK • - Abbott • - Wyeth etc. 2
    3. 3. Scope• The hepatitis burden- Worldwide & India• Hepatitis B – disease profile• What is an ideal vaccination schedule?• Why is 0, 1 & 6 the most effective? 3
    4. 4. Global Burden—Hepatitis B Virus Infection • 2 billion people infected with HBV • > 350 million have chronic HBV infection • >40 million in India • 600,000 HBV-related deaths • 93% of deaths were the result of chronic infection • 88% of the worlds population live in areas where the prevalence of chronic HBV infection is high (>8% HBsAg +) or moderate (2-7% HBsAg +)Scaling up Global Access to Hepatitis B Vaccination. WHO July 2009 4
    5. 5. Leading Causes of Infectious Disease Deaths WorldwideDisease Est. Deaths per YearLower respiratory tract infections ~4.2 millionDiarrheal diseases ~2.2 millionHIV/AIDS ~2.0 millionTuberculosis ~1.5 millionHepatitis viruses ~1 millionHepatitis B virus ~620,000Hepatitis C virus ~366,000*Malaria ~900,000Pertussis ~295,000Neonatal tetanus ~213,000Measles ~197,000Source: WHO, UNICEF, Perz et al, J Hepatology, 2006 5
    6. 6. Dr. Gaurav 6
    7. 7. Geographic distribution of chronic hepatitis B virus (HBV) infection — worldwide, 2006* 7
    8. 8. Three distinct levels of Hepatitis B endemicity Hepatitis B seroprevalence (Hadler& Margolis)Endemicity Area HBsAG Infected Adults Regions Transmission Seroprevalence Asia (except Japan and •Vertical India), Africa, most of •Horizontal Middle East, the Almost all infections are High >8% >70% Amazon basin of south acquired in infancy or America, most pacific early chidlhood, and few Island groups and adults remain Maoris susceptible to infection India, part of the Middle Mixed and East, Western Asia, transmission occurs in Japan, Eastern & all age groups but Southern Europe, and predominant period of Intermediate 2% - 8% 20% - 50% most south & Central transmission probably America occurs among young children, adolescents and young adults. USA, Canada, Western Primarily among adults Europe, Australia and Nevertheless, New Zealand transmission during the perinatal period and Low <2% <20% during childhood provides a significant contribution to the HBV carrier burden 8
    9. 9. 9
    10. 10. 10
    11. 11. 11
    12. 12. 12
    13. 13. 13
    14. 14. Risk of acquiring HBV from a needlestickSource-HBs Ag positive, HBe Ag negative—1-6%Source-HBs Ag positive, HBe Ag positive---22-40%HCV-3-10%, HIV-0.2-0.5% 14
    15. 15. Vertical Transmission Hepatitis BTHE BEST PREVENTIVE METHOD IS VACCINATION 15
    16. 16. HBV Vaccination – Fast Facts1. Plasma derived vaccines – 19822. Yeast derived vaccines – 19863. First Mass immunization program – Taiwan 19844. Most commonly used vaccination – more than 1 billion dosesgiven5. First vaccination to prevent cancer 16
    17. 17. Success of Hepatitis B vaccine • The vaccine has an outstanding record of safety and effectiveness. • Vaccination has excellent effectiveness - reduced the rate of chronic infection to less than 1% from 8-15 % • In 2009, 177 countries included the hepatitis B vaccine into their national schedule major increase compared with 31 countries in 1992, when WHO passed a resolution recommending global vaccination against hepatitis B 17Dr. Gaurav Gupta, Charak Care Clinics, Mohali
    18. 18. Questions needed to be asked regarding Ideal Schedule for Hep B vaccine?1. Has it been used for extensive period of time?2. Does it protect the highest “at risk” population?3. Are there enough evidence regarding its effectiveness?4. Are other countries using the same in their NationalSchedules?5. Can it be piggy-backed on to the National Schedule in ourCountry? 18
    19. 19. Hepatitis B immunizationBirth dose and interval between the doses are extremelyimportant : • not only for the robustness of the immune response, but • as well for the prevention of vertical and horizontal transmission and • the long term protection post-vaccination. 19
    20. 20. Importance of vaccination schedule at 0-1-6 mo/o vs 2-4-6 mo/o. Results: Anti-HBs Post-dose 3 Group 1 Group 2 Hep.B at 0-1-6 Hep.B at 2-4-6 100% 99.0%Anti-HBs ≥ 10 mIU/mL [97.2 ; 100] [94.3 ; 99.4] 3 643 mIU/mL 1 052 mIU/mLGMTs [502;709] [163;253] Post-dose 2 (at 2 months of age): Anti-HBs ≥ 10 mIU/mL in 47% of infants of group 1 versus only 9% in group 2 Greenberg D et al.- Ped. Inf. Dis. Journal. 21(8):769-776, August 2002 20
    21. 21. Ab titres (ShanvacB) with 0-1-2 &0-1-6 schedules 7000 6375.86 6000 5000 GMT (mIU/ml) 0,1,2 schedule GMT (mIU/ml) 0,1,6 schedule GMT (mIU/ml) 4000 3000 2000 1000 749.12 41.7 23.44 84.39 79.70 0 After 1st dose After 2nd dose After 3rd dose GMT (mIU/ml) 21
    22. 22. GMT in infant vaccinated against Hepatitis B by different vaccination schedules 22
    23. 23. WHO targets hepatitis B control in WesternPacific Region An universal vaccination program was launched in Taiwan in 1984 HBsAg positive rate in children < 12 y/o : • Before vaccination program: 9.8% • After the institution of program, – 4.8% at 5 years – 1.3% at 10 years – 0.7% at 15 years The annual rate of incidence of childhood HCC decreased from 0.52 to 0.13 per 100 000 children after the vaccination program. The schedule implemented is birth, 1 and 6 months of age. 23
    24. 24. Estimation of annual incidence of HBs Ag chronic carrier due to vertical transmission  What is the «cost» of a delayed schedule? Total Annual incidence of Universal HBsAg+ HBeAg Estimated chronic prevention Mothers + Infected Rate per carriage due of vertical % mother neonates 100 000 to vertical transmissi s (%) Births transm on (Yes/ %HBsA per year* No) g+ India (1996) No 4.6 18.0 0.67 605 162 563 Singapore Yes 3.4 39.0 0.92 827 474 (1998) Bangladesh No 3.5 30.2 0.76 687 25 690 Chauvin P, Ekra D, Plotkin S.- Vaccine. 2002 Jul 26;20(23-24):2848-50 24
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    26. 26. The Rationale1st Dose – At birth - Prevents vertical transmission2nd Dose – Min 4 wk later – Limited number of seroconversionafter 1st dose, hence closely spaced second dose – preventsimmediate horizontal transmission3rd Dose -- Min 8 weeks after 2nd Dose, -- Min 16 weeks after 1st Dose, -- After 24 weeks age, (ACIP/ AAP recommendations)Leads to increased antibody titres – Better Long Term protection 26
    27. 27. AAP recommendations - hepatitis B, 2012• Administer Monovalent HepB to all newborns before hospital discharge• The second dose should be administered at age of 1 to 2 months• The final dose should be administered no earlier than age 24 weeks 27Dr. Gaurav Gupta, Charak Care Clinics, Mohali
    28. 28. Comparision of vaccination schedule in different countries throughout world Country Hepatitis B vaccination schedule USA birth; 1-2, 6-18 months; Canada 1st contact; +1, >+2 months; England birth; 1, 2, 6 months; Germany 2, 4, 11-14 months; South Africa 6, 10, 14 weeks; Australia birth; 2, 4, 6 months; 1, 10-13 years; India Birth; 6, 10, 14 weeks; China birth; 1, 6 months;Ref: WHO. Immunization surveillance, assessment and monitoringAvailable at:http://www.who.int/immunization_monitoring/data/data_subject/en/index.html 28
    29. 29. International SchedulesMajority of schedules begin at birthMany vaccination schedules end at 6 months age or moreGap of at least 8 weeks between 2nd and 3rd dosesIf the gap is less, then a 4th dose given 29
    30. 30. Key Points• The GMTs with 0, 1, and 6 months schedule are upto 10 times higher than 0, 1, and 2 months schedule.• Infants who achieve higher Anti HBs titers maybe protected better in later years.• The seroprotection rates are found to be highest when the interval between the second and third dose is longer.• The classic 0, 1, and 6 months schedule yields a high seroconversion rate and relatively high titers of anti-HBs that will persist for an extended period of time. 30
    31. 31. IAP recommendationsHep B vaccine may be given in any of the following schedules:(i) Birth, 1 and 6 months(ii) Birth, 6 and 14 weeks(iii) 6, 10 and 14 weeks(iv) Birth, 6 weeks, 6 months(v) Birth, 6 weeks,10 weeks, 14 weeksThe IDEAL schedule is 0 1 6 months. 31
    32. 32. 0, 1 & 6 months• Gold standard,• Protects high risk infants,• Enough evidence regarding long term efficacy (at least 25years), and being used by many countries,• Cannot be easily integrated with the national scheduleIAPCOI – Most widely used, IDEAL, High Antibody Titres 32
    33. 33. 0, 6 & 14 weeks•Not enough evidence regarding long term effectiveness•Protects High risk infants,•Can be piggy backed to existing EPI•Slightly lower titres since 3rd dose completed before 24 weeks- ? Clinical significanceIAPCOI – Recommended for Public Health since protectsagainst Vertical Transmission, and can be integrated with EPI 33
    34. 34. 6,10 & 14 weeks•Does NOT protect against vertical transmission•Can be piggybacked to EPI,IAPCOI – Only recommended for missed birth dose 34
    35. 35. Birth, 6,10 & 14 weeks•Protects against vertical transmission•Can be piggybacked to EPI,•Increases overall cost of vaccination 35
    36. 36. Birth 6 weeks & 6 monthsSimilar to the classic schedule of 0 1 & 6 monthsCan be partially piggybacked to EPI,IAP recommendation for Office Practice ?0, 4/6 week, 6 months 36
    37. 37. Interesting facts – IAPCOI recommendations•Catch-up vaccination schedule - 0,1 & 6 months for ALLchildren to prevent horizontal transmission.•For management of infants of HbsAg +ve mothers - the “closelyspaced schedule” should NOT be used. 37
    38. 38. Importance of a 6 month visit: pediatricians perspective• 24 wk (6 mo) visit introduces a potential visit between 14 weeks (DTP3) and 36 weeks (measles) to evaluate child development and monitor progress including • Major motor skills • Fine motor skills • Language • Vision and hearing • Social achievements and play• Evaluation of weaning issues 38
    39. 39. FAQWhen should double dose be given?In elderly, immunocompromised and chronic renal failure patients– 4 doses at 0,1,2 and 12 months, double dose is to be givenShould routine testing of HBs Ab be done after completion of vaccination schedule ?Only for a small minority of vaccinees including babies of HBsAg +ve mothers, close contacts of HbsAg +ve, health care workers and people with co-morbidities, 39
    40. 40. FAQWhat antibody titres signify a response?Antibody levels more than 10 mIu/ml signify a responseWhat should be done in Nonresponders?Non responders should be tested for Hepatitis B carrier status. If negative, repeat the complete vaccination schedule, 50% would respond , rest are permanently susceptible 40
    41. 41. FAQIs booster dose required ?• Routine boosters are NOT needed in healthy children and adults• Individuals who respond to the vaccination series and have levels of 10 mIU/ml after vaccination are protected against hepatitis B disease for life even if the levels drop to below protective levels or are undetectable later. This is due to Immune memory.• In immunocompromised and those who have CRF, CLD etc. levels should be regularly checked (? Yearly) and booster dose given when the levels fall below protective levels 41
    42. 42. FAQWhat the accelerated schedules for HBV vaccine?• 0, 1, 2 & 12 months• 0, 7 days, 21 days and 12 monthsWhat are the recommendations for premature babies?• Some infants born prematurely with low birth weight (<2000 g) may not respond well to vaccination at birth. However, by one month of chronological age, all premature infants, regardless of initial birth weight or gestational age, are likely to respond adequately.• Give birth dose, but don’t count it. Start afresh from1 month age 42
    43. 43. Longer needle length for Hep-B vaccination of macrosomic neonates• Use of a longer (1 in.) rather than a standard (5/8 in.) needle used for macrosomic neonates (birthweight over 4000 g) may affect antibody titers• Fifty nine healthy infants were vaccinated at birth, 1, and 6 months of age with hepatitis B vaccine,• Macrosomic infants who were immunized with a longer needle achieved significantly higher antibody titers to hepatitis B surface antigen than standard needle length (median, 3890.2 vs 1311.7 mIU/mL)Ref: Vaccine, Volume 30, (21), 2 May 2012, 3155–58 43
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