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CDC Recommendation for Hepatitis B Vaccination among Adults with Diabetes: Grading of Scientific Evidence in Support of Key Recommendations

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Evidence of benefits, harms, values and preferences, and cost effectiveness were reviewed in accordance with GRADE methods to determine the recommendation category (Ahmed F, Temte JL, Campos-Outcalt D, Schünemann HJ; for the ACIP Evidence Based Recommendations Work Group (EBRWG). Methods for developing evidence-based recommendations by the Advisory Committee on Immunization Practices (ACIP) of the U.S. Centers for Disease Control and Prevention (CDC). Vaccine 29(49):9171-6, 2011). Pooled data from 6 placebo-controlled randomized trials (5798 subjects) indicated a relative risk for hepatitis B infection events of 0.37 (95% CI 0.29, 0.48) among vaccinated subjects, although evidence type was downgraded for indirectness as trials did not focus on subjects with diabetes. Pooled data from 5 observational studies (285 subjects with diabetes) indicated 91.6% of subjects with diabetes achieved seroprotection, although evidence type was downgraded for imprecision due to small numbers. No serious vaccine-related adverse events were reported in any study. The Institute of Medicine found evidence supporting a causal relationship between hepatitis B vaccination and anaphylaxis in yeast-sensitive individuals; the risk of anaphylaxis following hepatitis B vaccine is estimated at 1.1 per million doses. [IOM (Institute of Medicine). 2011. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press; Bohlke K, Davis RL, Marcy SM, Braun MM, DeStefano F, Black SB, Mullooly JP, Thompson RS; Vaccine Safety Datalink Team. Risk of anaphylaxis after vaccination of children and adolescents. Pediatrics 2003;112:815-20]

GRADE Tables: Hepatitis B Vaccination Among Persons with Diabetes

Table 1. Benefits and Harms of Hepatitis B Vaccination Among Persons with Diabetesa

OutcomeNo. of subjects (# studies)Incidence in controlsIncidence in vaccinatedRelative risk (95% CI) of hepatitis B infection events among vaccinatedSeroprotection proportion among subjects with diabetes (95% CI)Risk difference per 1000 (95% CI), vaccinated versus not vaccinatedNumber needed to vaccinate (NNV)
Hepatitis B infection events5798 (6 RCTs)10.7%b4.1%b0.37 (0.29, 0.48)b---67 (-76, -56)c261d
Seroprotection285 (5 Obs)------91.6% (87.6%, 94.4%)----
Serious adverse events6251 (6 RCTs and 3 Obs)0.0%e0.0%e--------
Anaphylaxis6251 (6 RCTs and 3 Obs)0.0%e0.0%e--------

Table 1 Footnotes
aSome studies include persons with and without diabetes
bFollow-up ranged from 12-29 months; figures do not account for person-time of follow-up for all studies; relative risk and 95% CI calculated from RevMan software version 5.1
cCalculated from GRADEprofiler software version 3.6 assuming fixed effects
dNumber needed to treat (number needed to vaccinate) calculated from modeling analysis of adults with diabetes ages ≥20 years (lifetime perspective)
eNo serious events reported. Study sizes not sufficient to detect rare serious adverse events

Table 2. Type of Evidence for Hepatitis B Vaccination Benefits and Harms among Persons with Diabetesa

OutcomeDesign (# studies)Risk of biasInconsistencyIndirectnessImprecisionOther considerationsEvidence type
Hepatitis B infection eventsRCT (6)No seriousNo seriousYes (-1)bNo seriousNo serious2
SeroprotectionObs (5)No seriousNo seriousNo seriousYes (-1)cNo serious4
Serious adverse eventsRCT (6)
Obs (3)
No seriousNo seriousYes (-1)bNo seriousNo serious2d
AnaphylaxisRCT (6)
Obs (3)
No seriousNo seriousYes (-1)bNo seriousNo serious2d

Table 2 Footnotes
aSome studies include persons with and without diabetes
bSubjects with diabetes not focus of RCT studies; one RCT used 3 mcg dose on 0,1,2 month schedule; one study used 5 mcg dose on 0,1,2 month schedule with subcutaneous administration
cTotal number of events <300, 95% CI 0.88, 0.94
dStudy sizes not sufficient to detect rare adverse events:  rate of anaphylaxis estimated 1.1 per million doses (95% CI 0.1, 3.9 per million doses); (Bohlke K. et al. Pediatrics 2003;112:815-20). Widespread vaccine use for 30 years has not revealed other serious adverse events (IOM (Institute of Medicine). 2011. Adverse Effects of Vaccines:  Evidence and Causality.  Washington, DC: The National Academies Press)

Table 3. Summary of Evidence for Benefits and Harms of Hepatitis B Vaccination among Adults with Diabetesa

ComparisonOutcomeStudy design (# studies)FindingsEvidence typeOverall evidence type
Hepatitis B vaccination vs. no vaccinationHepatitis B infection eventsRCT (6)Decreased risk among vaccinated22
--SeroprotectionObs (5)Seroprotection among subjects with diabetes similar to that among subjects without diabetes4--
--Serious adverse eventsRCT (6)
Obs (3)
No serious vaccine-related adverse events2b--
--AnaphylaxisRCT (6)
Obs (3)
No serious vaccine-related adverse events2b--

Table 3 Footnotes
aSome studies include persons with and without diabetes
bStudy sizes not sufficient to detect rare adverse events

Table 4. Considerations for Formulating Recommendations: Hepatitis B Vaccine for Adults with Diabetes

Key factorsComments
Balance between benefits and harmsBenefits are greater than potential harms
Evidence type for benefits and harmsBenefits: Evidence type 2 Harms: Approximately 30 year hepatitis B vaccine history indicates serious adverse events and anaphylaxis extremely rare
ValuesHigh values on preventable outcomesa for persons <60 years and moderate to high values for persons >60 years assigned by ACIP Hepatitis Work Group
Cost-effectivenessVaccination is most cost effective for adults with diabetes for ages <60 years
aPreventable outcomes consist of acute hepatitis, fulminant hepatitis, chronic hepatitis, cirrhosis, hepatocellular carcinoma, liver transplantation, death

Summary: Benefits are greater than potential harms; overall evidence is type 2. High values were placed on prevention of the morbidity and mortality of hepatitis B virus infection among adults with diabetes.

Study References

  1. Arslanoglu I, Cetin B, Isguven P, Karavus M. Anti-HBs response to standard hepatitis B vaccination in children and adolescents with diabetes mellitus. J Pediatric End & Metabolism 2002;15(4):389-95.
  2. Bouter KP, Diepersloot RJ, Wismans PJ, et al. Humoral immune response to a yeast-derived hepatitis B vaccine in patients with type 1 diabetes mellitus. Diabet Med 1992 Jan-Feb;9(1):66-9.
  3. Douvin C, Simon D, Charles MA, et al. Hepatitis B vaccination in diabetic patients. Randomized trial comparing recombinant vaccines containing and not containing pre-S2 antigen. Diabetes Care 1997 Feb;20(2):148-51.
  4. Li Volti S, Caruso-Nicoletti M, Biazzo F, et al. Hyporesponsiveness to intradermal administration of hepatitis B vaccine in insulin dependent diabetes mellitus. Arch Dis in Childhood 1998;78(1):54-7.
  5. Marseglia GL, Scaramuzza A, dAnnunzio G, Comolli G, Gatti M, Lorini R. Successful immune response to a recombinant hepatitis B vaccine in young patients with insulin-dependent diabetes mellitus. Diabetic Medicine 1996;13(7):630-3.
  6. Dienstag JL, Werner BG, Polk BF, et al. Hepatitis B vaccine in health care personnel: safety, immunogenicity, and indicators of efficacy. Ann Intern Med 1984 Jul;101(1):34-40.
  7. Szmuness W, Stevens CE, Harley EJ, et al. Hepatitis B vaccine: demonstration of efficacy in a controlled clinical trial in a high-risk population in the United States. N Engl J Med 1980 Oct 9;303(15):833-41.
  8. Francis DP, Hadler SC, Thompson SE, et al. The prevention of hepatitis B with vaccine. Report of the centers for disease control multi-center efficacy trial among homosexual men. Ann Intern Med 1982 Sep;97(3):362-6.
  9. Szmuness W, Stevens CE, Harley EJ, et al. Hepatitis B vaccine in medical staff of hemodialysis units: efficacy and subtype cross-protection. N Engl J Med 1982 Dec 9;307(24):1481-6.
  10. Crosnier J, Jungers P, Courouce AM, et al. Randomised placebo-controlled trial of hepatitis B surface antigen vaccine in French haemodialysis units: I, Medical staff. Lancet 1981 Feb 28;1(8218):455-9.
  11. Coutinho RA, Lelie N, Albrecht-Van Lent P, et al. Efficacy of a heat inactivated hepatitis B vaccine in male homosexuals: outcome of a placebo controlled double blind trial. Br Med J (Clin Res Ed) 1983 Apr 23;286(6374):1305-8.