Aetna considers hepatitis B vaccine a medically necessary preventive service for members with any of the following indications:

1. Infants, regardless of hepatitis B surface antigen (HBsAg) status of the mother; or

2. Children and adolescents (0 to 18 years) who have not been vaccinated previously; or

3. Adults (over 18 years of age) at increased risk for hepatitis B infection, including:

   • Health-care workers*
   • Hemophiliacs
   • Hepatitis C virus positive persons,
   • Household and sexual contacts of hepatitis B virus carriers
   • Injecting-drug users
   • Inmates of long-term correctional facilities*
   • International travelers to geographic areas of high endemicity*
   • Men who have sex with men
   • Persons who undergo hemodialysis
   • Persons with a history of multiple sex partners
   • Persons with a recent sexually transmitted disease; or
   • Persons with chronic liver disease

   • Persons with diabetes mellitus aged 19 through 59 years.

4. Transplant candidates of any age.

Aetna considers hepatitis B vaccine experimental and investigational for all other indications because its effectiveness for indications other than the ones listed above has not been established.

Booster doses of Hepatitis B vaccine are considered medically necessary only in certain circumstances:

• A booster dose is considered medically necessary for persons on hemodialysis when antibody to hepatitis B surface antigen (anti-HBs) levels decline to less than 10 mIU/ml.  For persons receiving hemodialysis, the Centers for Disease Control and Prevention (CDC) states that the need for booster doses should be assessed by annual testing for antibody to hepatitis B surface antigen (anti-HBs).
• When anti-HBs levels decline to less than 10 mIU/ml, annual anti-HBs testing and booster doses are considered medically necessary for other immunocompromised persons (e.g., HIV-infected persons, hematopoietic stem-cell transplant recipients, and persons receiving chemotherapy) with an ongoing risk for exposure.  According to the CDC, for these other immunocompromised persons, the need for booster doses has not been determined.
• For persons with normal immune status who have been vaccinated, booster doses are considered not medically necessary.

This policy is consistent with CDC guidelines.

*Note: Aetna generally does not cover immunizations required for travel or because of work-related risk.  Check contract language, limitations and exclusions for coverage details.

Pre-exposure immunization of susceptible persons with hepatitis B vaccine is the most effective means to prevent hepatitis B virus (HBV) transmission.  To reduce transmission of HBV and eventually to eliminate it, universal immunization is necessary.  Vaccination against HBV has been recommended as part of routine early childhood immunizations since 1991.  Accordingly, immunization of all children before or during adolescence is necessary and recommended.  Along with universal immunization efforts, immunization of adults belonging to identified high-risk groups is appropriate.  Post-exposure evaluation and treatment, including diagnostic testing and immunization in selected cases, is also appropriate to prevent HBV infection among individuals of all ages regardless of the presence or absence of risk factors.

These indications blend the recommendations of the Advisory Committee on Immunization Practices (ACIP), the American Academy of Pediatrics (AAP), and the American Academy of Family Physicians (AAFP).  These 3 groups, working with federal agencies, have approved a unified childhood immunization schedule.  The recommendations for hepatitis B vaccine in the unified schedule are generally similar to those recommended by the U.S. Preventive Services Task Force (USPSTF).  However, routine hepatitis B vaccine was recommended only in infancy in the unified schedule, whereas the USPSTF also recommends its routine use in all children and adolescents not previously immunized.  The ACIP and AAP have subsequently revised their recommendations for hepatitis B vaccine to include all children aged 11 to 12 years who have not previously been vaccinated; ACIP also recommends vaccinating unimmunized children under 11 years who are Pacific Islanders or who reside in households of first-generation immigrants from countries with high or intermediate HBV endemicity.

Three doses of hepatitis B vaccine are required for complete immunization.  For infants, the Centers for Disease Control and Prevention (CDC) and the ACIP recommend hepatitis B vaccine be incorporated into the routine vaccination schedules for children.

Hepatitis B vaccine has been administered using an accelerated immunization protocol for persons who are candidates for solid organ, bone marrow or stem cell transplantation to reduce the risk of hepatitis infection from administration of blood products and transplanted organs.

The annual recommended childhood and adolescent immunization schedule for January to December 2006 approved by the AAP, the ACIP of the CDC, and the AAFP (2006) states that vaccination of infants born to HBsAg-negative mothers can be delayed in rare circumstances, but only if a physician's order to withhold the vaccine and a copy of the mother's original HBsAg-negative laboratory report are documented in the infant's medical record.  Administering 4 doses of HepB is permissible (e.g., when combination vaccines are administered after the birth dose); however, if monovalent HepB is used, a dose at age 4 months is not needed.  For infants born to HBsAg-positive mothers, testing for HBsAg and antibody to HBsAg after completion of the vaccine series should be conducted at age 9 to18 months (generally at the next well-child visit after completion of the vaccine series).

In a randomized controlled trial (RCT), Cornejo-Juarez et al (2006) found that an increase dose of HBV vaccine did not increase the rate of response in HIV infected subjects.  These researchers assessed 2 doses of recombinant HBV vaccine (10 or 40 microg), intra-muscular (IM) at 0, 1 and 6 months.  Vaccination response was measured 30 to 50 days after last dose; titers of greater than 9.9 IU/L were considered positive.  A total of 79 patients were included, 48 patients (60.7 %) sero-converted.  Thirty-nine patients (49.3 %) received 10 microg vaccine dose, 24 patients (61.5 %) sero-converted.  Forty patients (50.7 %) received 40 microg vaccine dose, 24 (60 %) sero-converted.  There were no differences between the 2 doses.  A statistically significant higher sero-conversion rate was found for patients with CD4 cell counts at vaccination greater than or equal to 200 cell/mm3 (33 of 38 patients, 86.8 %), compared with those with CD4 less than 200 cell/mm3 (15 of 41, 36.6 %), (odds ratio of 11.44, 95 % confidence interval [CI]: 3.67 to 35.59, p = 0.003), there were no differences between 2 vaccine doses.  Using the logistic regression model, CD4 count less than 200 cell/mm3 were significantly associated with non-serological response (p = 0.003).  None other variables such as gender, age, risk exposure for HIV, viral load, type or duration of highly active anti-retroviral therapy or AIDS-defining illness, were associated with sero-conversion.  The authors concluded that an increase dose of HBV vaccine did not show to increase the rate of response in HIV infected subjects.  The only significant findings associated to the response rate was that a CD4 count greater than or equal to 200 cell/mm3, these investigators suggested this threshold at which HIV patients should be vaccinated.

Pasricha and colleagues (2006) evaluated the effectiveness of recombinant vaccine in treatment-naive HIV-positive patients and healthy controls, and ascertained differences if any, in different limbs of immune response.  A total of 40 HIV-positive patients and 20 HIV-negative controls, negative for HBsAg, HBsAbs and HBcAbs were vaccinated with 3 doses of 40 microg and 20 microg of vaccine, respectively.  Patients were divided into high-CD4 and low-CD4 group based on CD4+ lymphocytes of 200 and less than 200/mm3, respectively.  Group II consisted of healthy controls.  Detection of phenotypic markers was done by flow cytometry.  Cytokine estimation was done by sandwich ELISA.  HBsAbs were estimated in serum by ELISA.  After vaccination, CD4+, CD8+ and CD3+ cells increased significantly in all the groups.  There was no increase in natural killer cell activity in patients with high CD4+ lymphocytes and only a marginal increase in patients with low CD4+ lymphocytes (170 to 293/mm3) whereas a marked increase was observed in controls (252 to 490/mm3).  After vaccination, although an increase in memory cells was observed in HIV-positive patients, yet HBsAb levels were significantly lower than controls (p < 0.05) indicating a functional defect of memory cells in HIV/AIDS patients.  Basal interferon-gamma levels were also significantly lower in HIV/AIDS patients (p < 0.01).  Although the levels increased after vaccination, the peak level remained lower than in controls.  HBsAb titers were much lower in HIV-positive patients compared to controls. (high-CD4+ group: 8834 mIU/ml, low-CD4+ group: 462 mIU/ml versus controls: 16,906 mIU/ml).  IL-4 and IL-10 were low in patients.  The authors concluded that despite a double dose in patients, IL-4 and IL-10, which regulate antibody response, were also lower in patients, and this together with low CD4+ counts and lack of T help, accounted for low HBsAb levels.  Vaccination in patients with CD4+ lymphocytes less than 50/mm3 was ineffective.

It is also interesting to note that extended double-dosage HBV vaccination (2 cycles of 3 IM double doses [40 microg], given at month 0, 1, 2, and 3, 4, 5) following liver transplantation is ineffective (Di Paolo et al, 2006).

In a Cochrane review on hepatitis B immunization in persons not previously exposed to hepatitis B or with unknown exposure status, Mathew and colleagues (2008) concluded that in people not previously exposed to hepatitis B, vaccination has unclear effect on the risk of developing infection, as compared to no vaccination.  The risk of lacking protective antibody levels as well as serious and non-serious adverse events appear comparable among recipients and non-recipients of hepatitis B vaccine.

According to the CDC, pregnancy is not a contraindication to hepatitis B vaccination.  The CDC states that limited data indicate no apparent risk for adverse events to developing fetuses when hepatitis B vaccine is administered to pregnant women.  Current vaccines contain noninfectious HBsAg and should cause no risk to the fetus.  The CDC states that pregnant women who are identified as being at risk for HBV infection during pregnancy (e.g., having more than 1 sex partner during the previous 6 months, been evaluated or treated for an sexually transmitted disease, recent or current injection drug use, or having had an HBsAg-positive sex partner) should be vaccinated.

Lin and Vickery (2009) searched for large, high-quality studies related to hepatitis B screening in pregnancy that have been published since the 2004 USPSTF recommendation.  English-language studies indexed in PubMed and the Cochrane Database of Systematic Reviews and published between January 1, 2001 and March 5, 2008 were included in this study.  For benefits of screening and newborn prophylaxis, these investigators included systematic reviews; meta-analyses; and RCTs.  For harms of screening, they included systematic reviews; meta-analyses; RCTs; cohort studies; case-control studies; and case series of large, multi-site databases.  Abstracts and full articles were independently reviewed for inclusion by both reviewers.  Data on the benefits of screening, including benefits of hepatitis B immune globulin and hepatitis B vaccine prophylaxis of newborns of HBsAg-positive mothers, were extracted by 1 reviewer.  No new studies met inclusion criteria.  A 2006 systematic review of RCTs found that newborn prophylaxis reduced peri-natal transmission of HBV infection; all relevant trials were published in 1996 or earlier.  The authors concluded that no new evidence was found on the benefits or harms of screening for HBV infection in pregnant women.  Previously published RCTs support the 2004 USPSTF recommendation for screening.

In a Cochrane review, Poorolajal et al (2010) evaluated the benefits and harms of booster dose hepatitis B vaccination for preventing hepatitis B infection.  Randomized clinical trials addressing anamnestic immune response to booster of hepatitis B vaccine 5 years or more after primary vaccination in apparently healthy participants, vaccinated in a 3-dose or 4-dose schedules of hepatitis B vaccine without receiving additional dose or immunoglobulin were included in this analysis.  Two authors made the decisions if the identified publications on studies met the inclusion criteria or not.  Primary outcome measures included the proportion with anamnestic immune response in non-protected participants and signs of HBV infection.  Secondary outcomes were the proportion with local and systemic adverse event events developed following booster dose injection.  Weighted proportion were planned to be reported with 95 % confidence interval.  There were no eligible RCTs fulfilling the inclusion criteria of this review.  The authors were unable to identify RCTs on the topic.  They stated that there is a need for RCTs to formulate future booster policies for preventing HBV infection.

In a Cochrane review, Sangkomkamhang and colleagues (2011) evaluated the effectiveness and adverse effects of hepatitis B vaccine administered to pregnant women for preventing HBV infection in infants.  Randomized controlled trials assessing hepatitis B vaccination compared with placebo or no treatment during pregnancy for preventing infant infection were included in this analysis.  These investigators excluded quasi-RCTs and cross-over studies.  Two review authors independently assessed trial eligibility.  They were not able to include any studies.  The authors found no RCTs that assessed the effects of hepatitis B vaccine during pregnancy for preventing infant infection.  Consequently, this review can not provide guidance for clinical practice in this area.  However, it does identify the need for well-designed RCTs for the effect of hepatitis B vaccine during pregnancy on the incidence of infant infection and adverse effects.

On the basis of available information about HBV risk, morbidity and mortality, available vaccines, age at diagnosis of diabetes, and cost-effectiveness, the ACIP (2011) recommended the following:

• Hepatitis B vaccination should be administered to unvaccinated adults with diabetes mellitus who are aged 19 through 59 years (recommendation category A; evidence type 2).
• Hepatitis B vaccination may be administered at the discretion of the treating clinician to unvaccinated adults with diabetes mellitus who are aged 60 years or older (recommendation category B; evidence type 2).

Fabrizi et al (2012) stated that patients with chronic kidney disease typically show an impaired immune response to HBV vaccine compared with healthy individuals.  A variety of inherited or acquired factors have been implicated in this diminished response.  Some authors suggested a benefit with adjuvantation to improve the immunogenicity of existing HBV vaccines.  In a meta-analysis, these investigators evaluated the safety and effectiveness of adjuvantation for HBV vaccine in patients with chronic kidney disease.  Only prospective, RCTs were included.  These researchers used the random effects model of DerSimonian and Laird with heterogeneity and subgroups analyses.  The primary end-point of interest was the sero-protection rate after HBV vaccination with recombinant vaccine plus adjuvants (study group) versus recombinant vaccine alone (control group).  These investigators identified 10 studies involving 1,228 unique patients with chronic kidney disease.  Pooling of study results did not show a significant increase in sero-protection rate among study (HBV recombinant vaccine plus adjuvants) versus control (HBV recombinant alone) patients; the pooled odds ratio of sero-protection rate was 1.47 (95 % CI: 0.88 to 2.46, NS).  The pooled OR for sero-response rate after HBV vaccine (adjuvanted recombinant vaccine versus recombinant vaccine alone) did not change in the subgroup of studies based on novel adjuvant systems (i.e., HBV-AS04 or HBV-AS02), the pooled OR was 2.22 (95 % CI: 0.72 to 6.78), NS.  Q-test for heterogeneity being 10.819 (p = 0.004).  The authors concluded that this meta-analysis showed that adjuvanted hepatitis B vaccine did not significantly improve the sero-protection rate in patients with renal insufficiency.  These results do not support adjuvantation as an approach to increase the immunogenicity of existing recombinant vaccines towards HBV in this high-risk population.