Hepatitis B Vaccine

Number: 0410

Policy

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 workersFootnotes*
   • Hemophiliacs
   • Hepatitis C virus positive persons,
   • Household and sexual contacts of hepatitis B virus carriers
   • Injecting-drug users
   • Inmates of long-term correctional facilitiesFootnotes*
   • International travelers to geographic areas of high endemicityFootnotes*
   • 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
   • Persons with diabetes mellitus aged 19 through 59 years
   • Persons with chronic liver disease (including, but not limited to, hepatitis C virus infection, cirrhosis, fatty liver disease, alcoholic liver disease, autoimmune hepatitis, and an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level greater than twice the upper limit of normal); or
   • Pregnant women at risk for infection or an adverse infection-related pregnancy outcome

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.

Footnotes*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.

Background

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 approved by the AAP, the ACIP of the CDC, and the AAFP (2006) states that a monovalent dose of hepatitis B virus vaccine should be administered to all newborns within 24 hours of birth. 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 (OR) 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.

Cui and colleagues (2013) evaluated the associations between functional polymorphisms in the interleukin-4 (IL4) gene and individuals' responses to hepatitis B vaccine and their susceptibility to HBV infection.  A literature search on articles published before December 1st, 2012 was conducted in PubMed, Embase, Web of Science and China BioMedicine (CBM) databases.  Crude ORs with 95 % CIs were calculated.  Statistical analyses were performed using the STATA 12.0 software.  A total of 8 studies were eligible for inclusion in this meta-analysis, including 5 cross-sectional studies on individual's response to hepatitis B vaccine and 3 case-control studies on HBV infection risk.  The meta-analysis results showed that the T allele of rs2243250, the T allele of rs2070874, and the C allele of rs2227284 in IL4 gene were associated with high responses to hepatitis B vaccine.  Further subgroup analysis by ethnicity showed that there was a significant association between IL4 genetic polymorphisms and an individual's responses to hepatitis B vaccine among Asian populations, but similar association was not found among Caucasian populations.  However, there was no evidence indicating a correlation between IL4 genetic polymorphism and susceptibility to HBV infection.  The authors concluded that the findings of this meta-analysis suggested that rs2243250, rs2070874 and rs2227284 polymorphisms in IL4 gene may play an important role in determining the response to hepatitis B vaccine, especially among Asian populations.  However, they stated that further studies are still needed to evaluate the associations between IL4 genetic polymorphisms and HBV infection risk.

Zhang et al (2014) noted that combined immunization with hepatitis B immunoglobulin (HBIG) plus hepatitis B vaccine (HB vaccine) can effectively prevent peri-natal transmission of hepatitis B virus (HBV).  With the universal administration of HB vaccine, anti-HBs conferred by HB vaccine can be found increasingly in pregnant women, and maternal anti-HBs can be passed through the placenta.  These researchers evaluated the effect of hepatitis B immunization on preventing mother-to-infant transmission of HBV and on the immune response of infants towards HB vaccine.  From 2008 to 2013, a prospective study was conducted in 15 centers in China.  HBsAg-positive pregnant women and their infants aged 8 to 12 months who completed immunoprophylaxis were enrolled in the study and tested for HBV markers (HBsAg, anti-HBs, HBeAg, anti-HBe and anti-HBc).  Ante-partum administration of HBIG to HBsAg-positive women was based on individual preference.  HBsAg-negative pregnant women and their infants of 7 to 24 months old who received HB vaccines series were enrolled and tests of their HBV markers were performed.  A total of 1,202 HBsAg-positive mothers and their infants aged 8 to 12 months were studied and 40 infants were found to be HBsAg positive with the immunoprophylaxis failure rate of 3.3 %.  Infants with immunoprophylaxis failure were all born to HBeAg-positive mothers of HBV-DNA greater than or equal to 6 log₁₀copies/ml.  Among infants of HBeAg-positive mothers, immunoprophylaxis failure rate in vaccine plus HBIG group, 7.9 % (29/367), was significantly lower than the vaccine-only group, 16.9 % (11/65), p = 0.021; there was no significant difference in the immunoprophylaxis failure rate whether or not antepartum HBIG was given to the pregnant woman, 10.3 % (10/97) versus 9.0 % (30/335), p = 0.685.  Anti-HBs positive rate was 56.3 % (3,883/6,899) among HBsAg-negative pregnant women and anti-HBs positive rate was 94.2 % in cord blood of anti-HBs-positive mothers.  After completing the HB vaccine series, anti-HBs positive rate among infants with maternal anti-HBs titers of less than 10 IU/L, 10 to 500 IU/L and greater than or equal to 500 IU/L was 90.3 % (168/186), 90.5 % (219/242) and 80.2 % (89/111), respectively, p = 0.011.  Median titers of anti-HBs (IU/L) among infants in the 3 groups was 344.2, 231.9 and 161.1, respectively, p = 0.020.  The authors concluded that HBIG plus HB vaccine can effectively prevent mother-to-infant transmission of HBV, but no HBV breakthrough infection was observed in infants born to HBeAg-negative mothers who received HB vaccine with or without HBIG after birth.  They stated that ante-partum injection of HBIG has no effect on preventing HBV mother-to-infant transmission; high maternal titer of anti-HBs can transplacentally impair immune response of infants towards HB vaccine.

Machaira et al (2015) stated that the cost-effectiveness of augmenting immunization against hepatitis B infection with HBIG remains controversial, particularly for the subpopulation of babies of HBsAg+/HBeAg- mothers that are considered as low-infective.  These researchers evaluated the effectiveness of vaccine alone compared with vaccine plus HBIG for the immunization of babies of HBsAg+/HBeAg- mothers.  They searched PubMed, Scopus and Cochrane Central Register of Controlled Trials databases to identify studies comparing the effectiveness of combined immunization (vaccine plus HBIG) with vaccine alone in neonates of HBsAg+/HBeAg- mothers.  A systematic review and meta-analysis of eligible studies was performed.  A total of 9 eligible studies were identified (4 RCTs).  No difference was found regarding the primary outcome of this meta-analysis, namely occurrence of hepatitis B infection, between neonates who received vaccine only, compared with those who received both vaccine and HBIG (4 studies, 3,426 patients, OR = 0.82, 95 % CI: 0.41 to 1.64).  This finding was consistent with regards to sero-protection rate (4 studies, 1,323 patients, OR = 1.24, 95 % CI: 0.97 to 1.58).  Safety data were not reported in the included studies.  The authors concluded that available limited published evidence suggested that vaccine alone seems to be equally effective to the combination of HBIG and hepatitis B vaccine for neonates of HBsAg+/HBeAg- mothers in preventing infection.  They stated that further studies are needed in order to clarify the potential benefit of combined immunization to this specific subgroup of patients.

Booster Dose Vaccination

In a Cochrane review, Poorolajal and Hooshmand (2016) evaluated the benefits and harms of booster dose hepatitis B vaccination, more than 5 years after the primary vaccination, for preventing HBV infection in healthy individuals previously vaccinated with the hepatitis B vaccine, and with hepatitis B surface antibody (anti-HBs) levels below 10 mIU/ml.  These investigators searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, Science Citation Index Expanded, conference databases, and reference lists of articles to January 2016.  They also contacted authors of articles.  In addition, they searched ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform for ongoing trials (May 2016).  Randomized clinical trials addressing anamnestic immune response to a booster dose of hepatitis B vaccine, more than 5 years after the primary vaccination, in apparently healthy participants, vaccinated in a 3-dose or 4-dose schedule of the hepatitis B vaccine during the primary vaccination, without receiving an additional dose or immunoglobulin.  Both review authors decided if the identified studies met the inclusion criteria or not.  Primary outcomes included the proportion of participants with anamnestic immune response in non-protected participants and signs of HBV infection.  Secondary outcomes were the proportion of participants that developed local and systemic adverse events following a booster dose injection.  These researchers planned to report the weighted proportion with 95 % CIs.  There were no eligible randomized clinical trials fulfilling the inclusion criteria of this review.  The authors were unable to include any randomized clinical trials on the topic; only randomized clinical trials will be able to provide an answer as to whether a booster dose vaccination is able to protect against hepatitis B infection.

SBP (HBsAg-Binding Protein) Adjuvant for Hepatitis B Vaccine

Wang and colleagues (2017) stated that although adjuvants are a common component of many vaccines, there are few adjuvants licensed for use in humans due to concerns about their toxic effects.  There is a need to develop new and safe adjuvants, because some existing vaccines have low immunogenicity among certain patient groups.  In this study, SBP, a hepatitis B surface antigen binding protein that was discovered through screening a human liver cDNA expression library, was introduced into hepatitis B vaccine.  A good laboratory practice, non-clinical safety evaluation was performed to identify the side effects of both SBP and SBP-adjuvanted hepatitis B vaccine.  The results indicated that SBP could enhance the HBsAg-specific immune response, thus increasing the protection provided by the hepatitis B vaccine.  The authors concluded that given the encouraging safety data obtained in this study, further evaluation of SBP as a vaccine adjuvant for human use is warranted.  They stated that this research has the potential to accelerate adjuvant development for HBV vaccine and for other vaccine types in the future.

Heplisav-B (Hepatitis B Vaccine)

On February 21, 2018, the ACIP voted unanimously in favor of including Heplisav-B (HepB-CpG) on its list of ACIP recommended products for use to vaccinate adults against hepatitis B.  Heplisav-B was approved by the Food and Drug Administration (FDA) in November 2017; it is indicated for prevention of infection caused by all known subtypes of hepatitis B virus in adults 18 years of age and older.  The CDC's ACIP (2018) has published its guidance on use of Heplisav-B.  The vaccine is recommended for adults at risk for acquiring HBV.  These include people at risk from sexual transmission, incarcerated people, people with HIV, injection drug users, and household contacts of infected people, among others.  The new vaccine is one of 5 approved inactivated HBV vaccines.  Heplisav-B contains a novel immuno-stimulatory sequence adjuvant; 2 doses are administered just 1 month apart, making it "an important option for prevention of HBV", the authors wrote in MMWR.  In randomized trials, sero-protective antibody to hepatitis B surface antigen levels were obtained in 90 to 100 % of subjects receiving Heplisav-B, versus 71 % to 90 % of those receiving another HBV vaccine, Engerix-B.  The vaccine's safety has not been tested in pregnancy, so the committee recommends that pregnant women receive an alternative HBV vaccine.

Immune Response to Hepatitis B Vaccine in Patients with Chronic Hepatitis C Infection

Liu and colleagues (2018) stated that hepatitis B virus and hepatitis C virus (HCV) co-infection can add to the severity of hepatitis and the risks of liver cirrhosis and hepato-cellular carcinoma (HCC).  Whether chronic HCV infection decreases antibody response to hepatitis B vaccination is still controversial.  These researchers evaluated the influence of HCV infection on antibody response to hepatitis B vaccination by a systematic review of published works with a meta-analysis of clinical trials.  The random-effects model of DerSimonian and Laird with heterogeneity and sensitivity analyses were used in this study.  The end-point of interest was the rate of patients showing sero-conversion of antibody responses at completion of hepatitis B vaccination schedule among patients with chronic HCV infection versus healthy controls.  These investigators identified 11 studies involving 704 patients with HCV and 812 controls.  The results showed a significant decrease in antibody sero-conversion rates among patients with HCV versus healthy controls (pooled OR = 0.17 [95 % CI: 0.11 to 0.28]).  The p-value was 0.21 for the test of study heterogeneity.  Stratified analysis in subgroups of interest and sensitivity analysis did not meaningfully change these results.  The meta-analysis showed patients with hepatitis C infection had a statistically significant lower rate of sero-conversion in comparison to healthy controls, both in cirrhotic and non-cirrhotic patients.  The authors concluded that chronic HCV infection can decrease the immune response to a standard schedule of hepatitis B vaccination; further studies are needed to examine the optimum vaccination schedule for patients with chronic HCV infection.

Pregnant Women at Risk for Infection or an Adverse Infection-Related Pregnancy Outcome

The CDC (2020) has recently released an updated schedule for adult vaccines including those for hepatitis B.  It states that “For hepatitis B, a new addition to the list of vulnerable patients who may possibly benefit from vaccination is pregnant women at risk for infection or an adverse infection-related pregnancy outcome”.

Prevention of Mother-to-Child Transmission in HBV Surface Antigen (HBsAg)-Positive Pregnant Women

Guidelines from the Centers for Disease Control and Prevention (Schillie, et al., 2018) state that perinatal HBV transmission can be prevented by identifying HBV-infected (i.e., hepatitis B surface antigen [HBsAg]-positive) pregnant women and providing hepatitis B immune globulin and hepatitis B vaccine to their infants within 12 hours of birth.

In a systematic review and meta-analysis, Chen and colleagues (2020) examined the benefits and harms of hepatitis B immune globulin (HBIG) and hepatitis B vaccine (HBVac) in preventing mother-to-child transmission (MTCT) in HBV surface antigen (HBsAg)-positive pregnant women during ante-natal period.  A total of 7 electronic databases including PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), WanFang Database, Chinese Biomedical Literature Database (CBM), VIP Database for Chinese Technical Periodicals (VIP), and 3 clinical trial registry platforms were searched from inception date to December 2017; only RCTs were included in this study.  The Cochrane risk of bias tool was used to evaluate the risk of bias.  The outcomes were analyzed by Review Manager 5.3 software.  A total of 16 RCTs involving 2,440 HBsAg-positive pregnant women were included in the meta-analysis.  Compared with placebo group, HBIG and HBVac group had a significant decrease in the number of newborns who were HBsA- positive (relative risks [RR]: 0.2, 95 % CI: 0.18 to 0.40, p < 0.00001) and HBV-DNA-positive (RR: 0.25, 95 % CI: 0.09 to 0.71], p = 0.010), and had a significant increase in the number of anti-HBs-positive newborns (RR: 3.95, 95 % CI: 3.11 to 5.00, p < 0.00001).  After 1-year follow-up, the number of HBsAg-positive newborns continued to decline (RR: 0.09, 95 % CI: 0.04 to 0.20, p < 0.00001) and the number of anti-HBs-positive newborns continued to increase in HBIG and HBVac group (RR: 1.30, 95 % CI: 1.22 to 1.38], p < 0.00001).  Compared with HBIG group, HBIG and HBVac group had no significant difference in the number of HBsAg-positive newborns (RR: 1.68, 95 % CI: 0.66 to 4.30, p = 0.28), and had a significant decrease in the number of HBsAg-positive newborns (RR: 0.31, 95 % CI: 0.12 to 0.84, p = 0.02).  Furthermore, only 1 study reported 2 swelling cases, 4 studies reported no adverse events (AEs), and 11 studies did not report AEs.  The authors concluded that HBIG and HBVac could be an effective alternative for HBsA- positive pregnant women to prevent MTCT; however, due to the limitations of the study, the long-term safety and efficacy of HBIG and HBVac still need long-term and high-quality research to confirm.

The authors stated that this study had several drawbacks.  First, only 1 study conducted personnel evaluation, blinding of outcome assessment, and subjects; thus, these researchers could not examine the risks of bias of the results.  Second, this study was not registered in a database; however, before these researchers initiated the study, they had made a pre-defined protocol.  Third, these investigators searched all the electronic databases from inception date to December 2017.  After screening the studies, they included 16 RCTs from 2000 to 2017; approximately 17 years from the 1st publication and last publication may have affected the results due to the time factor.  Fourth, because most of the trials did not report the AEs, these researchers could not confirm the safety for pregnant women and newborns.  Fifth, these investigators reviewed the 16 included RCTs, but they could not be sure that HBIG and HBVac were the same contents.  Furthermore, HBV infection was the major cause of end-stage liver diseases in China, among which 30 % to 50 % were due to MTCT and were associated with increased risk of morbidity and mortality later in life.  Anti-viral therapies could also provide benefits in HBsAg-positive pregnant women, but this review was not designed to examine the efficacy of these agents.  And the authors found no comparative benefits and harms between HBIG+HBVac and anti-virals; therefore, they could not draw comparative conclusions.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met:
90636, 90739 - 90748	Hepatitis B vaccine
HCPCS codes covered if selection criteria are met:
G0010	Administration of hepatitis B vaccine
ICD-10 codes covered if selection criteria are met:
A50.01 - A64	Infections with a predominantly sexual mode of transmission
B17.10 - B17.11 B18.2 B19.20 - B19.21	Hepatitis C
B20	Human immunodeficiency virus [HIV] disease
B97.35	Human immunodeficiency virus, type 2 [HIV 2] as the cause of diseases classified elsewhere
D65 - D68.9	Coagulation defects [hemophiliacs]
D69.1	Qualitative platelets defects
E08.00 - E13.9	Diabetes mellitus
F11.10 - F19.99	Drug dependence and nondependent abuse of drugs [injecting-drug users]
K70.0 - K70.9, K73.0 - K73.9, K74.0 - K74.69, K75.4, K76.0 - K76.1,K76.81 - K76.9	Chronic liver diseases and cirrhosis
O35.3xx0 - O35.3xx9	Maternal care for (suspected) damage to fetus from viral disease in mother [pregnant women at risk for infection]
O98.411 - O98.43	Viral hepatitis complicating pregnancy [pregnant women at risk for infection]
Z00.110	Health examination for newborn under 8 days old
Z00.111	Health examination for newborn 8 to 28 days old
Z00.121	Encounter for routine child health examination with abnormal findings
Z00.129	Encounter for routine child health examination without abnormal findings
Z00.3	Encounter for examination for adolescent development state
Z02.0	Encounter for examination for admission to educational institution [school children age 0-18]
Z02.1	Encounter for pre-employment examination [healthcare workers]
Z02.2	Encounter for examination for admission to residential institution [students]
Z02.89	Encounter for other administrative examination [admission to prison] [pregnant women at risk for infection]
Z20.5	Contact with and (suspected) exposure to viral hepatitis
Z21	Asymptomatic human immunodeficiency virus [HIV] infection status
Z22.4	Carrier of infections with a predominantly sexual mode of transmission
Z22.50 - Z22.59	Carrier of viral hepatitis
Z23	Encounter for immunization
Z51.11	Encounter for antineoplastic chemotherapy
Z72.51 - Z72.53	High risk sexual behavior [history of multiple sex partners]
Z76.82	Awaiting organ transplant status
Z94.0	Kidney transplant status
Z94.1	Heart transplant status
Z94.2	Lung transplant status
Z94.3	Heart and lung transplant status
Z94.4	Liver transplant status
Z94.6	Bone transplant status
Z94.81	Bone marrow transplant status
Z94.82	Intestine transplant status
Z94.83	Pancreas transplant status
Z94.84	Stem cells transplant status
Z94.89 - Z94.9	Other and unspecified transplanted organ and tissue status
Z99.2	Dependence on renal dialysis

The above policy is based on the following references: