Authors: Ellisa Zhang, PharmD Candidate 2020 and April Pottebaum, PharmD, BCPS
Hepatitis B Risk
Based on a national health survey, an estimated 850,000 people are living with hepatitis B in the United States.1 However, this number could be an underestimate since studies evaluating migration data and prevalence of hepatitis B in foreign countries estimate that this number could be as high as 2.2 million. 1 The hepatitis B virus (HBV) is a DNA virus that replicates in the liver and can progress to a chronic infection that leads to an increased risk of liver cirrhosis and hepatocellular carcinoma.1,2 HBV is transmitted through infected blood and body fluids via percutaneous or mucosal contact.1 It can also remain infectious on non-living surfaces in the environment for at least 7 days. Thus, patients on dialysis are especially at risk for acquiring HBV due to increased exposure to blood with frequent dialysis treatments as well as use of shared dialysis equipment.2
Patients with end-stage renal disease (ESRD) are more susceptible to infection due to a weakening of the immune system secondary to uremia.3 Production of T-cells is decreased and alterations of costimulatory molecules CD80 and CD86 impair the activity of antigen-presenting cells in this patient population.This suppresses the adaptive immune response, leading to a higher rate of infection, a lower response rate to vaccinations, and a shorter duration of seroprotection against antigens.3 Fifty to seventy percent of dialysis patients respond to the hepatitis B vaccine, but only 40% will maintain protection against HBV three years after their vaccination series, as compared to initial response rates of > 90% in healthy adults aged < 40 years and 75% in adults aged 60 years.1,4 Studies evaluating causes of reduced seroconversion in ESRD patients show conflicting results, likely because these studies have small sample sizes and different methodologies for administering the hepatitis B vaccines.4-6 Since patients vaccinated in earlier stages of renal disease showed higher rates of seroconversion, it is advisable to start hepatitis B vaccinations before patients become dialysis dependent.7,8
Current Hepatitis B Vaccine Recommendations
Updated guidance on use of HBV vaccines in adults on hemodialysis was provided by ACIP in January 2018. Due to the increased risk of exposure to HBV, serological testing is recommended before vaccination for patients receiving hemodialysis.1 Testing includes the hepatitis B surface antigen (HBsAg), antibody to hepatitis B surface antigen (anti-HBs), and antibody to hepatitis B core antigen (anti-HBc). Anti-HBs levels >10 mIU/mL generally indicate seroprotection against HBV infection, but the cutoff values could differ based on the assay used. While testing is not required for vaccination, it can reduce costs by avoiding vaccination in persons who are already immune. In settings where testing is not feasible, vaccination should continue as administration of the vaccine to individuals who are immune due to acute or chronic HBV infection or previous vaccination does not increase the risk for adverse events.1
For patients > 20 years old on dialysis, either high-dose Engerix-B® (40 mcg) or high-dose Recombivax HB® (40 mcg) given IM is recommended.1 Engerix-B® is a 4-dose series given at months 0, 1, 2, and 6 while Recombivax HB® is a 3-dose series given at months 0, 1, and 6. If the vaccination series is interrupted, it does not need to be restarted. If the second dose is delayed, it should be administered as soon as possible, and then the third dose must be separated from the second dose by at least 8 weeks. If the third dose is delayed, it should be administered as soon as possible.1 The series should be completed with vaccines from the same manufacturer when possible.9
Although serologic testing for immunity is not routinely performed after vaccination of most individuals, anti-HBs levels should be assessed 1 to 2 months after completion of the vaccination series in dialysis patients.1 For most assays, if the level is >10 mIU/mL, then the patient is considered immune and does not need further vaccinations. However, if the level is <10 mIU/mL, then the patient should complete another full vaccination series, and another anti-HBs titer should be checked 1 to 2 months after this revaccination. If there is still no serologic response, then a test for HBsAg is recommended to determine infection status. A positive HBsAg indicates HBV infection, so the patient would need to be educated about strategies to prevent the spread of infection. If the HBsAg is negative, the patient is still susceptible to HBV infection, so he or she should be counseled on how to prevent infection and the importance of receiving hepatitis B immune globulin (HBIG) if exposed to infected blood.1
Annual anti-HBs testing is recommended in dialysis patients to determine if a booster dose of hepatitis B vaccine is needed. Patients should receive a booster dose of hepatitis B vaccine if the anti-HBs level falls to <10 mIU/mL. Testing to assess the efficacy of the booster dose is not necessary.1 Figure 1 provides a summary of these recommendations.
New Vaccine on the Market
Heplisav-BTM by Dynavax is a newer HBV vaccine that was FDA-approved in November 2017 for adults 18 years and older. Heplisav-B™ is an attractive alternative to Engerix-B® or Recombivax HB® for hepatitis B vaccination due to a more convenient dosing schedule as well as better seroprotection.10 It is a 2-dose series, with doses administered IM at least one month apart. While the other HBV vaccines use aluminum hydroxide as an adjuvant, Heplisav-BTM uses a novel adjuvant cytosine phosphoguanine oligonucleotide (CpG1018). CpG1018 is synthesized from bacterial DNA and helps stimulate the immune system by activating the toll-like receptor 9 (TLR-9) pathway.10
The clinical trials that led to approval of Heplisav-B™ were phase 3 noninferiority studies which compared response rates of Heplisav-BTM to Engerix-B®.11-13 In a study of healthy patients aged 18-55 years, Heplisav-B™ was shown to provide significantly higher rates of seroprotection as compared to Engerix-B® (97.9% vs 81.1%).11 Another study in healthy adults aged 40-70 years also found a significantly higher response to Heplisav-B™ as compared with Engerix-B® (94.8% vs 72.8%).12 Similar results were also observed in a study of patients with type 2 diabetes.13 While Heplisav-BTM did demonstrate increased efficacy as compared to Engerix-B® in each of these studies, it also caused more injection-site reactions.11-13 Despite these promising findings, the studies did not include patients on dialysis, so use of Heplisav-B™ cannot be routinely recommended in this patient population until more data is available.14 A study is currently enrolling patients on hemodialysis to assess the safety and efficacy of Heplisav-BTM with an estimated completion date of April 2021.15
Even with the potential for improved immunogenicity with Heplisav-B™, ACIP still recommends testing for anti-HBs to determine vaccine response in hemodialysis patients and other populations at risk for HBV infection.14 Since there is limited data about switching between Heplisav-BTM and the other hepatitis B vaccines (i.e. Engerix-B® or Recombivax HB®), these vaccines should not be interchanged. If a patient receives one dose of Heplisav-BTM and one dose of another hepatitis B vaccine, then the vaccination series should be completed with a total of three vaccine doses.14
Patients on dialysis are at higher risk for HBV infection compared to the general population due to the nature of dialysis procedures requiring frequent vascular access and a suppressed immune system secondary to uremia. Furthermore, patients on dialysis have lower response rates to hepatitis B vaccines and decreased ability to maintain seroprotection against HBV. It is essential to ensure patients on dialysis are vaccinated appropriately and monitored annually for seroprotection to the hepatitis B virus. While alternative strategies for hepatitis B vaccination are needed to combat this problem and a newer HBV vaccine is showing promise for improved immunogenicity, further studies are needed to fully assess efficacy in this patient population. ACIP offers the most current evidence-based recommendations for vaccination to prevent HBV infection.
Current Recommendations on the Prevention of HBV Infection in Patients Undergoing Hemodialysis