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Introduction

Hepatitis B could be considered the "forgotten hepatitis." While much focus has been placed on the current hepatitis C epidemic, hepatitis B is often overlooked and misunderstood, with many missed opportunities to prevent serious liver damage due to chronic hepatitis B virus (HBV) infection.¹ Vaccination is highly effective in preventing people from contracting the infection.² However, many high-risk candidates for the vaccine are not identified and many others do not receive the vaccine—or do not adhere to the full vaccination series to confer adequate protection from the virus. Pharmacists are an important part of the National Viral Hepatitis Action Plan's goal to decrease the number of new HBV infections.³ Many pharmacists administer hepatitis B vaccines, and pharmacists also play an essential role in educating patients and other healthcare providers about the benefits of vaccination, vaccine selection, and administration procedures.⁴ Questions may arise about what to do if a patient does not complete the series, which vaccines to use for which patients, and whether vaccine types are interchangeable. This program will address these key questions while providing a thorough overview of hepatitis B screening and prevention to enable pharmacists to identify at-risk patients and administer appropriate preventive strategies.

National and Global Impact of Hepatitis B

Worldwide, an estimated 2 billion individuals have been infected with hepatitis B virus (HBV). The World Health Organization (WHO) reports that 257 million persons currently live with chronic, lifelong HBV infection.^5,6 On a global basis, HBV is significantly more prevalent than hepatitis B or HIV, as shown in Figure 1.⁷

Figure 1. Worldwide Burden of Hepatitis B Viral Infection

Data adapted from: Matthews P, et al. J Clin Virology. 2014;61:20-33.

While the prevalence of HBV infection is greatest in African and Asian countries (Figure 2), the impact in this country is still significant.⁸ Between 850,000 and 2.2 million people in the United States have chronic HBV infection, but only about a third of them are diagnosed and of those, only a third are on treatment.² Among the overarching goals of the National Viral Hepatitis Action Plan is to increase the proportion of people with chronic HBV who are aware of their infection from 30% to 60%.³

New HBV infections in the U.S. have spiked in recent years. Surveillance data from the Centers for Disease Control and Prevention (CDC) showed nearly 22,000 newly diagnosed cases of acute HBV infection in the U.S. in 2015, an increase of 20.7% from the previous year.⁹ Acute infection rates tend to be highest among adults aged 30 to 39.¹⁰ Much of this new transmission can be attributed to misuse of prescription opioids and intravenous heroin use among persons who inject drugs. In the 7 years from 2006 to 2013, the rate of acute HBV infections increased by 114% in the Appalachian region (Kentucky, Tennessee, and West Virginia) where opioid abuse is prevalent.¹¹

Figure 2. Global Distribution of Hepatitis B Infection

Source: Centers for Disease Control and Prevention (CDC). Chapter 4. Travel-related infectious diseases. In: Yellow Book. Updated July 1, 2019

"Diagnosed" is a key word when it comes to describing HBV. According to the CDC, as many as 91% of HBV cases go unreported or undiagnosed (Figure 3),⁵ and many of the individuals who are infected with HBV are simply unaware that they have this infection.¹² HBV infection often remains relatively silent until signs of severe chronic disease appear, such as cirrhosis or end-stage liver disease.

Not everyone who contracts HBV develops a chronic infection. Some cases resolve on their own, but in other cases the person remains an asymptomatic carrier, or a vector for spreading the infection.¹³ The risk for chronic infection is extremely high in infants—as approximately 90% of those exposed become chronically infected. By comparison, only 2% to 6% of adults who are infected will go on to develop chronic HBV.¹² Among those who do develop chronic HBV, a high proportion will develop serious complications including cirrhosis, hepatocellular carcinoma, and/or end-stage liver disease. In untreated individuals with predominantly HBeAg positive chronic hepatitis B, the incidence of cirrhosis ranges from 2 to 5.4 per 100 person-years, with a 5-year cumulative incidence of cirrhosis of 8% to 20%.¹⁴

HBV infection accounts for approximately 45% of cases of hepatocellular carcinoma and 30% of all cirrhosis cases.¹⁵

Hepatocellular carcinoma and cirrhosis are costly to treat and usually terminal. About 25% of individuals with chronic HBV infection die prematurely from cirrhosis or liver cancer. HBV is associated with about 5,000 deaths annually in the U.S. and nearly 900,000 deaths worldwide.⁶

These statistics underscore the need for identifying at-risk individuals and vaccinating. Pharmacists can take a proactive role in encouraging high-risk patients to be tested and initiating vaccination where permitted.

Figure 3. Tip of the Iceberg: Estimates of Undiagnosed HBV

Source: National Notifiable Diseases Surveillance System. CDC Hepatitis Statistics 2017. Available at: https://www.cdc.gov/hepatitis/statistics/2017surveillance/index.htm#ref05

What is Hepatitis B?

The hepatitis B virus is an enveloped deoxyribonucleic acid (DNA) virus that infects the liver, triggering hepatocellular necrosis and inflammation.¹⁵ HBV is transmitted via exposure to blood, semen, or other body fluids from an infected person.⁶

HBV is highly infectious—as much as 50 to 100 times more infectious than the human immunodeficiency virus (HIV).⁶ The virus can survive on environmental surfaces outside of the body for at least 7 days.⁶ The stages of HBV infection are outlined in Table 1.¹⁶ After exposure, there is an incubation period, after which the patient may develop an acute infection. The acute infection resolves on its own in most adults with normal immune status. Acute infection is usually asymptomatic but can range widely, from subclinical disease to fulminant hepatic hepatitis leading to chronic HBV. When symptomatic, the patient with acute HBV may experience fever, fatigue, nausea, and vomiting. These symptoms are usually self-limited and resolve spontaneously without treatment.¹⁵ Anorexia, dark urine, and clay-colored stool are symptoms that often prompt people to seek medical advice. In adults, the period of latency (time from acute to chronic infection) may be prolonged for many years. During that time the person can unknowingly transmit the virus to others.¹⁷ Those who recover fully will develop lifelong immunity.¹⁸ However, if the infection does not resolve, the person may either be a silent carrier or go on to develop chronic HBV with a high risk for serious liver damage.

Whether or not a person develops chronic infection is dependent on a combination of host, viral, and environmental factors. Groups at higher risk for developing chronic HBV include^19,20:

• Infants
• Older males
• Persons with diabetes
• Immunocompromised persons (e.g., coinfection with HIV)

Screening Recommendations and At-Risk Populations in the US

Modes of HBV transmission include sexual contact, sharing needles, syringes, or other equipment for injecting drugs, occupational exposure among healthcare workers, and vertical transmission from mother to infant during birth. Risk factors for transmission of HBV include:⁹

• Needle-sharing when using injectable drugs
• Sexual contact with infected individuals
• Contact with blood or open sores of infected persons
• Healthcare workers exposed to blood or contaminated body fluids
• Needle sticks
• Diabetes
• Hemodialysis treatment
• Travel to countries with high or intermediate HBV prevalence

Figure 4. Distribution of Foreign-Born Individuals in the U.S. Living With Chronic HBV Infection

Source: Kowdley KV, Wang CC, Welch S, et al. Prevalence of chronic hepatitis B among foreign-born persons living in the United States by country of origin. Hepatology. 2012;56(2):422-433.

The National Viral Hepatitis Action Plan was established to focus on reducing the rates of new hepatitis B and C infections, including a goal of decreasing the number of new HBV infections by at least 60% by the year 2020 (Table 2).³ This requires improved surveillance at many levels, including implementation of routine screening in at-risk populations. The CDC has issued recommendations for routine screening in certain high-risk populations, which includes people born in regions where HBV is endemic at high or intermediate levels (HBsAg prevalence ≥2%) (Table 3).¹⁸ Among people born in the U.S., routine screening is recommended for those who were not vaccinated as infants and those whose parents were born in regions with high HBV endemicity (HBsAg prevalence ≥8%).²⁰

While these guidelines are clearly defined for screening of at-risk populations, there are a number of real-world barriers to screening, some clinician-related and some patient-related. Clinician-related barriers to screening include lack of awareness of current screening recommendations and suboptimal screening rates in at-risk populations. For example, in a 2017 survey of 277 primary care providers in San Francisco (an area with a large Asian immigrant population), only 42% reported screening over 50% of patients who fell into at-risk categories.²¹ In a survey of 109 physicians in New York City, 53 % answered incorrectly that a 25-year-old patient from China should be screened for HBV.²² Similar findings have been seen in communities with other Asian immigrant populations.^23,24

Patient-related barriers to screening may include lack knowledge of HBV transmission, risk factors, and health consequences; a "disconnect" between knowledge of HBV causing serious liver disease and the importance of screening; language barriers; lower socioeconomic status; low level of education; cultural beliefs/values, and stigma about HBV infection, which may occur particularly among East Asians. Many foreign-born adults are difficult to reach with screening/treatment programs, particularly if they are uninsured or are undocumented immigrants.²⁴

Interpretation of Serology

Interpretation of serology is a critical part of the hepatitis B screening and treatment process. It is essential for pharmacists to interpret serology to determine what patients are eligible for immunization. The hepatitis B panel consists of three parts:²⁵

1. HBsAg (hepatitis B surface antigen). Positive/reactive result means that the person has active infection and can spread the virus. This could indicate either an acute or a chronic infection.
2. Total Anti-HBs or HBsAb (hepatitis surface antibody). Positive/reactive result means that the person is immune to HBV, either due to recovery from a past infection or receiving the vaccine. The individual cannot transmit the virus to others
3. Anti-HBc or HBcAb (hepatitis core antibody). Positive/reactive result indicates past or current HBV infection. Unlike the surface antibody, presence of the core antibody does not confer protection against HBV. Interpretation of this serology is based on findings of the previous two parts. Positive core antibody in the presence of both negative surface antigen and surface antibody can occur through a number of different circumstances, detailed under the asterisk* in Table 4.²⁶

Additionally the hepatitis e antigen (HBeAg) is a marker of an actively replicating HBV virus infection. People with positive HBeAg have active replication in their liver cells, more virus circulating in their blood, and thus are more infectious, with a higher likelihood of transmitting HBV to others.²⁵

Vaccines for the Prevention of HBV Infection

HBV Vaccine Background

Our ability to identify and prevent HBV all started with the work of late Barry Blumberg, MD, a National Institutes of Health scientist. Blumberg was awarded the 1965 Nobel Prize in Medicine for discovering the hepatitis B virus. His eureka moment came with the discovery of a surface antigen (later identified to be HBV) in a blood sample of an aboriginal Australian with "yellow jaundice." Blumberg was also involved in developing an HBV screening test and the first HBV vaccine.²⁷

The early 1981 HBV vaccine was derived from plasma, but in 1986 this was discontinued in favor of a genetically engineered (DNA recombinant) HBV vaccine. The recombinant HBV vaccines introduced in the 1980s contain aluminum adjuvants, which are commonly utilized in non-live vaccines (including hepatitis A and B, Haemophilusinfluenzae type b, and pneumococcal vaccines) to boost immune response to the vaccine.²⁸ In 2017, a newer HBV vaccine with a novel non-aluminum adjuvant—cytoside phosphoguanine (CpG) 1018—was approved by the FDA.²⁹ The three available vaccines are described below and summarized in Table 5.^29-31 Because there are clinically meaningful differences in the dosage of the three HBV vaccines, they are identified by their brand names for clarity.

Traditional recombinant vaccines (aluminum adjuvant)

Recombivax HB

Recombivax HB is a recombinant vaccine for HBV initially approved in 1986. The vaccine is available in 0.5-mL (5 mcg) prefilled syringes (pediatric formulation); 1-mL (10 mcg) single-dose vials and prefilled syringes (adult formulation); and 1-mL (40 mcg) single-dose vials (dialysis formulation). The dosage schedule requires a 2- or 3-injection series as shown below:³¹

• Birth through 19 years: 3-dose series (5ug) at 0, 1, and 6 months
• Adolescents (age 11 through 15 years): Either a 3-dose series (5ug) at 0, 1, and 6 months; or 2-dose series (10ug) at 0 and 4 to 6 months.
• Adults age 20 and older: 3-dose series (10ug) at 0, 1, and 6 months
• Adults on hemodialysis: 3-dose series (40ug) at 0, 1, and 6 months.

Engerix-B

Engerix-B is a recombinant vaccine for HBV initially approved in 1989. The vaccine is available in 0.5-mL (10 mcg) prefilled syringes and 1-mL (20 mcg) single-dose vials and prefilled syringes. The dosage schedule requires a 3- or 4-injection series as shown below:³⁰

• Birth through 19 years: 3-dose series (10ug) at 0, 1, and 6 months
• Adults age 20 and older: 3-dose series (20ug) at 0, 1, and 6 months
• Adults on hemodialysis: 4-dose series (40ug each) at 0, 1, 2, and 6 months.

Non-aluminum adjuvant, 2-dose vaccine

Heplisav-B

Heplisav-B is a single-antigen HBV vaccine approved by the FDA in November 2017. This vaccine differs from the two formulations listed above (Recombivax and Engerix) because it utilizes a non-aluminum adjuvant not contained in any other U.S. vaccines to date.³² Other key differences between Heplisav-B and the older recombinant vaccines are its dosage schedule (with a standard 2-dose series instead of 3) and the age range (approved for adults only), as shown below:²⁹

• Supplied as single-dose vial or prefilled syringe. A single dose is 0.5 mL.
• Dosage schedule, adults age 18 or older: 2 (two) doses (0.5 mL each) administered one month apart.

The adjuvant, CpG 1018, is thought to work by activating dendritic cells and promoting T-helper (Th1) cell differentiation. This activation appears to produce higher, sustained antibody responses, by generating large numbers of anti-HBsAg-secreting plasmacytes and HBsAg-specific memory cells.³³ Relative to the other HBV vaccines, Heplisav-B has been shown to stimulates improved seroprotection. FDA approval of hepatitis B vaccine recombinant–adjuvanted was based on data from three pivotal Phase 3 trials involving nearly 10,000 adults.²⁹ In the largest phase 3 trial (N=6,665), Heplisav-B had a statistically significant higher rate of protection relative to the active comparator, Engerix-B (95.4% vs 81.3% for Engerix-B).²⁹

Table 5. Available Hepatitis B Vaccines

Source: Kowdley KV, Wang CC, Welch S, et al. Prevalence of chronic hepatitis B among foreign-born persons living in the United States by country of origin. Hepatology. 2012;56(2):422-433.

Special Considerations for HBV vaccines

Interchangeability

With three HBV vaccines available and some differences in the dosage forms and dosage schedules, an area of potential confusion is the interchangeability of the vaccines. In particular, interchangeability may be a problem when the patient returns for a second dose and there is no record of which vaccine he or she initially received, or the pharmacy does not have the appropriate stock on hand (See Case Presentation 1). Ideally, when feasible, the same manufacturer’s vaccine should be used to complete a full HBV vaccine series. However, if the prior manufacturer is unknown or that vaccine is unavailable, the patient should complete the series of 3 doses using the longest recommended dosing interval, with the assumption that an traditional recombinant vaccine (Recombivax or Engerix) was used. According to the Advisory Committee on Immunization Practices:³⁴

• Dose 1 and Dose 2 should be separated by at least 4 weeks. Dose 2 and Dose 3 should be separated by at least 8 weeks. Dose 1 and Dose 3 should be separated by at least 16 weeks.
• Any doses separated by a shorter interval would need to be repeated.

With the 2-dose hepatitis B vaccine (Heplisav-B), any series that contains 2 doses of this vaccine, separated by at least 4 weeks, is considered appropriate.³⁴

Safety and tolerability
Contraindications to the HBV vaccine include severe allergic reaction, such as anaphylaxis, after a previous dose of any hepatitis B vaccine or to any component of the vaccine, including yeast.^29-31 The most common adverse reactions reported for the vaccines are injection site pain or soreness and systemic reactions including fatigue (11% to 17%) and headache (8% to 17%).

Vaccination for persons with diabetes

Because of the immunocompromised status in people with diabetes, CDC guidelines recommend HBV vaccination for all unvaccinated adults with diabetes younger than age 60. The CDC emphasizes the importance of HBV vaccination as soon as possible after a diagnosis of diabetes.³⁵ Despite the fact that this recommendation has been heavily promoted since 2011, it is estimated that fewer than 30% of adults with diabetes have been immunized against hepatitis B.³⁵

Reduced seroprotection

Approximately 5% to 15% of people who receive the traditional vaccines are nonresponders.^5,6 The seroprotection rate (anti-HBs ≥10 mIU/mL) for traditional vaccines ranges from 70.5% to 90.2%, depending on the patient population immunized. Younger adults tend to have high seroprotection rates, between 90% and 100%. However, the proportion of adults who achieve seroprotection from the 3-dose vaccines begins to drop off notably after age 40 and is less than 75% by age 60.^36,37 Other factors associated with decreased response rates in adults include male gender, obesity, history of smoking, and concomitant illnesses, including diabetes.³⁸

Delayed seroprotection

With standard 3-dose HBV vaccines, between 45% and 70% of persons age 40 and younger do not achieve seroprotection until after they have received the third vaccine dose, at 6 months. Because of this, these individuals remain at risk for contracting HBV infection until they have completed the series.¹⁶ This delay in achieving seroprotection may be particularly important for certain individuals at risk for exposure to HBV, including healthcare workers, injection-drug users, and people traveling to an HBV-endemic area.³² For these patients, the 2-dose vaccine would be preferred.

Pregnancy

Although the available vaccines have not been specifically studied in pregnant women, CDC guidelines for vaccination of pregnant women (updated August 2016) recommend vaccination in women who are at risk for HBV, as follows:³⁹

• "Pregnancy is not a contraindication to vaccination. Limited data suggest that developing fetuses are not at risk for adverse events when hepatitis B vaccine is administered to pregnant women. Available vaccines contain noninfectious HBsAg and should cause no risk of infection to the fetus."

• "Pregnant women who are identified as being at risk for HBV infection during pregnancy(e.g., having more than one sex partner during the previous 6 months, been evaluated or treated for an STD, recent or current injection drug use, or having had an HBsAg-positive sex partner) should be vaccinated."³⁹

• The newer two-dose hepatitis B vaccine has not been studied in pregnant women and there are insufficient data to recommend use in pregnant women. Animal data demonstrated no fetal risk. A pregnancy registry is available for pregnant women exposed to Heplisav-B.²⁹

Coinfection with HIV or HCV

In the U.S., about 10% of all people living with HIV also have HBV infection.⁹ HIV, HCV, and HBV share common pathways of transmission, including injection drug use, sexual intercourse, and mother-to-child transmission. Viral coinfection has been associated with reduced survival rates, increased risk of progression to liver disease, and increased risk of hepatotoxicity associated with antiretroviral therapy.⁴⁰ Case Presentation 1 discusses HBV vaccination in a patient with HIV coinfection. 

Postvaccination testing

Postvaccination testing for antibody to hepatitis B surface antigen (anti-HBs) is recommended for certain groups 1 to 2 months after the last dose of vaccine. This includes people with HIV or HCV coinfection.¹⁸ In addition, the CDC recommends postvaccination testing for healthcare providers who have a high risk of occupational exposure to blood or body fluids (e.g., those with direct patient contact, at risk of needlestick or sharps injury, and laboratory workers who draw, test or handle blood specimens).⁴¹ Healthcare workers who are low risk for contact with HBV-infected fluids need not have postvaccination testing, but should be tested if they are exposed postvaccination.⁴¹

The Pharmacist's Role in HBV Prevention

Pharmacists currently deliver approximately 28% of adult vaccinations.⁴Because the HBV vaccines are administered in a series, receiving vaccination from a pharmacist can enhance the convenience for patients to promote completion of the full series. Pharmacies that track their patients will be better able to help them adhere to the schedule and complete the series.

Challenges: Initiating the vaccination series

Encouraging adults to initiate the HBV vaccination series is a considerable challenge. This is due in part to healthcare access barriers in at-risk individuals as well as limited formal programs to encourage adult immunization, although these have increased in recent years.³ A 2014 analysis found that vaccination levels for HBV were low (only about 25%) among adults age 19 and older.⁴² A 2011 study showed that only 34.7% of adults in high-risk groups for HBV had ever received the vaccine.⁴³ Vaccination rates are also low among people with diabetes—at least 75% of people with a diagnosis of diabetes had not been vaccinated as of 2015.³⁵ It is important for pharmacists to discuss HBV vaccination with patients who have diabetes.

Nonadherence to conventional 3-dose vaccine series

Even after the individual has taken the first steps to receive a first dose of the HBV vaccine, adherence to subsequent doses drops off sharply, especially if the 3-dose vaccine is used. In the Vaccine Safety Datalink, a large retrospective study involving more than 88,000 adult HBV vaccine recipients, only 54% had received all 3 doses within 1 year and only 64% of those vaccinated received all 3 doses of the vaccine.⁴⁴

High-risk populations do not necessarily fare better, although there is more at stake. In a study involving an STD clinic population of men who have sex with men, only 43% of patients received all 3 doses of HBV vaccine, even when it was administered on an accelerated schedule (0, 1, and 4 months rather than the recommended 6 month dosing period).⁴⁵ People at high risk for HBV are often living in circumstances that make it difficult to adhere to the regimen—they may be using illicit drugs or other substances, living in poverty, or facing significant health and/or life challenges including comorbid HIV or HCV infection.^40,46,47 In a CDC-funded study of 14 health departments across the country that implemented pilot vaccination programs between 2012 and 2015, nearly 48,000 doses of HBV vaccine were administered. However:⁴⁸

• Among persons receiving dose 1, only 40% received dose 2
• Among those receiving doses 1 and 2, only 22% received dose 3
• STD clinics had the lowest adherence to the 3-dose schedule, at just 17%

Low adherence to the 3-series schedule has been observed even among healthcare professionals, who have higher risk associated with their jobs and also more information about the severity of the infection.⁴⁹ Risks for healthcare workers for contracting HBV should not be underestimated. Healthcare workers who had needle sticks involving HBV-infected blood have a 37% to 62% of developing serologic HBV infection and a 22% to 31% risk for developing clinical hepatitis if the blood was positive for both HBsAg and hepatitis Be antigen.⁵⁰

To address the problem of nonadherence to the HBV vaccine series, the CDC's Advisory Committee on Immunization Practices recommended the use of Heplisav-B for prevention of prevention of HBV in persons age 18 and over. In a February 2018, statement, the advisory committee noted, "The benefits of protection with 2 doses administered over 1 month make HepB-CpG an important option for prevention of HBV."³⁴ Heplisav B has not been studied in patients undergoing dialysis, immunocompromised patients, or pediatric patients; therefore recommendations cannot be made in these patient populations.²⁹

Patient counseling

Pharmacists who administer the HBV vaccine should be prepared to counsel patients about the importance of completing the series in order to confer protection against the virus. Patients should be advised that all the available HBV vaccines are derived from non-infectious, purified HBsAg and cannot cause a hepatitis B infection.^29-31 Patients should be advised to report any potential adverse events to their healthcare provider and should be given appropriate Vaccine Information Statements prior to vaccination. These are available from the CDC website at www.cdc.gov/vaccines, Pharmacists should coordinate with patient and provider to report adverse events to the Vaccine Adverse Event Reporting System (VAERS; www.vaers.hhs.gov).⁵¹

Conclusion

Vaccination is highly effective in preventing people from contracting HBV. However, many high-risk candidates for the vaccine are not identified and many others do not receive the vaccine. Pharmacists are an important part of the National Viral Hepatitis Action Plan's goal to decrease the number of new HBV infections. Many pharmacists administer hepatitis B vaccines, and pharmacists also play an essential role in educating patients and other healthcare providers about the benefits of vaccination, vaccine selection, and administration procedures.⁴ Pharmacists must be aware of which vaccines are recommended for individual patients, whether vaccine types are interchangeable, how to encourage patients to adhere to the full vaccination series.

References

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