Elimination of Hepatitis B virus transmission in an endemic area in Western Alaska

Highlights

• •Hepatitis B vaccination at birth and in childhood reduces liver cancer rates.
• •Universal screening and vaccination of those who are seronegative can reduce transmission.
• •Significant reduction of hepatitis B is possible in endemic regions.
• •Collaboration between local institutions and the government helps eradicate hepatitis B.

Abstract

Objectives

In the US, hepatitis B virus (HBV) is only endemic in western Alaska, where 90% of the population are Alaska Native (AN) peoples; in the 1970s, the incidence of hepatocellular carcinoma (HCC) in children was the highest in the world. In the 1980s, we screened 53,860 AN peoples for HBV infection, administered HBV vaccine to 43,618 HBV seronegative persons, and initiated universal newborn vaccination. In this study, we examine the impact of this effort 40 years later.

Methods

This is a population-based outcome study. We used vaccine and electronic health records to examine rates of newborn vaccination between 2015 and 2019 and changes in HBV incidence rates, as well as the prevalence of HCC in persons under 30 years of age over a 50-year period.

Results

Between 2015 and 2019, approximately 90% of newborns received an HBV birth dose, and over 80% received a second HBV vaccine dose by 18 months of age. Annual incidence of new hepatitis B surface antigen-positive tests among AN peoples ranged from 1.4-2.6 per 100,000, down from 6.2 between 1993 and 1997. No hepatitis B surface antigen-positive or HCC cases have been identified in AN peoples under 20 since 1993.

Conclusions

Mass population-based vaccination of seronegative persons, with continuing universal newborn immunization, halted transmission of HBV in western Alaska.

Introduction

Hepatitis B virus (HBV) is the most common viral infection globally, with 296 million persons estimated to have chronic hepatitis B (CHB) [1]. The World Health Organization (WHO), Centers for Disease Control and Prevention (CDC), and others have established goals to decrease the public health threat that HBV poses by reducing new HBV infections [2,3]. While HBV infection is endemic in many countries, it is not endemic in the United States except in western Alaska. In western Alaska, most residents are Alaska Native (AN) peoples, 90% of whom live in isolated rural communities without direct access to the road system, some hundreds of kilometers from the nearest hospital. Most persons with CHB in the rest of the United States were born in endemic areas of the world.

In 1972, persons with acute symptomatic HBV infection and others with hepatocellular carcinoma (HCC) were observed at the hospital in Bethel, Alaska, and among persons living in the 50 remote communities served by this hospital. A serosurvey in 1974 of residents from two rural communities where acute HBV infections occurred found the prevalence of hepatitis B surface antigen (HBsAg) to be 23.1% and 8.4% [4]. Subsequently, residents from these two communities, plus 10 additional communities, were invited to enroll in an HBV prevalence and prospective incidence study from 1974 to 1978, and were tested every 6 months for HBsAg, antibody to hepatitis B core antigen, and antibody to HBsAg during this period. Of the 1280 persons seronegative for all HBV markers, 189 acquired acute HBV infection, defined as becoming positive for HBsAg. The annual incidence of new HBV infections among those seronegative at enrollment was 3164 per 100,000 person-years [5]. The proportion of persons infected after birth and under 5 years of age who developed CHB was 28%, compared to less than 10% of those infected older than 30 years of age [6]. High rates of HBV-associated HCC and HBV-associated vasculitis were found in this region [7,8].

In 1981, a phase IV HBV vaccine trial was conducted in these 12 rural communities in collaboration with two Alaska Native Tribal Health Corporations, the CDC, and the State of Alaska Department of Health. This trial showed a significant reduction in HBV transmission [9]. After licensure of the HBV vaccine, the Alaska Native Tribal Health Corporations intensely lobbied the Alaska Congressional Delegation, and Congress appropriated $10 million to screen and vaccinate the entire population, including all racial groups residing in over 200 rural Alaskan communities statewide, and to initiate universal newborn vaccination. In addition, all AN peoples residing in the major urban areas were offered screening and vaccination.

This funding was used to contract with Alaska Native Tribal Health Corporations and the State of Alaska Department of Health to provide screening and vaccination for HBV infections between 1983 and 1987. During this period, we screened 53,860 of the estimated 75,000 AN persons (72%) living in Alaska, and 43,618 persons who were seronegative for HBV markers received HBV vaccine, including 90% of the AN population and other racial groups living in the hepatitis B endemic areas: communities in western Alaska, from Kodiak Island up to the Arctic Ocean [10]. We subsequently found that hepatitis Delta was not present, based on testing for antibody to hepatitis D virus (anti-HDV) among 603 AN peoples with CHB [11]. Later, the US Congress established a federally funded Liver Disease and Hepatitis Program (LDHP) that has been continually active since the mid-1980s.

The purpose of this current study is to evaluate the long-term outcomes 40 years after conducting the mass HBV screening and vaccination program and instituting universal newborn vaccination in the AN population described above. We examined a 5-year period three decades after the mass vaccination program, to determine if more than 90% of AN newborns received a HBV birth dose vaccination, consistent with targets set by international organizations for 2030 [2,3]. This paper also examines the impact the HBV vaccine had on the incidence and prevalence of new and chronic HBV infections, as well as the incidence of HCC in children over the past 40 years in the AN population, to determine if HBV vaccination can reduce the adverse complications of HBV infection over time.

Methods

The Alaska Native Tribal Health Consortium (ANTHC), a tribally owned and operated comprehensive statewide health care system, maintains an electronic database that has recorded HBV testing results since 1972, HCC surveillance results since the 1980s, and HBV treatment with oral antiviral agents results since the mid-1990s, allowing us to examine follow-up of persons with CHB over time.

Vaccination rates in newborns and infants

For this analysis, we examined de-identified HBV vaccination records from the State of Alaska Section of Epidemiology Immunization Information System, VacTrAK, by geographic region, who received a birth dose and the proportion of infants who received at least three doses of HBV recombinant vaccine for all infants born in Alaska between January 1, 2015, and December 31, 2019. VacTrAK provided the age of the child in days and the borough where each HBV vaccine dose was administered. Vaccine doses administered on day 0 or 1 were considered to have been administered within the first 24 hours. The proportion of children who received three vaccine doses by ages 12, 15, and 18 months was also determined. Boroughs were mapped to the State of Alaska-administered Public Health Regions for this report. The State does not provide race data for vaccine recipients.

Maintaining contact with AN peoples with chronic HBV infection

In the late 1980s, we started mailing biannual letters to all HBsAg-positive persons instructing them to go to their community clinic for a 6-month blood draw for alpha-fetoprotein (AFP) and HBV seromarkers. We added HBV DNA levels and liver function tests (LFTs) in 2000, and. liver ultrasound for those persons who were at the highest risk of HCC: men ages 40 and over, women ages 50 and over, persons with cirrhosis, and those with a family history of HCC. Five of the eight HBV genotypes found worldwide (A2, B6, C2, D2, 3, and F1b) are found in this population. Iin 2017, we added the recommendation that all persons infected with HBV genotype F have 6-month liver ultrasound performed, as we found those infected with HBV genotype F had a high risk of HCC at any age [12].

New HBsAg-positive and CHB cases were identified through two sources: the ANTHC LDHP registry and the State of Alaska infectious disease database, which requires that all new positive results for HBsAg be reported, even if tested at out-of-state commercial laboratories. The clinical registry system is linked to all 13 Tribal computerized health care medical records systems statewide. Three times per week, all pertinent laboratory and radiology reports are automatically downloaded into this system so that the data are kept up to date. Laboratory and radiography results are reviewed by hepatology Registered Nurses (RNs), with abnormal results reviewed and acted upon by hepatology providers. Overall incidence rates were calculated using bridged-race population data from the Alaska Department of Labor. We also examined the change in incidence rates in the 12 communities previously mentioned in the Yukon-Kuskokwim (YK) Delta Region in Southwest Alaska, where the 4.5-year prospective incidence studies prior to vaccination had been conducted, and compared those numbers to incidence rates in these same communities after the year 2000 [5].

New HCC cases were identified using the National Cancer Institute (NCI)-funded Alaska Native Tumor Registry (ANTR), which was established in 1974. We also reviewed all 13 Tribal corporations’ electronic medical records databases to identify additional cases of HCC.

Finally, we reviewed the records in 2024 of those persons with HBV infection who consented to participate in our Hepatitis B Long-Term Prospective Cohort Study to determine how many persons were still alive, how many died, and how many died of a liver-related cause.

Results

Birth dose

We found that the proportion of newborns vaccinated at birth between 2015 and 2019 varied widely by Alaska region, from 44% to 100% (Figure 1). The highest proportion of newborns who received a birth dose was found in the Northern and Southwest regions of Alaska, where all deliveries occur in tribally operated healthcare hospitals. In these facilities, located in areas endemic for HBV, every effort is made to give the HBV vaccine at birth to all residents, both AN and non-AN persons, resulting in approximately 90% of newborns receiving a birth dose. In the regions with major metropolitan areas, such as Anchorage, Mat-Su, and Interior Alaska, where both Tribal and private hospitals are located, the proportion receiving a birth dose was much lower, ranging from 53% to 77%.

Figure 1.

Percent of newborns (all races) in each Public Health Region in Alaska who receive first hepatitis B virus vaccine dose within 24 hours of birth.

Three dose coverage

At 12 months of age, the proportion of children who received three doses ranged from 69% in Interior Alaska to 88% in Anchorage. By 15 and 18 months of age, those proportions increased slightly: 70% to 89% at 15 months and 71% to 90% at 18 months (Figure 2). For more detailed information about vaccination characteristics by region, see Appendix tables.

Figure 2.

Percent of children (all races) born between 2015 and 2019 who received three doses of hepatitis B virus vaccine by age 12, 15, or 18 months.

HBsAg-positive incidence

Between 1972 and 1999, 1658 AN peoples were identified as HBsAg-positive, yet the date of their actual HBV infection could not be determined. Since newly identified cases of persons who are found to be HBsAg-negative but positive for antibody to hepatitis B core antigen (anti-HBc) are not required to be reported to the State of Alaska, we are unable to determine the number of asymptomatic cases of HBV who would have recovered after a new acute infection. Between January 1, 1993, and December 31, 2021, only an additional 74 AN peoples were diagnosed with CHB, defined as HBsAg positive for at least 1 year. Most had never been tested for HBsAg previously. Currently, eight individuals younger than 35 years old are HBsAg-positive per the clinical registry, and zero between ages 36–40 years old.

Figure 3 shows the number of AN peoples newly identified statewide as HBsAg positive for 5-year time periods after the mass screening campaign, starting with 1993-1997 (midpoint year 1995), along with the 5-year incidence rates per 100,000 AN peoples. The annualized incidence of AN peoples newly identified as HBsAg-positive since 1998 has sharply decreased, from 6.2 per 100,000 in 1993-1997 (midpoint year 1995), to 1.9 per 100,000 in 1998-2002 (midpoint year 2000), and remained below 3.0 per 100,000 through 2021.

Figure 3.

Hepatitis B surface antigen-positive - 5-year incidence counts and rates among Alaska Native peoples statewide.

HBV, hepatitis B virus.

Statewide, there have been no new symptomatic hepatitis B cases in AN peoples under the age of 20 years since 1995, as evidenced both by cases reported to the state and by Tribal Health Organization (THO) electronic records. In addition, no CHB cases have been identified in AN peoples of any age since 2000 in the YK Delta region in southwestern Alaska, which is the area where surveillance was first established and where the most intense monitoring has occurred. The population in the YK Delta is approximately 82% AN.

Incidence of HCC in AN children since 1969

Figure 4 shows the annual incidence of HCC in AN peoples in Alaska who are ≤40 years old since 1975. The incidence peaked between 1980 and 1990, reaching 12.5 per 100,000 in all AN peoples ≤40 years old regardless of HBV status, primarily due to the availability of better radiographic instrumentation, local availability of ultrasound and CT in regional hospitals, and MRI at the Alaska Native Medical Center. Since 1999, no cases of HCC have been identified in AN persons ≤20 years old. Currently, the youngest living person with HCC is 43 years old.

Figure 4.

HCC among AN peoples ≤40 years of age - Five year time periods.

AN, Alaska Native; HCC, of hepatocellular carcinoma.

Ongoing contact for AN peoples who are positive for HBsAg

A clinical registry for all AN peoples found to be HBsAg-positive was established in the 1980s. All patients in the registry are linked to care through the LDHP and are sent letters every 6 months, reminding them to complete AFP and LFT blood tests for HCC surveillance, with fewer than 1% of linked patients with CHB (n = 8) requesting us to stop sending them reminder letters.

Of the 1,658 persons found to be HBsAg-positive during and after the mass screening program, we have consented 1240 to our long-term hepatitis B cohort study, which was established in 1995. Of those, 768 are still living and 442 are deceased. After review of statewide Tribal Health electronic medical records and newly reported HBsAg-positive test results to the State of Alaska, currently there are only 8 AN persons younger than 35 years old who are HBsAg positive and none between ages 35-40 years old.

HCC diagnoses and liver-related death among AN peoples with CHB

Between 1971 and 2021, 81 AN peoples with CHB (75 CHB alone and 6 in combination with hepatitis C) were diagnosed with HCC. As shown in Figure 5, 5-year HCC incidence due to CHB alone peaked at 4.2 per 100,000 person-years in 1981-1985 and dropped to a low of 0.4 per 100,000 person-years in 2011-2015 (p-value for decreasing trend = 0.001). Of the 442 who died over the past 40 years, 31 died of liver-related causes. The remaining individuals died from non-liver-related causes. Since 1995, only one person under 30 years old developed HCC.

Figure 5.

HCC among AN peoples with CHB - Five year time periods.

AN, Alaska Native; CHB, chronic hepatitis B; HCC, of hepatocellular carcinoma.

Between 1971 and 1982, 18 AN peoples with CHB were diagnosed with HCC, and only one survived, resulting in a 5-year tumor-free survival rate of 5.6%. Since surveillance began in the mid-1980s, between 1983 and 2021, 63 AN peoples were diagnosed with HCC due to CHB, with a 31.7% 5-year tumor-free survival after initial or most recent HCC diagnosis.

Discussion

AN peoples are the only US-born population found to have high prevalence rates of HBV infection, acquired mostly at birth or early in life [4,5]. AN peoples were the first population in the world where, over 40 years ago, universal HBV screening and vaccination were offered to all ages found to be seronegative for HBV infection, and newborn vaccination was implemented to maintain ongoing population immunity. This article reviews the current vaccination rates and HCC incidence to demonstrate that our HBV vaccination and screening program, enacted in the 1980s, has eliminated HBV-caused HCC in people younger than 40 and reduced the public health threat of HBV transmission.

To determine if ongoing newborn vaccination continues as originally planned, we analyzed vaccination data and found that the highest proportions of babies who received the birth dose (95% and 96%) lived in the Northern and Southwest Public Health Regions of Alaska, where HBV is endemic and AN people represent 82% of the population. Statewide, 73% of newborns of all races received a birth dose, and 82% had received three doses by 18 months of age. In the HBV-endemic areas, hospitals are owned and operated by AN THOs, and pregnant women of all races give birth there. This likely explains the higher birth vaccine coverage in these areas. Most AN peoples in these regions live in isolated communities. Pregnant women come into larger towns with hospitals several weeks before their due date, staying in pre-maternal homes until they deliver.

More children living in urban areas compared to rural areas received all three doses by 18 months of age. This could be related to the fact that childhood vaccinations are more readily available on time in urban areas, where public health nurses and established tribal health and private clinics are located. In small rural communities, vaccinations are usually administered by visiting public health nurses and depend on when these nurses make visits to each community. Also, all AN pregnant women are screened for HBsAg in the second trimester and those who test positive undergo HBV DNA testing. Since 1996, if levels are above 20,000 IU/mL, they are given tenofovir for the rest of their pregnancy. Infants of HBsAg-positive mothers receive hepatitis B immune globulin at birth with HBV vaccine and are tested for HBsAg and HBV DNA at 9 months to 12 months of age. After adding antiviral prophylaxis for pregnant females with high viral levels, no infants tested at 9 to 12 months of age have been HBsAg positive, providing evidence that newborn transmission has halted in the endemic area.

Although HBV immunization is now a routine childhood vaccination administered to many infants globally, the HBV birth dose is not covered by the Global Alliance Vaccine Initiative for vulnerable countries [13]. Our results indicate a need for practice and policy change to provide global routine newborn and childhood HBV vaccination.

The Alaska HBV Program demonstrates that the universal birth dose, coupled with completion of the series, can halt transmission of HBV in children, evidenced by the small number of HBsAg-positive individuals who are less than 35 years old. Our data show that the number of AN children with CHB in Alaska has fallen to zero, resulting in the elimination of HBV infection in this age group [14]. In addition, new acute and CHB cases are now rare in rural Alaska. In the prospective study of HBV infection incidence in the 1970s in 12 rural communities, the annual incidence was 3164 new HBV cases per 100,000 AN peoples, of which approximately 13% became CHB carriers [5,6]. Within these same communities in the endemic region in western Alaska, only one new HBsAg-positive person was identified since the year 2000, thus demonstrating an annual incidence of <0.1/100,000. Statewide, over the past 25 years, annual incidence decreased from 6.2 to 1.4-2.6 new HBsAg-positive diagnoses per 100,000 AN peoples. It is likely that some of these persons may have been among the 28% of AN persons who did not partake in the HBV screening and vaccination program in the 1980s, had not previously been tested for HBV, and may have been infected prior to the vaccination program. Determining the exact reduction of new cases of HBV would have required a return to these isolated communities, finding as many persons as possible from the original survey, and testing them for HBV markers. This was not possible without substantial additional funding to support travel and personnel costs. Besides that, many of those participants may have died during the past 45 years or moved out of their communities. Therefore, we relied on HBsAg-positive cases, as all testing for HBV markers is downloaded into the HBV clinical registry and reviewed by LDHP clinicians. We captured most new HBsAg-positive cases by utilizing these resources, though missing some new untested asymptomatic cases remains a possibility.

More importantly, the disappearance of HCC in AN children under 20 years of age since 1999 in Alaska, from 2.85/100,000 (the highest in the world), combined with a decrease in the incidence in all age groups to <1/100,000, demonstrates the effectiveness of this vaccination program [14]. Finally, a longitudinal study in Alaska following persons vaccinated from 6 months of age through adulthood illustrates that the HBV vaccine protects for at least 35 years and booster doses are not necessary [15]. Thus, vaccination to prevent new HBV infections remains effective for decades, likely reducing economic and health-related quality of life costs for care of liver-related cirrhosis and HCC.

Limitations

Even with the reporting of HBsAg-positive test results and statewide availability of electronic health records, it is possible that we missed cases of CHB. However, even if an individual seeks liver care elsewhere, they still may access the Tribal Health System for prescription medications or other aspects of their care, increasing the likelihood that their case will come to the attention of the ANTHC LDHP.

HBV vaccination data may be missing from the state VacTrAK system, resulting in an underestimate of vaccination coverage. Some assignments of infants to Public Health Regions may also be incorrect, especially in cases where infants received different vaccine doses in different regions. In these cases, we attempted to make reasonable assumptions about where the infants likely resided.

Conclusion

HBV transmission has dramatically reduced in the AN population living in HBV-endemic areas due to ongoing newborn vaccination rates, which meet national and international goals for HBV reduction. In addition, the incidence of new infections in AN peoples significantly decreased, and HCC in children disappeared in Alaska in the past 30 years. Globally, preventing new HBV infections in newborns and infants is the first step to achieving the elimination of HBV, followed by universal screening and vaccination of all adults. Since universal newborn vaccination programs are not present in all HBV-endemic areas of the world, and many births take place outside of a hospital or clinic setting, millions of newborns are still acquiring preventable HBV infection each year [1]. Our experience in Alaska demonstrates that preventing HBV transmission, halting the surging number of new CHB cases, and preventing HBV-associated HCC in children and young adults can be accomplished.

Funding

Centers for Disease Control and Prevention (CDC-RFA-CK20-2003; award number NU50CK000590-01-00c).

CRediT authorship contribution statement

Brian J McMahon: Conceptualization, Methodology, Writing – original draft, Writing – review & editing, Supervision, Project administration, Funding acquisition. Janet M Johnston: Methodology, Software, Validation, Formal analysis, Formal analysis, Data curation, Writing – original draft, Writing – review & editing. Lesleigh Kowalski: Formal analysis, Data curation, Writing – review & editing, Visualization. Mary Snowball: Writing – review & editing. Michael G Bruce: Writing – review & editing. Nathan Furukawa: Writing – review & editing. Karen Miernyk: Investigation, Writing – review & editing. Lisa Townshend-Bulson: Writing – review & editing.

Declaration of competing interest

The authors have no competing interests to declare.