BACKGROUND:Vaccination is effective at preventing chronic HBV infection and its complications, but the duration of protection and need for booster doses have not been determined. METHODS:We administered a 3-dose primary series of plasma-derived hepatitis B vaccine to Alaska Native persons aged 6 months or above who resided in an HBV-endemic area of western Alaska. Persons with antibody to hepatitis B surface antigen (anti-HBs) ≥10 milli-international units per milliliter (mIU/mL) at 6 months after series completion were followed through 41 years after vaccination. Beginning at 22 years, participants with anti-HBs <10 mIU/mL were offered a booster dose (ie, challenge dose) of recombinant hepatitis B vaccine and retested 4 weeks later as a surrogate for immune memory. Combining these immune-memory data with a survival model estimating anti-HBs persistence, we estimated the overall proportion with serologic evidence of protection at 22, 30, 35, and 41 years. We also described breakthrough hepatitis B infections. RESULTS:During 1981-1982, 1351 persons completed the hepatitis B vaccine primary series and had anti-HBs ≥10 mIU/mL at 6 months after vaccination; median age at enrollment was 13 years (range: 0.5-77). The overall proportion with serologic evidence of protection was 95% at 22 years, 95% at 30 years, 88% at 35 years, and 91% at 41 years after vaccination. At 41 years, 32% had circulating anti-HBs ≥10 mIU/mL, and 59% had immune memory. During 41 years of follow-up, 16 (1%) persons had evidence of a breakthrough infection; none developed chronic hepatitis B. CONCLUSIONS:We found serologic evidence of protection among Alaska Native persons 41 years after primary hepatitis B vaccination. Our findings support the recommendation that booster doses are not needed in endemic areas.

BACKGROUND:Surveillance for HCC remains important after hepatitis C cure. Improved sensitivity of screening with alpha-fetoprotein (AFP) by using a parametric empirical Bayes (PEB) algorithm, which incorporates an individual patient's longitudinal AFP measurements, was previously demonstrated in a retrospective analysis of clinical trial data prior to widespread hepatitis C cure. METHODS:We analyzed de-identified data extracted from the medical records of participants in the Alaska Hepatitis C Study, which aims to enroll all Alaska Native persons living in Alaska with a history of hepatitis C.We compared the performance characteristics of AFP as a screening test using the PEB method versus a fixed cutoff (FC) method in an observational setting, separately for HCC surveillance in active and cured hepatitis C. RESULTS:The PEB and FC methods were applied to AFP levels from participants with F3/F4 fibrosis who had active hepatitis C (173 no HCC, 14 HCC) or after they achieved hepatitis C cure (162 no HCC, 12 HCC). Compared to a fixed 20 ng/mL cutoff, demonstrating 91.2% specificity in active hepatitis C, PEB increased sensitivity from 64.3% to 71.4%. After cure, a fixed 7.2 ng/mL cutoff demonstrated 91.2% specificity, and PEB increased sensitivity from 58.3% to 91.7%. CONCLUSIONS:The PEB algorithm can increase sensitivity and lead to earlier detection of HCC among patients with F3/F4 fibrosis, both in active and even more so in cured hepatitis C. Lower AFP levels after cure indicate that for either PEB or FC methods, screening parameters, such as cutoffs for a target specificity, should be specified separately by hepatitis C treatment status for HCC surveillance.

Background and Aims:Modeling hepatocellular carcinoma (HCC) risk in Alaska Native (AN) peoples with chronic hepatitis B virus (HBV) infection is important for risk stratification and surveillance. Existing HCC risk prediction models use baseline characteristics ascertained at the time of HBV diagnosis, rather than predicting HCC risk within 5 years of a relevant time point (such as a clinic visit), and do not include the HBV genotype (GT). We aimed to develop an HCC risk prediction model that addresses these limitations. Methods:We used longitudinal data from a cohort of 1163 AN peoples with HBV. We considered age, sex, GT, serum alpha fetoprotein (AFP), along with serum alanine transaminase, albumin, aspartate aminotransferase, bilirubin, hepatitis B-e-antigen, platelet count, and fibrosis 4 score. To build a 5-year risk model, we structured the longitudinal data into multiple 5-year segments, using AFP as the landmark biomarker. We used the generalized estimation equation approach as well as the Random Forest approach to build risk prediction models. Results:Among the 11 predictors included in our final models, AFP was the most important followed by platelet count and GT. Based on cross-validation, the generalized estimation equation model had an area under the receiver operating characteristic curve of 0.81, with 46.5% sensitivity at 90% specificity for 5-year HCC risk prediction. The Random Forest model was superior with an area under the receiver operating characteristic curve of 0.88 and 70% sensitivity at 90% specificity, outperforming the PAGE-B, mPAGE-B, REACH-B and REAL-B models. Conclusion:We developed an HCC risk prediction model using rich information from different time points in a patient's disease trajectory. Our model can accurately estimate HCC risk at different time points during follow-up for risk stratification and risk-based surveillance.

We evaluated factors associated with the presence of hepatitis A virus antibodies 23 years after initiating vaccination at ages 6-15 months. Among 67 participants, 86% (42/49) of those vaccinated at ages 12-15 months and 61% (11/18) of those vaccinated at 6 months remained seropositive at 23 years. Lack of maternal antibodies at enrollment and higher initial vaccine response were independently associated with higher antibody concentrations at 23 years. Further research is needed to assess the duration of hepatitis A vaccine protection and possible need for a booster dose.

Death rates from primary liver cancer (hepatocellular carcinoma [HCC]) have continued to rise in the United States over the recent decades despite the availability of an increasing range of treatment modalities, including new systemic therapies. Prognosis is strongly associated with tumor stage at diagnosis; however, most cases of HCC are diagnosed beyond an early stage. This lack of early detection has contributed to low survival rates. Professional society guidelines recommend semiannual ultrasound-based HCC screening for at-risk populations, yet HCC surveillance continues to be underused in clinical practice. On April 28, 2022, the Hepatitis B Foundation convened a workshop to discuss the most pressing challenges and barriers to early HCC detection and the need to better leverage existing and emerging tools and technologies that could improve HCC screening and early detection. In this commentary, we summarize technical, patient-level, provider-level, and system-level challenges and opportunities to improve processes and outcomes across the HCC screening continuum. We highlight promising approaches to HCC risk stratification and screening, including new biomarkers, advanced imaging incorporating artificial intelligence, and algorithms for risk stratification. Workshop participants emphasized that action to improve early detection and reduce HCC mortality is urgently needed, noting concern that many of the challenges we face today are the same or similar to those faced a decade ago and that HCC mortality rates have not meaningfully improved. Increasing the uptake of HCC screening was identified as a short-term priority while developing and validating better screening tests and risk-appropriate surveillance strategies.

Background and Aims: A functional cure and therapeutic end point of chronic HBV infection is defined as the clearance of HBsAg from serum. Little is known about the long-term durability of HBsAg loss in the Alaskan Native population. Approach and Results: We performed a retrospective cohort study of Alaska Native patients with chronic HBV-monoinfection from January 1982 through December 2019. The original group in this cohort was identified during a 1982 to 1987 population-based screening for 3 HBV serologic markers in 53,000 Alaska Native persons. With close to 32,000 years of follow-up, we assessed the frequency and duration of HBsAg seroclearance (HBsAg-negative for > 6 mo). We examined factors associated with HBsAg clearance and followed persons for a median of 13.1 years afterward to assess the durability of HBsAg clearance. Among 1079 persons with an average length of follow-up of 33 years, 260 (24%) cleared HBsAg at a constant rate of 0.82% per person/per year. Of the 260 persons who cleared, 249 (96%) remained HBsAg-negative, while 11 persons had ≥ 2 transient HBsAg-positive results in subsequent follow-up. Conclusions: Of the patients with chronic HBV monoinfection, 0.82% of people per year achieved a functional cure. HBsAg seroclearance was durable for treated and nontreated patients and lasted, on average, over 13 years without seroreversion.

BACKROUND AIMS A functional cure and therapeutic endpoint of chronic hepatitis B virus (HBV) infection is defined as clearance of hepatitis B surface antigen (HBsAg) from serum. Little is known about the long-term durability of HBsAg loss in the Alaskan Native population. APPROACH RESULTS We performed a retrospective cohort study of Alaskan Native patients with chronic HBV-monoinfection from January, 1982 through December 2019. The original group in this cohort were identified during a 1982 to 1987 population-based screening for three HBV serologic markers in 53,000 Alaska Native persons. With close to 32,000 years of follow-up, we assessed the frequency and duration of HBsAg seroclearance (HBsAg negative for >6 mo). We examined factors associated with HBsAg clearance and followed persons for a median of 13.1 years afterwards to assess durability of HBsAg clearance. Among 1,079 persons with an average length of follow-up of 33 years, 260 (24%) cleared HBsAg at a constant rate of 0.82% per person/per year. Of 260 persons who cleared, 249 (96%) remained HBsAg negative while 11 persons had≥ 2 transient HBsAg positive results in subsequent follow-up. CONCLUSIONS Of patients with chronic HBV monoinfection, 0.82% of people per year achieved a functional cure. HBsAg seroclearance was durable for treated and non-treated patients and lasted on average over 13 years without seroreversion. The findings and conclusions in this report are those of the authors and do not necessarily represent the official positions of the Centers for Disease Control and Prevention.

Background and AimHigh autoimmune hepatitis (AIH) and overlap syndrome (OS) prevalence have been previously documented among Alaska Native people. The purpose of this project is to report changes in AIH/OS prevalence over time, clinical characteristics, and factors associated with biochemical remission. MethodsWe reviewed medical records for Alaska Native/American Indian (AN/AI) patients diagnosed with AIH/OS between 1984 and 2021. Point prevalence was calculated based on AIH/OS patients alive at the end of 2021 and at 5-year intervals from July 1, 2000, to July 1, 2020. ResultsWe identified 189 AN/AI persons diagnosed with AIH or OS (157 AIH, 32 OS). Of these 189, 137 were alive at the end of 2021 for a point prevalence of 91.2 per 100 000 (95% confidence interval [CI]: 77.2-107.8)-75.9 (95% CI: 63.2-91.2) for AIH and 15.3 (95% CI: 10.2-23.0) for OS. Prevalence for both AIH and OS has risen steadily since 2000. Eighty-nine consented participants (62.7%) achieved biochemical remission with a median time from diagnosis to start of remission of 1.9 years (IQR 0.5-5.0 years). Consented patients with fatty liver were less likely to achieve remission, but their time to remission was shorter than for patients without fatty liver. ConclusionThe AN/AI population in Alaska continues to have the highest reported prevalence of AIH/OS in the world, with prevalence rising steadily since 2000. High reported AIH/OS prevalence is likely due in part to strong referral networks for liver disease. Detection and treatment can lead to biochemical remission and improved health outcomes.

In a comparison between 50 Alaska Native persons with chronic hepatitis B who cleared HBV surface antigen (HBsAg) and 50 Alaska Native age-, sex-, and HBV genotype-matched controls, we found differences in changes in HBV DNA and HBV RNA levels over time but no difference in hepatitis B core-related antigen. These findings suggest that serial HBV DNA and HBV RNA may be associated with HBV functional cure defined by HBsAg clearance.

HCC, the most common form of primary liver cancer, is the fastest rising cause of cancer-related death in the United States. HCC disproportionately affects racial and ethnic minorities in the United States. A practical framework is needed to organize the complex patient, provider, health system, and societal factors that drive these racial and ethnic disparities. In this narrative review, we adapted and applied the National Institute on Minority Health and Health Disparities (NIMHD) Research Framework to the HCC care continuum, as a step toward better understanding and addressing existing HCC-related disparities. We first summarize the literature on HCC-related disparities by race and ethnicity organized by the framework's 5 domains (biological, behavioral, physical/built environment, sociocultural environment, and health care system) and 4 levels (individual, interpersonal, community, and societal) of influence. We then offer strategies to guide future research initiatives toward promotion of health equity in HCC care. Clinicians and researchers may help mitigate further inequities and better address racial and ethnic disparities in HCC care by prioritizing the following in HCC research: (1) increasing racial and ethnic minority representation, (2) collecting and reporting HCC-related data by racial and ethnic subgroups, (3) assessing the patient experience of HCC care by race and ethnicity, and (4) evaluating HCC-specific social determinants of health by race and ethnicity. These 4 priorities will help inform the development of future programs and interventions that are tailored to the unique experiences of each racial and ethnic group.

Background. Hepatitis C virus (HCV) infection incidence rates in the United States have increased since 2010 as a byproduct of the opioid crisis despite the introduction of direct-acting antiviral agents in 2013. HCV infection is associated with higher rates of liver-related and nonhepatic causes of death. Methods. This study compared demographic characteristics and age-adjusted death rates from 1995 to 2016 among Alaska Native (AN) adults infected with HCV (AK-HepC) to rates among the AN and non-AN adult populations living in Alaska. Liver-related disease (LRD) and other disease-specific age-adjusted death rates were compared between the populations. Results. The all-cause death rate among the AK-HepC cohort was 2.2- and 3.4-fold higher than AN and non-AN adults, respectively, and remained stable over time in all populations. The LRD death rate among the AK-HepC cohort was 18- and 11-fold higher than the non-AN and AN, respectively. The liver cancer rate among the AK-HepC cohort was 26-fold higher compared to the Alaska statewide population. The AK-HepC cohort had elevated rates of death associated with nonhepatic diseases with circulatory disease having the highest rate in all populations. Among liver cancer deaths in the AK-HepC cohort, 32% had HCV listed as a contributing cause of death on the death certificate. Conclusions. Death rates in the AK-HepC cohort remained stable since 1995 and higher compared to the general population. People with HCV infection had an elevated risk for all-cause, liver-related, and nonhepatic causes of death. Hepatitis C infection may be underrepresented as a cause of mortality in the United States.