Zanzibar, a low-resource semiautonomous region of Tanzania, has an estimated prevalence of hepatitis B virus (HBV) infections of 3.6%. To assess the feasibility of care and treatment, a 5-year hepatitis B demonstration project was implemented in Zanzibar during January 2017-December 2021, following the 2015 WHO HBV care and treatment guidelines. Participants included adults (aged ≥ 18 years) who tested positive for HBV surface antigen and tested negative for HIV and hepatitis C antibody. Participants were examined for clinical signs of liver disease and testing was conducted at baseline to assess treatment eligibility and every 6-12 months thereafter. Tenofovir disoproxil fumarate (TDF) was provided at no cost to treatment-eligible participants. Clinical and laboratory data were analysed to assess improvement in proximal disease outcomes. Among 596 participants enrolled, the median age was 32 years (IQR 26-39) and 365 (61%) were male. Of those enrolled, 268 (45%) returned for ≥ 1 follow-up visit, with a median of 511 days of follow-up. Overall, 58 patients initiated treatment: 15 met treatment criteria based on liver cirrhosis alone; 13 by APRI > 1.5; among those with HBV DNA results, six met criteria based on HBV DNA levels and ALT activity; 24 met ≥ 2 criteria. Significant decreases in ALT activities, APRI scores and HBV DNA levels were observed among those treated. This hepatitis B care and treatment programme was demonstrated to be feasible in a low-resource setting. Despite challenges, testing and linkage to care is critical to decrease the global burden of hepatitis B.

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.

Background Direct-acting antiviral (DAA) drugs have been effective in the treatment of chronic hepatitis C virus (HCV) infection. Limited data are available on safety, tolerability, and efficacy in American Indian or Alaska Native people. We aim to evaluate the treatment outcomes of sofosbuvir-based regimens for treatment of HCV in a real life setting in Alaska Native/American Indian (AN/AI) people.Methods AN/AI patients within the Alaska Tribal Health System with confirmed positive anti-HCV and HCV RNA, who were 18 years of age and older were included in the study. Pretreatment baseline patient characteristics, treatment efficacy based on sustained virologic response (SVR) 12 weeks after treatment completion, and adverse effects were assessed. The following treatments were given according to the American Association for the Study of Liver Diseases/Infectious Disease Society of America (AASLD/IDSA) HCV Guidance: ledipasvir/sofosbuvir, sofosbuvir plus weight-based ribavirin, and sofosbuvir/velpatasvir.Results We included 501 patients with a mean age of 54.3 (range 21.3 -78.3) in the study. Overall SVR was achieved in 95.2% of patients who received one of the three DAA regimens. For those with cirrhosis, overall SVR was 92.8% and for those with genotype 3 91.1% achieved SVR. The most common symptom experienced during treatment was headache. Joint pain was found to decrease during treatment. One person discontinued sofosbuvir plus ribavirin due to myocardial infarction and one discontinued sofosbuvir/velpatasvir due to urticaria.Conclusions In the real-world setting, sofosbuvir-based treatment is safe, effective, and well tolerated in AN/AI patients. Sustained virologic response was high regardless of HCV genotype or cirrhosis status.Competing Interest StatementPartial funding from Gilead Sciences.Funding StatementPartial funding from Gilead Sciences.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Alaska Area Institutional Review Board (IHS IRB #2) Dr. Shanda Lohse, Chair, Alaska Area IRB Terry Powell, Administrator, Alaska Area IRB 4315 Diplomacy Drive - RMCC Anchorage, AK 99508 Phone: 907-729-3924 or 907-729-3917 Email: akaalaskaareaIRB{at}anthc.orgAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAccess to data for this study is subject to tribal review. Requests for data should be directed to the Alaska Native Tribal Health Consortium Privacy Officer c/o Ethics and Compliance Services, 4315 Diplomacy Drive, Anchorage, AK 99508.

BACKGROUND: The duration of protection from hepatitis B vaccination in children and adults is not known. In 1981, we used three doses of plasma-derived hepatitis B vaccine to immunize a cohort of 1578 Alaska Native adults and children from 15 Alaska communities who were 6 months or older. METHODS: We tested persons for anti-HBs levels 35 years after receiving the primary series. Those with levels <10 mIU/ml received 1 booster dose of recombinant hepatitis B vaccine 2-4 weeks later and were then evaluated on the basis of anti-HBs measurements 30 days post-booster. RESULTS: Among the 320 recruited, 112 persons had not participated in the 22 nor 30-year follow-up study (Group 1) and 208 persons had participated but were not given an HBV booster dose (Group 2). Among the 112 persons in Group 1 who responded to the original primary series, 53 (47.3%) had an anti-HBs level ≥10 mIU/ml. Among group 1, 73.7% (28/38) of persons available for a booster dose responded to it with an anti-HBs level ≥10 mIU/ml at 30 days. Initial anti-HBs level after the primary series was correlated with higher anti-HBs levels at 35 years. Among 8 persons who tested positive for anti-HBc, none tested positive for HBsAg nor HBV DNA. CONCLUSIONS: Based on anti-HBs level ≥10 mIU/ml at 35 years and a 73.7% booster dose response, we estimate 86% of participants had evidence of protection 35 years later. Booster doses are not needed in the general population at this time.

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.

BACKGROUND: Direct-acting antiviral (DAA) drugs have been effective in the treatment of chronic hepatitis C virus (HCV) infection. Limited data are available on safety, tolerability, and efficacy in American Indian or Alaska Native people. We aim to evaluate the treatment outcomes of sofosbuvir- based regimens for treatment of HCV in a real life setting in Alaska Native/American Indian (AN/AI) people. METHODS: AN/AI patients within the Alaska Tribal Health System with confirmed positive anti-HCV and HCV RNA, who were 18 years of age and older were included in the study. Pretreatment baseline patient characteristics, treatment efficacy based on sustained virologic response (SVR) 12 weeks after treatment completion, and adverse effects were assessed. The following treatments were given according to the American Association for the Study of Liver Diseases/Infectious Disease Society of America (AASLD/IDSA) HCV Guidance: ledipasvir/sofosbuvir, sofosbuvir plus weight-based ribavirin, and sofosbuvir/velpatasvir. RESULTS: We included 501 patients with a mean age of 54.3 (range 21.3-78.3) in the study. Overall SVR was achieved in 95.2% of patients who received one of the three DAA regimens. For those with cirrhosis, overall SVR was 92.8% and for those with genotype 3 91.1% achieved SVR. The most common symptom experienced during treatment was headache. Joint pain was found to decrease during treatment. One person discontinued sofosbuvir plus ribavirin due to myocardial infarction and one discontinued sofosbuvir/velpatasvir due to urticaria. CONCLUSIONS: In the real-world setting, sofosbuvir-based treatment is safe, effective, and well tolerated in AN/AI patients. Sustained virologic response was high regardless of HCV genotype or cirrhosis status.

The hepatitis A vaccine is recommended for all children greater than or equal to 1 year of age, however, the duration of vaccine protection is unknown and protection through adulthood is crucial to prevent symptomatic hepatitis later in life. We report on 25 years of follow-up of a cohort of Alaska Native individuals who were vaccinated in early childhood. We assessed the duration of vaccine protection by calculating the geometric mean concentration and proportion of participants with protective levels of IgG antibody to hepatitis A virus (anti-HAV) (≥20 mIU/mL) every 2 to 3 years. We estimated the amount of time until the anti-HAV dropped below protective levels using survival analyses. At 25 years, 43 of the original 144 participants were available, mean anti-HAV levels were 91.5 mIU/mL, and 35 (81.4%) had protective levels of anti-HAV. Using data from all persons and all time points, a survival analysis estimated 78.7% of participants had protective levels of anti-HAV at 25 years. The high level of protective antibodies in this cohort indicate that supplemental doses of hepatitis A vaccine are not needed 25 years after completion of the vaccine series.

BACKGROUND AND AIMS: Information is limited regarding hepatitis B virus (HBV) genotype and the outcome of chronic HBV (CHB) infection. We examined HBV genotype on hepatocellular carcinoma (HCC) occurrence in Alaska Native (AN) persons with CHB where five HBV genotypes are found, A2, B6, C2, D and F1. APPROACH AND RESULTS: We calculated HCC incidence per 1000 person-years of follow-up to determine which groups by age, sex, and genotype met current American Association for the Study of Liver Diseases HCC surveillance criteria. We used Poisson regression to compare HCC risk by genotype, age, sex, and Alaska region. Incidence of HCC was calculated using the sex specific AASLD cutoff recommended for the Asian population of 50 years for women and 40 years for men. HCC screening was conducted semiannually using alpha-fetoprotein levels and abdominal ultrasound. Among 1185 AN persons, median follow up was 35.1 years; 667 (63%) were male. The HBV genotype distribution was: 49% D, 18% F, 13% A, 6% C, 3% B, 0.1% H, and 12% undetermined. Sixty-three cases of HCC occurred. HCC incidence for genotype F was 5.73 per 1000 person-years of follow-up, followed by 4.77 for C, 1.28 for A, 0.47 for D and 0.00 for B. The HCC risk was higher for genotypes F (Relative rate [RR] : 12.7, 95% confidence interval [CI]: 6.1-26.4) , C (RR: 10.6, 95% CI: 4.3-26.0) and A (RR: 2.9, 95% CI: 1.0-8.0) compared to genotypes B or D. Among males < 40 years of age and females < 50 years of age, genotype F had the highest incidence (4.79/1000 person-years). CONCLUSIONS: HBV genotype was strongly associated with HCC HBV genotype should be considered in risk factor stratification.

Following increases in reported cases of hepatitis A, we assessed the impact of hepatitis A vaccine in Alaska Native persons. During 1996-2018, only 6 cases of hepatitis A were identified, all in unvaccinated adults. Populations can be protected against hepatitis A by achieving sufficient vaccination coverage over time.

Introduction. Gastric cancer is a health disparity in the Alaska Native people. The incidence of Helicobacter pylori infection, a risk factor for non-cardia gastric adenocarcinoma, is also high. Gastric cancer is partially associated with the virulence of the infecting strain.Aim. To genotype the vacA s, m and i and cag pathogenicity island (cagPAI) genes in H. pylori from Alaskans and investigate associations with gastropathy.Methodology. We enrolled patients with gastritis, peptic ulcer disease (PUD) and intestinal metaplasia (IM) in 1998-2005 and patients with gastric cancer in 2011-2013. Gastric biopsies were collected and cultured and PCR was performed to detect the presence of the right and left ends of the cagPAI, the cagA, cagE, cagT and virD4 genes and to genotype the vacA s, m and i regions.Results. We recruited 263 people; 22 (8 %) had no/mild gastritis, 121 (46 %) had moderate gastritis, 40 (15%) had severe gastritis, 38 (14 %) had PUD, 30 (11 %) had IM and 12 (5 %) had gastric cancer. H. pylori isolates from 150 (57%) people had an intact cagPAI; those were associated with a more severe gastropathy (P</=0.02 for all comparisons). H. pylori isolates from 77 % of people had either the vacA s1/i1/m1 (40 %; 94/234) or s2/i2/m2 (37 %; 86/234) genotype. vacA s1/i1/m1 was associated with a more severe gastropathy (P</=0.03 for all comparisons).Conclusions. In this population with high rates of gastric cancer, we found that just over half of the H. pylori contained an intact cagPAI and 40 % had the vacA s1/i1/m1 genotype. Infection with these strains was associated with a more severe gastropathy.

Most persons with chronic HCV infection in the United States are undiagnosed or linked to care. We describe a program for the management of Alaska Native patients with HCV infection utilizing a computerized registry and statewide liver clinics resulting in higher linkage to care (86%) compared to national estimates (approximately 25%).

Background: Helicobacter pylori isolates from Alaska have demonstrated a high prevalence of antimicrobial resistance. Objective(s): To determine treatment failure in three groups, and analyse the relationship between treatment failure and antimicrobial resistance. Method(s): Antimicrobial susceptibility was determined using agar dilution and Etest. Treatment success was determined using the urea breath test 2 months after antimicrobial therapy. Result(s): Among 303 treated adult patients, 103 (34%) failed initial treatment despite a 91% compliance with medication. About 222 (73%) patients were treated with a clarithromycin-based regimen, 55 (18%) with a metronidazole-based regimen, 15 (5%) with a regimen that contained clarithromycin and metronidazole and 11 (4%) with other antimicrobials. Among 260 culture-positive patients, 156 (60%) were infected with metronidazole-resistant isolates, 74 (28%) clarithromycin-resistant, 52 (20%) clarithromycin/metronidazole-resistant, 40 (15%) levofloxacin-resistant, 11 (4%) clarithromycin/metronidazole/levofloxacin-resistant and nine (3%) amoxicillin-resistant. Overall, 34% of patients were treated with at least one antibiotic to which their infecting organism was resistant. Among patients treated with clarithromycin-based regimens, treatment failed in 72% of patients carrying clarithromycin-resistant H pylori vs 20% with clarithromycin-sensitive strains (RR = 3.7, P < 0.001). Among patients treated with metronidazole-based regimens, treatment failed in 19% of patients carrying metronidazole-resistant H pylori vs 24% with metronidazole-sensitive strains (P = 0.72). Conclusion(s): A high proportion of H pylori isolates demonstrate resistance to clarithromycin, metronidazole or levofloxacin. Over one third of H pylori-infected patients were treated with an antibiotic to which their infecting organism demonstrated resistance. Clarithromycin resistance is associated with a greater risk for failure with clarithromycin-based multidrug regimens compared to clarithromycin-sensitive; resistance to metronidazole did not affect treatment failure.

Recent reports have found a rise in Hepatitis C virus (HCV) infection in reproductive age women in the USA. Surveillance data suggests one group that is at increased risk of HCV infection is the American Indian and Alaska Native population (AI/AN). Using the National Center for Health Statistics (NCHS) birth certificate and the Indian Health Services, Tribal, and Urban Indian (IHS) databases, we evaluated reported cases of HCV infection in pregnant women between 2003 and 2015. In the NCHS database, 38 regions consistently reported HCV infection. The percentage of mothers who were known to have HCV infection increased between 2011 and 2015 in both the AI/AN population (0.57% to 1.19%, p < 0.001) and the non-AI/AN population (0.21% to 0.36%, p < 0.001). The IHS database confirmed these results. Individuals with hepatitis B infection or intravenous drug use (IDU) had significantly higher odds of HCV infection (OR 16.4 and 17.6, respectively). In total, 62% of HCV-positive women did not have IDU recorded. This study demonstrates a significant increase in the proportion of pregnant women infected with HCV between 2003 and 2015. This increase was greater in AI/AN women than non-AI/AN women. This highlights the need for HCV screening and prevention in pregnant AI/AN women.

Viral hepatitis is a major public health threat and a leading cause of death worldwide. Annual mortality from viral hepatitis is similar to that of other major infectious diseases such as HIV and tuberculosis. Highly effective prevention measures and treatments have made the global elimination of viral hepatitis a realistic goal, endorsed by all WHO member states. Ambitious targets call for a global reduction in hepatitis-related mortality of 65% and a 90% reduction in new infections by 2030. This Commission draws together a wide range of expertise to appraise the current global situation and to identify priorities globally, regionally, and nationally needed to accelerate progress. We identify 20 heavily burdened countries that account for over 75% of the global burden of viral hepatitis. Key recommendations include a greater focus on national progress towards elimination with support given, if necessary, through innovative financing measures to ensure elimination programmes are fully funded by 2020. In addition to further measures to improve access to vaccination and treatment, greater attention needs to be paid to access to affordable, high-quality diagnostics if testing is to reach the levels needed to achieve elimination goals. Simplified, decentralised models of care removing requirements for specialised prescribing will be required to reach those in need, together with sustained efforts to tackle stigma and discrimination. We identify key examples of the progress that has already been made in many countries throughout the world, demonstrating that sustained and coordinated efforts can be successful in achieving the WHO elimination goals.

We summarised available hepatitis C virus (HCV) surveillance data for 2012-14 from Arctic/sub-Arctic countries/regions. We sent a HCV data collection template by email to public health authorities in all jurisdictions. Population statistics obtained from census sources for each country were used to estimate rates of reported acute and chronic/undifferentiated HCV cases. Seven countries with Arctic regions (Canada, Denmark, Finland, Greenland, Norway, Sweden and the United States, represented by the state of Alaska), including three Canadian territories and one province, as well as 11 Russian subnational Arctic regions, completed the data collection template. Data on acute HCV infection during 2014 was available from three Arctic countries and all Russian Arctic regions (rate range 0/100,000 population in Greenland, as well as Nenets and Chukotka Automous Okrugs (Russian subnational Arctic regions) to 3.7/100,000 in the Russian Republic of Komi). The rate of people with chronic/undifferentiated HCV infection in 2014 ranged from 0/100,000 in Greenland to 171.2/100,000 in Alaska. In most countries/regions, the majority of HCV-infected people were male and aged 19-64 years. Differences in surveillance methods preclude direct comparisons of HCV surveillance data between Arctic countries/regions. Our data can inform future efforts to develop standardised approaches to HCV surveillance in the Arctic countries/regions by identifying similarities/differences between the surveillance data collected.

Helicobacter pylori infection is common among Alaska native (AN) people, however scant gastric histopathologic data is available for this population. This study aimed to characterise gastric histopathology and H. pylori infection among AN people. We enrolled AN adults undergoing upper endoscopy. Gastric biopsy samples were evaluated for pathologic changes, the presence of H. pylori, and the presence of cag pathogenicity island-positive bacteria. Of 432 persons; two persons were diagnosed with gastric adenocarcinoma, two with MALT lymphoma, 40 (10%) with ulcers, and 51 (12%) with intestinal metaplasia. Fifty-five per cent of H. pylori-positive persons had cag pathogenicity island positive bacteria. The gastric antrum had the highest prevalence of acute and chronic moderate-severe gastritis. H. pylori-positive persons were 16 and four times more likely to have moderate-severe acute gastritis and chronic gastritis (p < 0.01), respectively. An intact cag pathogenicity island positive was correlated with moderate-severe acute antral gastritis (53% vs. 31%, p = 0.0003). H. pylori-positive persons were more likely to have moderate-severe acute and chronic gastritis compared to H. pylori-negative persons. Gastritis and intestinal metaplasia were most frequently found in the gastric antrum. Intact cag pathogenicity island positive was correlated with acute antral gastritis and intestinal metaplasia.

Background: Vaccination, screening, and linkage to care can reduce the burden of chronic hepatitis B virus (HBV) infection. However, recommendations vary among organizations, and their implementation has been suboptimal. The American College of Physicians' High Value Care Task Force and the Centers for Disease Control and Prevention developed this article to present best practice statements for hepatitis B vaccination, screening, and linkage to care. Methods: A narrative literature review of clinical guidelines, systematic reviews, randomized trials, and intervention studies on hepatitis B vaccination, screening, and linkage to care published between January 2005 and June 2017 was conducted. Best Practice Advice 1: Clinicians should vaccinate against hepatitis B virus (HBV) in all unvaccinated adults (including pregnant women) at risk for infection due to sexual, percutaneous, or mucosal exposure; health care and public safety workers at risk for blood exposure; adults with chronic liver disease, end-stage renal disease (including hemodialysis patients), or HIV infection; travelers to HBV-endemic regions; and adults seeking protection from HBV infection. Best Practice Advice 2: Clinicians should screen (hepatitis B surface antigen, antibody to hepatitis B core antigen, and antibody to hepatitis B surface antigen) for HBV in high-risk persons, including persons born in countries with 2% or higher HBV prevalence, men who have sex with men, persons who inject drugs, HIV-positive persons, household and sexual contacts of HBV-infected persons, persons requiring immunosuppressive therapy, persons with end-stage renal disease (including hemodialysis patients), blood and tissue donors, persons infected with hepatitis C virus, persons with elevated alanine aminotransferase levels (≥19 IU/L for women and ≥30 IU/L for men), incarcerated persons, pregnant women, and infants born to HBV-infected mothers. Best Practice Advice 3: Clinicians should provide or refer all patients identified with HBV (HBsAg-positive) for posttest counseling and hepatitis B-directed care.

OBJECTIVES: The objectives of this study were to determine the prevalence of hepatitis C virus-associated inflammatory arthritis, to describe its clinical and immunologic correlates, and to identify features that are characteristic of arthritis in chronic hepatitis C. METHODS: Participants with chronic hepatitis C infection enrolled in a population-based cohort study in Alaska and who had not received anti-viral treatment for hepatitis C were recruited. In a cross-sectional study, we assessed joint symptoms and signs, performed autoantibody and cytokine testing, and abstracted medical records for features of hepatitis C and arthritis. RESULTS: Of the 117 enrolled participants, 8 (6.8%) had hepatitis C-associated arthritis. The participants with arthritis were younger than those without (median age: 45 vs. 52, p = 0.02). Rheumatoid factor was commonly present among patients with hepatitis C-associated arthritis. The only studied autoantibody found more commonly in patients with HCV arthritis than those without arthritis was anti-nuclear antibody (63% vs. 23%, p = 0.026). The only joint symptom significantly more common in hepatitis C arthritis was self-reported joint swelling (75% vs. 26%, p = 0.007). Features of fibromyalgia were more common and functional status was worse in those with arthritis than those without. No cytokines differed in patients with and without arthritis. There were no associations of arthritis or autoantibodies with liver-related outcomes. CONCLUSIONS: In this study of a cohort of individuals with chronic HCV infection, HCV-associated arthritis was present in less than 10%. Few serologic features distinguished participants with or without arthritis, but self-reported joint swelling was more common in those with arthritis.

Long-term prospective studies of the outcomes associated with HCV infection are rare and critical for assessing the potential impact of HCV treatment. Using liver biopsy as a start point, we looked at development of end stage liver disease (ESLD), hepatocellular carcinoma (HCC) and liver-related death (LRD) according to fibrosis stage, among a cohort of American Indian/Alaska Native persons in Alaska. Persons were classified as having no/mild (Ishak=0,1), moderate (Ishak=2), or severe (Ishak=3,4) fibrosis or cirrhosis (Ishak=5,6). We examined time until development of ESLD, HCC and LRD and report survival probabilities at 3, 5, 7 and 10-years. Of 407 persons, 39%(n = 150) had no/mild fibrosis, 32%(n = 131) had moderate fibrosis, 22%(n = 88) had severe fibrosis and 9%(n = 38) had cirrhosis. The average time of follow-up was 7.3 years. Within 5 years of biopsy, 1.7% (95% confidence interval (CI):0.4,6.8) of persons with none/mild fibrosis developed ESLD compared to 7.9% (CI:4.0,15.2), 16.4% (CI:9.6,27.2) and 49.0% (CI:33.0,67.7) with moderate, severe fibrosis, and cirrhosis, respectively (p<0.01). The 5-year outcome of HCC was 1.0% (CI:0.1,7.0), 1.0% (CI 0.1,6.6), 1.1% (CI:0.2,7.7) and 13.4% (CI:4.4,36.7) among persons with none/mild, moderate fibrosis, severe fibrosis and cirrhosis, respectively (p<0.01). Five years following biopsy, 0.0% (CI:0.0,14.8) of persons with none/mild fibrosis had suffered an LRD compared to 1.0% (CI:0.2,7.5) of persons with moderate fibrosis, 4.7% (CI:1.5,14.1) with severe fibrosis and 16.3% (CI:7.0,35.1) with cirrhosis (p<0.01). Conclusion For prevention of HCC, LRD and ESLD in the short-term, HCV therapy should target those with more than mild fibrosis. This article is protected by copyright. All rights reserved.

Hepatitis A vaccine is recommended for children ≥1 year old to prevent hepatitis A virus (HAV) infection. However the duration of vaccine-induced immunity is unknown. We evaluated a cohort of Alaska Native persons 20 years after HAV vaccination. Children aged 3-6 years had been previously randomized to receive 3 doses of HAV vaccine (360 ELISA units/dose) at: A) 0,1,2 months; B) 0,1,6 months; and C) 0,1,12 months. We measured anti-HAV antibody concentrations every 2-3 years; described geometric mean concentrations (GMC) and the proportion with protective antibody (≥20 mIU mL-1) over time; and modelled change in GMC using fractional polynomial regression. Of 144 participants, after 20 year 52 (36.1%) were available for follow-up (17, 18, 17 children in Groups A, B and C, respectively). Overall, 46 (88.5%) of 52 available participants had anti-HAV antibody concentrations ≥20mIU mL-1 and overall GMC was 107 mIU mL-1. Although GMC levels were lower in Group A (60; CI 34-104) than in Group B (110; CI 68-177), or Group C (184; CI 98-345) (B versus C: p=0.168; A versus B/C: p=0.011), there was no difference between groups after adjusting for peak antibody levels post vaccination (p=0.579). Models predicted geometric mean concentrations of 124 mIU mL-1 after 25 years, and 106 mIU mL-1 after 30 years. HAV vaccine provides protective antibody levels 20 years after childhood vaccination. Lower antibody levels in Group A may be explained by a lower initial peak response. Our results suggest a booster vaccine dose is unnecessary for at least 25-30 years.

Sirs, We appreciate the interest in our study from Professors Chen and Liaw and the opportunity to provide additional information.1 As we acknowledged in our paper, the wide confidence intervals for our risk estimates resulting from the relatively small number of case- and control-patients developing HCC were an important limitation to our study.2 Thus, it is possible that we failed to detect a real reduction in HCC risk because of insufficient statistical power. As requested, we recalculated the risk for developing HCC after excluding the 2 case-patients who received antiviral treatment before HBsAg seroclearance and the 32 control-patients who had received antiviral treatment. After adjusting for age at cohort entry and initial anti-hepatitis B e antibody status, we did not detect a difference in HCC risk among case-compared with control-patients after excluding patients who had received antiviral treatment (adjusted hazard ratio: 0.7; 95% confidence interval: 0.2–2.7). The effect of age at HBsAg seroclearance on risk for HCC is complex and could be partly related to the specific HBV genotypes represented in a population. It has been demonstrated that the duration of hepatitis B e antigen persistence and the risk for HCC is substantially higher for persons with HBV genotype C compared with other genotypes.3,4 The majority of patients in the study indicating an increased risk for HCC among persons aged ≥50 years at the time of HBsAg seroclearance were infected with HBV genotype C.5,6 In contrast, the majority of patients in our study population were infected with HBV genotype D. Therefore, the risk for HCC associated with a later age of HBsAg seroclearance among Alaska Native persons compared with other geographic regions is unclear because of differences in the prevalence of HBV genotypes. Furthermore, the age at HBsAg seroclearance should not affect our interpretation of the relative risk for HCC between case- and control-patients because the majority of participants acquired HBV infection in early childhood and our analysis adjusted for case-patients’ HBsAg duration prior to seroclearance. We also speculated in our paper that ongoing low-level HBV DNA replication with continued integration into the host hepatocyte could have contributed to persistent HCC risk after HBsAg seroclearance. Further study is necessary to determine the relative importance of HBV viremia early in the course of disease versus persistence of viremia after HBsAg clearance in the development of HCC.

BACKGROUND: The aspartate aminotransferase-to-platelet ratio index (APRI) and a fibrosis index calculated using platelets (FIB-4) have been proposed as noninvasive markers of liver fibrosis. GOALS: To determine APRI/FIB-4 accuracy for predicting histologic liver fibrosis and evaluate whether incorporating change in index improves test accuracy in hepatitis C virus (HCV)-infected Alaska Native persons. STUDY: Using liver histology as the gold standard, we determined the test characteristics of APRI to predict Metavir ≥F2 fibrosis and FIB-4 to predict Metavir ≥F3 fibrosis. Index discrimination was measured as the area under the receiver operator characteristic curve. We fit a logistic regression model to determine whether incorporating change in APRI/FIB-4 over time improved index discrimination. RESULTS: Among 283 participants, 46% were female, 48% had a body mass index >30, 11% had diabetes mellitus, 8% reported current heavy alcohol use. Participants were infected with HCV genotypes 1 (68%), 2 (17%), or 3 (15%). On liver histology, 30% of study participants had ≥F2 fibrosis and 15% had ≥F3 fibrosis. The positive predictive value of an APRI>1.5/FIB-4>3.25 for identifying fibrosis was 77%/78%. The negative predictive value of an APRI<0.5/FIB-4<1.45 was 91%/87%. The area under the receiver operator characteristic curve of an APRI/FIB-4 for identifying fibrosis was 0.82/0.84. Incorporating change in APRI/FIB-4 did not improve index discrimination. CONCLUSIONS: The accuracy of APRI/FIB-4 for identifying liver fibrosis in HCV-infected Alaska Native persons is similar to that reported in other populations and could help prioritize patients for treatment living in areas without access to liver biopsy. Change in APRI/FIB-4 was not predictive of degree of fibrosis.

BACKGROUND & AIMS: Few studies have examined factors associated with disease progression in hepatitis C virus (HCV) infection. We examined the association of 11 risk factors with adverse outcomes in a population-based prospective cohort observational study of Alaska Native/American Indian persons with chronic HCV infection. METHODS: We collected data from a population-based cohort study of liver-related adverse outcomes of infection in American Indian/Alaska Native persons with chronic HCV living in Alaska, recruited from 1995 through 2012. We calculated adjusted hazard ratios (aHR) and 95% CIs for end-stage liver disease (ESLD; presence of ascites, esophageal varices, hepatic encephalopathy, or coagulopathy), hepatocellular carcinoma (HCC), and liver-related death using a Cox proportional hazards model. RESULTS: We enrolled 1080 participants followed for 11,171 person-years (mean, 10.3 years); 66%, 19%, and 14% were infected with HCV genotypes 1, 2, and 3, respectively. On multivariate analysis, persons infected with HCV genotype 3 had a significantly increased risk of developing all 3 adverse outcomes. Their aHR for ESLD was 2.1 (95% CI, 1.5-3.0), aHR for HCC was 3.1 (95% CI, 1.4-6.6), and aHR for liver-related death was 2.4 (95% CI, 1.5-4.0) compared to genotype 1. Heavy alcohol use was an age-adjusted risk factor for ESLD (aHR, 2.2; 95% CI, 1.6-3.2), and liver-related death (aHR: 2.9; 95% CI, 1.8-4.6). Obesity was a risk factor for ESLD (aHR, 1.4; 95% CI, 1.0-1.9, and diabetes was a risk factor for ESLD (aHR, 1.5; 95% CI, 1.1-2.2). Male sex was a risk factor for HCC (aHR, 3.6; 95% CI, 1.6-8.2). CONCLUSIONS: In a population-based cohort study of American Indian/Alaska Native persons with chronic HCV infection, we found those infected with HCV genotype 3 to be at high risk for ESLD, HCC, and liver-related death.

Integration of hepatitis B vaccination into national immunization programs has resulted in substantial reductions of hepatitis B virus (HBV) transmission in previously high endemic countries. The key strategy for control of the HBV epidemic is birth dose and infant vaccination. Additional measures include use of hepatitis B immunoglobulin (HBIG) and diagnosis of mothers at high risk of transmitting HBV and use of antiviral agents during pregnancy to decrease maternal DNA concentrations to undetectable concentrations. Despite the substantial decrease in HBV cases since vaccination introduction, implementation of birth dose vaccination in low-income and middle-income countries and vaccination of high-risk adults remain challenging.

OBJECTIVES: To evaluate the hepatocellular carcinoma (HCC) risk in Alaska Native children and young adults with hepatitis B virus (HBV). STUDY DESIGN: Retrospective analysis of a population-based cohort of Alaska Native persons with HBV followed during 1982-2012. All individuals with HBV were offered HCC screening regardless of age using alpha-fetoprotein every 6 months; persons with an elevated alpha-fetoprotein or persons at high-risk for HCC, such as cirrhosis, family history of HCC, were offered ultrasound. We calculated the HCC incidence/1000 person-years from date of cohort entry until death, diagnosis of HCC, or attaining the age of 40 years (males) or 50 years (females). RESULTS: We followed 1083 subjects with HBV (56% male) comprising 5 genotypes (A2 [12.5%], B6 [1.7%], C [5.3%], D [49.7%], F1 [18.6%], unknown [12.4%]) for a median of 23.4 years/person. We observed 22 HCC cases (incidence/1000 person-years follow-up: 1.0); 19 HCC cases among persons with genotype F1. There was no significant difference in HCC incidence between males (1.4) and females (0.6). The HCC incidence was significantly higher for persons with genotype F1 (4.4) compared with genotype A2 (0.4) and D (0.2) and remained higher among persons with HBV genotype F1 excluding persons with HCC family history/cirrhosis (1.9). CONCLUSIONS: Alaska Native children and young adults with HBV genotype F1 are at high risk for HCC and should receive HCC surveillance. For males <40 years of age and females <50 years of age with HBV in regions of the world with a high genotype F prevalence, testing/confirming genotype F can identify persons who could benefit from HCC surveillance.

BACKGROUND: Long-lasting protection resulting from hepatitis B vaccine, despite loss of antibody against hepatitis B virus (HBV) surface antigen (anti-HBs), is undetermined. METHODS: We recruited persons from a cohort vaccinated with plasma-derived hepatitis B vaccine in 1981 who have been followed periodically since. We performed serological testing for anti-HBs and microRNA-155 and assessed HBV-specific T-cell responses by enzyme-linked immunospot and cytometric bead array. Study subgroups were defined 32 years after vaccination as having an anti-HBs level of either ≥10 mIU/mL (group 1; n = 13) or <10 mIU/mL (group 2; n = 31). RESULTS: All 44 participants, regardless of anti-HBs level, tested positive for tumor necrosis factor alpha, interleukin 10, or interleukin 6 production by HBV surface antigen-specific T cells. The frequency of natural killer T cells correlated with the level of anti-HBs (P = .008). The proportion of participants who demonstrated T-cell responses to HBV core antigen varied among the cytokines measured, suggesting some natural exposure to HBV in the study group. No participant had evidence of breakthrough HBV infection. CONCLUSIONS: Evidence of long-lasting cellular immunity, regardless of anti-HBs level, suggests that protection afforded by primary immunization with plasma-derived hepatitis B vaccine during childhood and adulthood lasts at least 32 years.

BACKGROUND AND AIMS: Alaska Native peoples have an increased rate of hepatocellular carcinoma compared to the United States population. Viral hepatitis is a risk factor for malignancy and the leading cause of hepatocellular carcinoma in Alaska. With the introduction of hepatitis B immunization in 1982, as well as the emergence of hepatitis C virus in this population, the epidemiology and etiology of hepatocellular carcinoma in Alaska have changed. METHODS: Using the Alaska Native Tumor Registry, all cases of viral and non-viral hepatocellular carcinoma occurring from 1969 through 2013 were identified and reviewed. Incidence rates per 100,000 population were calculated for hepatocellular carcinoma overall and by etiologic category. RESULTS: 152 cases of hepatocellular carcinoma were identified in 148 Alaska Native persons. Overall tumor rate was 3.82 per 100,000 and did not change significantly over the study period. Hepatitis B associated cases decreased significantly over the study period (p=0.048) and were eliminated in persons under the age of 20. Hepatitis C associated cases increased significantly (P<0.001). Undetermined hepatocellular carcinoma rates also decreased. (p=0.034) CONCLUSIONS: Overall hepatocellular carcinoma rates in Alaska Native peoples remained stable over the study period, but the epidemiology and etiology are changing. Two decades after routine hepatitis B immunization, the hepatocellular carcinoma age distribution has shifted to cases presenting later in life. This is consistent with an aging hepatitis B infected population with no new infected young persons coming into the population, as well as the emergence of hepatitis C in adults. This article is protected by copyright. All rights reserved.

BACKGROUND: The American Association for the Study of Liver Diseases (AASLD) recommends semi-annual hepatocellular carcinoma (HCC) screening using ultrasound (US) in persons with chronic hepatitis B (CHB) virus infection at high risk for HCC such as Asian males aged ≥40 years and Asian females aged ≥50 years. OBJECTIVE: To analyse the cost-effectiveness of 2 HCC screening methods in the Alaska Native (AN) health system: US-alone, or screening by alpha-fetoprotein (AFP) initially and switching to US for subsequent screenings if AFP >10 ng/mL (AFP-->US). DESIGN: A spreadsheet-based model was developed for accounting the costs of 2 hypothetical HCC screening methods. We used epidemiologic data from a cohort of 839 AN persons with CHB who were offered HCC screening by AFP/US semi-annually during 1983-2012. We assumed that compared with AFP-->US, US-alone identifies 33% more tumours at an early stage (defined as a single tumour ≤5 cm or ≤3 tumours ≤3 cm in diameter). Years of life gained (YLG) attributed to screening was estimated by comparing additional years of survival among persons with early- compared with late-stage tumours. Screening costs were calculated using Medicare reimbursement rates in 2012. Future screening costs and YLG were projected over a 30-year time horizon using a 3% discount rate. RESULTS: The total cost of screening for the cohort by AFP-->US would have been approximately $357,000 ($36,000/early-stage tumour detected) compared to $814,000 ($59,000/early-stage tumour detected) by US-alone. The AFP-->US method would have yielded an additional 27.8 YLG ($13,000/YLG) compared with 38.9 YLG ($21,000/YLG) for US-alone. Screening by US-alone would incur an additional $114,000 per extra early-tumour detected compared with AFP-->US and $41,000 per extra YLG. CONCLUSIONS: Although US-alone HCC screening might have yielded more YLG than AFP-->US, the reduced costs of the AFP-->US method could expand access to HCC screening in resource constrained settings.

BACKGROUND: Hepatocellular carcinoma (HCC) risk after resolving chronic hepatitis B virus (HBV) infection is unclear. AIM: To compare HCC risk between Alaska Native (AN) patients with and without hepatitis B surface antigen (HBsAg) seroclearance. METHODS: We selected persons with (case-patients) and without (control-patients) HBsAg seroclearance from a cohort of 1346 chronically HBV-infected AN patients followed during 1982-2013. We attempted to match two control-patients/case-patient on sex, HBV genotype, and age. Person-years of follow-up for case-patients began on the date of HBsAg resolution and for control-patients began on the date equivalent to the cohort entry date plus the years of HBsAg duration for their corresponding case-patient. We compared HCC risk using a Cox proportional hazards model. RESULTS: The 238 case-patients (4 with HCC) and 435 control-patients (9 with HCC) were similar in age [P-value (P) = 0.30], sex (P = 0.53) and HBV genotype (P = 0.99). Case-patients had longer person-years of follow-up than control-patients (11.7 vs. 10.1 years; P = 0.04). The HCC rate/100 000 persons was similar between case- (132) and control-patients (178; P = 0.65). The adjusted hazard ratio comparing case- and control-patients was similar for HCC [0.7; 95% confidence interval (CI): 0.2-2.4], increased for each 1-year increment for age (1.1; CI: 1.0-1.1; P < 0.01), and was greater if the initial HBeAg was positive (3.5; CI: 1.1-11.0; P = 0.03). CONCLUSIONS: Hepatitis B surface antigen seroclearance was not associated with reduced HCC risk; the HCC risk estimates are limited by wide 95% confidence intervals. Persons meeting HCC surveillance indications prior to HBsAg seroclearance could benefit from continued surveillance after seroclearance.

BACKGROUND: There have been few reports of hepatitis C virus (HCV) treatment results with interferon-based regimens in indigenous populations. OBJECTIVE: To determine interferon-based treatment outcome among Alaska Native and American Indian (AN/AI) population. DESIGN: In an outcomes study of 1,379 AN/AI persons with chronic HCV infection from 1995 through 2013, we examined treatment results of 189 persons treated with standard interferon, interferon plus ribavirin, pegylated interferon plus ribavirin and triple therapy with a protease inhibitor. For individuals treated with pegylated interferon and ribavirin, the effect of patient characteristics on response was also examined. RESULTS: Sustained virologic response (SVR) with standard interferon was 16.7% (3/18) and with standard interferon and ribavirin was 29.7% (11/37). Of 119 persons treated with pegylated interferon and ribavirin, 61 achieved SVR (51.3%), including 10 of 46 with genotype 1 (21.7%), 38 of 51 with genotype 2 (74.5%) and 13 of 22 with genotype 3 (59.1%). By multivariate analysis, SVR in the pegylated interferon group was associated with female sex (p=0.002), estimated duration of infection (p=0.034) and HCV genotype (p<0.0001). There was a high discontinuation rate due to side effects in those treated with pegylated interferon and ribavirin for genotype 1 (52.2%). Seven of 15 genotype 1 patients treated with pegylated interferon, ribavirin and telaprevir or boceprevir achieved SVR (46.7%). CONCLUSIONS: We had success with pegylated interferon-based treatment of AN/AI people with genotypes 2 and 3. However, there were low SVR and high discontinuation rates for those with genotype 1.