ABSTRACT The International Circumpolar Surveillance (ICS) program is a population-based surveillance network for invasive bacterial diseases throughout Arctic countries and territories. The ICS quality control program for Streptococcus pneumoniae serotyping and antimicrobial susceptibility testing has been ongoing since 1999. Current participating laboratories include the Provincial Laboratory for Public Health in Edmonton, Alberta; Laboratoire de santé publique du Québec in Sainte-Anne-de-Bellevue, Québec; the Centers for Disease Control’s Arctic Investigations Program in Anchorage, Alaska; the Neisseria and Streptococcus Reference Laboratory at Statens Serum Institut in Copenhagen, Denmark; the Department of Clinical Microbiology, Landspitali in Reykjavik, Iceland; and Public Health Agency of Canada’s National Microbiology Laboratory in Winnipeg, Manitoba. From 2009 to 2020, 140 isolates of S. pneumoniae were distributed among the six laboratories as part of the quality control program. Overall serotype concordance was 96.9%, with 99.3% concordance to pool level. All participating laboratories had individual concordance rates >92% for serotype and >97% for pool. Overall concordance by modal minimum inhibitory concentration (MIC) for testing done by broth microdilution or Etest was 99.1%, and >98% for all antimicrobials tested. Categorical concordance was >98% by both CLSI and EUCAST criteria. For two laboratories performing disc diffusion, rates of concordance by modal MIC were >97% for most antimicrobials, except chloramphenicol (>93%) and trimethoprim/sulfamethoxazole (>88%). Data collected from 12 years of the ICS quality control program for S. pneumoniae demonstrate excellent (≥95%) overall concordance for serotype and antimicrobial susceptibility testing results across six laboratories. IMPORTANCE Arctic populations experience several social and physical challenges that lead to the increased spread and incidence of invasive diseases. The International Circumpolar Surveillance (ICS) program was developed to monitor five invasive bacterial diseases in Arctic countries and territories. Each ICS organism has a corresponding interlaboratory quality control (QC) program for laboratory-based typing, to ensure the technical precision and accuracy of reference testing services for these regions, and identify and correct potential problems. Here, we describe the results of the ICS Streptococcus pneumoniae QC program, from 2009 to 2020. Excellent overall concordance was achieved for serotype and antimicrobial susceptibility testing results across six laboratories. Ongoing participation in these QC programs ensures the continuation of quality surveillance systems within Arctic populations that experience health disparities.

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.

Background. Despite use of highly effective conjugate vaccines, invasive pneumococcal disease (IPD) remains a leading cause of morbidity and mortality and disproportionately affects Indigenous populations. Although included in the 13-valent pneumococcal conjugate vaccine (PCV13), which was introduced in 2010, serotype 3 continues to cause disease among Indigenous communities in the Southwest USA. In the Navajo Nation, serotype 3 IPD incidence increased among adults (3.8/100 000 in 2001–2009 and 6.2/100 000 in 2011–2019); in children the disease persisted although the rates dropped from 5.8/100 000 to 2.3/100 000. Methods. We analysed the genomic epidemiology of serotype 3 isolates collected from 129 adults and 63 children with pneumococcal carriage (n=61) or IPD (n=131) from 2001 to 2018 of the Navajo Nation. Using whole-genome sequencing data, we determined clade membership and assessed changes in serotype 3 population structure over time. Results. The serotype 3 population structure was characterized by three dominant subpopulations: clade II (n=90, 46.9 %) and clade Iα (n=59, 30.7 %), which fall into Clonal Complex (CC) 180, and a non-CC180 clade (n=43, 22.4 %). The proportion of clade II-associated IPD cases increased significantly from 2001 to 2010 to 2011–2018 among adults (23.1–71.8 %; P<0.001) but not in children (27.3–33.3 %; P=0.84). Over the same period, the proportion of clade II-associated carriage increased; this was statistically significant among children (23.3–52.6 %; P=0.04) but not adults (0–50.0 %, P=0.08). Conclusions. In this setting with persistent serotype 3 IPD and carriage, clade II has increased since 2010. Genomic changes may be contributing to the observed trends in serotype 3 carriage and disease over time.

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.

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.

Background Haemophilus influenzae serotype a (Hia) can cause severe invasive disease, especially in young children. In 2018, 4 invasive Hia cases occurred in an Alaska community. We used whole-genome sequencing (WGS) to evaluate the relationship of the bacteria from this community and other Alaska patients with invasive Hia. Methods All carriage (n = 15) and invasive (n = 4) Hia isolates from the outbreak community, together with 15 nonoutbreak Alaska invasive Hia surveillance isolates from 2018, were tested for antimicrobial susceptibility and characterized using WGS. Results Phylogenetic analysis of both invasive and carriage Hia isolates revealed 2 major clades that differed by an average of 300 core single-nucleotide polymorphisms (SNPs). All isolates from the outbreak community were clustered in 1 subclade, within a larger clade containing 3 nonoutbreak invasive Hia isolates. Comparative genomics did not reveal any genetic mutations that distinguished carriage from invasive isolates. Three (20%) community isolates were rifampin resistant and had a previously unreported mutation in the rpoB gene. Conclusions In the outbreak community, Hia isolates from carriers were indistinguishable from the invasive Hia isolates. Overall, invasive Hia isolates from Alaska in 2018 were genetically similar. The rifampin resistance mutation is concerning as rifampin is the first-line medication for Hia prophylaxis.

BACKGROUND AND AIMS: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 old. APPROACH AND RESULTS:We tested persons for antibody to hepatitis B surface antigen (anti-HBs) levels 35 years after receiving the primary series. Those with levels <10 mIU/ml received one booster dose of recombinant hepatitis B vaccine 2-4 weeks later and were then evaluated on the basis of anti-HBs measurements 30 days postbooster. Among the 320 recruited, 112 persons had not participated in the 22- or 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 of 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 antibody to hepatitis B core antigen, none tested positive for HBsAg or HBV DNA. CONCLUSIONS:Based on anti-HBs level ≥10 mIU/ml at 35 years and a 73.7% booster dose response, we estimate that 86% of participants had evidence of protection 35 years later. Booster doses are not needed in the general population at this time.

Background. Haemophilus influenzae serotype a (Ilia) can cause invasive disease similar to serotype b; no Ilia vaccine is available. We describe the epidemiology of invasive Hia disease in the United States overall and specifically in Alaska during 2008-2017. Methods. Active population- and laboratory-based surveillance for invasive Hia disease was conducted through Active Bacterial Core surveillance sites and from Alaska statewide invasive bacterial disease surveillance. Sterile-site isolates were serotyped via slide agglutination or real-time polymerase chain reaction. Incidences in cases per 100 000 were calculated. Results. From 2008 to 2017, an estimated average of 306 invasive Hia disease cases occurred annually in the United States (estimated annual incidence: 0.10); incidence increased by an average of 11.1% annually. Overall, 42.7% of cases were in children aged <5 years (incidence: 0.64), with highest incidence among children aged <1 year (1.60). Case fatality was 7.8% overall and was highest among adults aged >65 years (15.1%). Among children aged <5 years, the incidence was 17 times higher among American Indian and Alaska Native (AI/AN) children (8.29) than among children of all other races combined (0.49). In Alaska, incidences among all ages (0.68) and among children aged <1 year (24.73) were nearly 6 and 14 times higher, respectively, than corresponding US incidences. Case fatality in Alaska was 10.2%, and the vast majority (93.9%) of cases occurred among AI/AN. Conclusions. Incidence of invasive Hia disease has increased since 2008, with the highest burden among AI/AN children. These data can inform prevention strategies, including Hia vaccine development.

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.

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.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.Funding Information: This study is supported by in-kind personnel support and from a cooperative agreement (U50/CCU022279) between the Centers for Disease Control and Prevention and the Alaska Native Tribal Health Consortium.Declaration of Interests: None of the authors have any conflicts to disclose.Ethics Approval Statement: This study was approved by the Alaska Area and the Centers for Disease Control and Prevention Institutional Review Boards, as well as the Yukon-Kuskokwim Health Corporation and the Norton Sound Regional health boards. Additionally, the study was approved by the Southcentral Foundation and the Alaska Native Tribal Health Consortium. At the 35-year follow-up, the continued study objectives were described, and all participants signed written informed consent to participate.

Abstract Background Haemophilus influenzae serotype a (Hia) is an important cause of infection among Alaska Native children. In 2018, 4 invasive Hia cases (iHia) occurred in an Alaska community. Our response aimed to prevent more iHia and evaluate Hia carriage in the community. Whole genome sequencing (WGS) was performed to compare Hia from iHia patients across Alaska in 2018, and from healthy outbreak community members. Methods We collected oropharyngeal (OP) samples from outbreak community members. Children aged < 10 years and people in close contact with cases (contacts) were offered rifampin prophylaxis. A second set of OP samples was collected 8 weeks later. Isolates from iHia from across the state were collected as part of the state surveillance. Hia was detected by PCR and culture, then characterized by antimicrobial susceptibility and WGS. Results At baseline, contacts had a higher prevalence of Hia carriage than non-contacts (4/27(14.8%) vs 7/364(1.9%), p=0.0043). Eight weeks after rifampin prophylaxis, carriage prevalence did not significantly change among contacts (5/42(11.9%) to 6/25(24%), p=0.18) or non-contacts (7/368(1.9%) to 2/114(1.8%), p=0.47). Phylogenetic analysis of 19 iHia isolates and 15 isolates from healthy outbreak community members, revealed two major clades that differed by an average of 300 core single nucleotide polymorphisms (SNPs). Invasive and carriage isolates from the outbreak community were clustered in one clade, along with 3 non-outbreak iHia isolates. Isolates from this community differed from each other by an average of 1.2 core SNPs. Comparative genomics did not reveal any genetic mutations that distinguished carriage from invasive isolates. Three (20%) community isolates were rifampin-resistant and had a previously unreported mutation in the rpoB gene. Conclusion We found Hia carriage prevalence was highest among persons in contact with iHia cases. Long-term community carriage was not affected by rifampin prophylaxis, possibly due to staggered prophylaxis. In the outbreak community, Hia isolates from carriers were nearly genetically identical to iHia isolates. Overall, iHia isolates from Alaska in 2018 were genetically similar. The mutation conferring rifampin resistance is concerning, as rifampin is used to prophylax contacts of iHia cases. Disclosures All Authors: No reported disclosures

In this long-term observational study, we examined the patterns of HBsAg reduction in a cohort of patients with HBeAg (+) and (-) chronic hepatitis B (CHB) who achieved spontaneous HBsAg clearance CHB Patients were selected from an antiviral treatment-naive Alaska Native population who achieved HBsAg seroclearance from 1973 to 2009 with samples at least 2 years prior to HBsAg loss. ADVIA Centaur HBsAg and HBeAg quantitative assays (Siemens Healthcare Diagnostics, USA) were utilized. 17 HBeAg (+) and 48 HBeAg (-) patients with predominantly HBV genotypes D and F were enrolled. The average follow-up was 19.5 years and 16.4 years respectively. Rate of HBsAg clearance was significantly slower among the HBeAg (+) patients (p=0.001). HBsAg loss was more uniform at a rate of about 4% over 25 years for HBeAg (-) patients. Among the HBeAg (+) patients, the average decline in HBeAg (1.8 log IU/ml/year) and HBsAg (1.5 log IU/ml /year) from baseline to HBeAg loss were similar (p=0.2). The rate of HBsAg reduction was significantly faster before (1.5 log IU/ml/year) compared to after (0.4 log IU/ml /year) HBeAg clearance (p=0.004). The kinetic of HBsAg decline after HBeAg loss was similar to that among the HBeAg (-) patients (0.3 log IU/ml /year). The observation of a biphasic decline in HBsAg titers prior to and after HBeAg seroclearance is novel. HBsAg quantification over time provides valuable information on the natural course of CHB. Its kinetic can predict HBsAg loss especially in the HBeAg (-) phase of CHB.

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

Background. Between May and July 2018, 4 Haemophilus influenzae serotype a (Hia) infections occurred in a remote Alaska community. We performed a public health response to prevent further illness and understand Hia carriage. Methods. We collected oropharyngeal samples community-wide to evaluate baseline carriage. Risk factors were evaluated by interview. We offered prophylactic rifampin to individuals in contact with invasive Hia patients (contacts) and to all children aged <10 years. Oropharyngeal samples were collected again 8 weeks after rifampin distribution. Samples were tested using real-time polymerase chain reaction and culture. Results. At baseline, 4 of 27 (14.8%) contacts and 7 of 364 (1.9%) noncontacts (P < .01) carried Hia. Contacts aged <10 years were more likely to carry Hia at any timepoint (11/18 [61%]) compared to contacts aged >= 10 years (3/34 [8.8%]), noncontacts aged <10 years (2/139 [1.4%]), and noncontacts >= 10 years (6/276 [2.2%]) (P < .001 for all). Hia carriers were clustered in 9 households (7% of total households). At the household level, carriage was associated with households with >= 1 contact (prevalence ratio [PR], 5.6 [95% confidence interval (CI), 1.3-21.6]), crowding (PR, 7.7 [95% CI, 1.1-199.5]), and >= 3 tobacco users (PR, 5.0 [95% CI, 1.219.6]). Elevated carriage prevalence persisted in contacts compared to noncontacts 8 weeks after rifampin distribution (6/25 [24%] contacts, 2/114 [1.8%] noncontacts; P < .001). Conclusions. Hia carriage prevalence was significantly higher among contacts than noncontacts. Rifampin prophylaxis did not result in a reduction of Hia carriage prevalence in this community.

Background. Chronic hepatitis C virus (HCV) infection diminishes immune function through cell exhaustion and repertoire alteration. Direct acting antiviral (DAA)-based therapy can restore immune cell subset function and reduce exhaustion states. However, the extent of immune modulation following DAA-based therapy and the role that clinical and demographic factors play remain unknown. Methods. We examined natural killer (NK) cell, CD4(+), and CD8(+) T cell subsets along with activation and exhaustion phenotypes across an observational study of sofosbuvir-based treatment for chronic HCV infection. Additionally, we examined the ability of clinical variables and duration of infection to predict 12 weeks of sustained virologic response (SVR12) immune marker outcomes. Results. We show that sofosbuvir-based therapy restores NK cell subset distributions and reduces chronic activation by SVR12. Likewise, T cell subsets, including HCV-specific CD8(+) T cells, show reductions in chronic exhaustion markers by SVR12. Immunosuppressive CD4(+) regulatory T cells decrease at 4-weeks treatment and SVR12. We observe the magnitude and direction of change in immune marker values from pretreatment to SVR12 varies greatly among participants. Although we observed associations between the estimated date of infection, HCV diagnosis date, and extent of immune marker outcome at SVR12, our regression analyses did not indicate any factors as strong SVR12 outcome predictors. Conclusion. Our study lends further evidence of immune changes following sofosbuvir-based therapy. Further investigation beyond SVR12 and into factors that may predict posttreatment outcome is warranted.

Abstract Background Between May and July 2018, four invasive cases of Haemophilus influenzae type a (Hia) occurred in a remote Alaska community. A public health response was performed to prevent further illness and to understand local Hia transmission. Methods The team identified close contacts of the Hia patients, collected oropharyngeal (OP) swabs and provided prophylactic rifampin. Close contacts were persons who spent ≥4 hours with a Hia patient for ≥ 5 of the 7 days preceding hospitalization. Five days later, OP swabs were collected community-wide and prophylactic rifampin was offered to community members aged <10 years. Eight weeks later, OP swabs were collected from all willing community members. Samples were tested using PCR and culture to identify Hi carriage. Results No Hia cases occurred in this community after the response. The pretreatment carriage prevalence is shown in Figure 1. There was a significant difference in prevalence of Hia carriage between contacts (4/27, 14.8%) and non-contacts (7/364, 1.9%) (P = 0.0043). Contacts aged <10 years were significantly more likely to carry Hia compared with contacts aged ≥10 years (11/18 [61.1%] vs. 3/34 [8.8%], P = 0.0001). The case households had the highest proportion of individuals who carried Hia at any time, with 54%–60% of individuals in three case households carrying Hia at least once. Hia carriage was eliminated in two carriers who completed treatment and were tested immediately after rifampin prophylaxis. Testing 8 weeks later found that the prevalence of carriage did not significantly change in the contacts (5/42 [11.9%] to 6/25 [24%], P = 0.18) or the non-contacts (7/368 [1.9%] to 2/114 [1.8%], P = 0.47). Conclusion Children aged <10 years who had close contact with the Hia patients were the most likely to carry Hia. These findings suggest that people who do not have close contact do not benefit from prophylaxis as they have very low Hia carriage. While rifampin prophylaxis eliminated carriage of Hia in the short term, carriage prevalence did not change in the long term. Further research is needed to understand why contacts have such a high prevalence of carriage even after receiving appropriate prophylactic medication. Disclosures All authors: No reported disclosures.

Hepatitis B virus (HBV) genotype F1b infection is strongly associated with hepatocellular carcinoma (HCC) in young Alaskan Native (AN) people. However, the mechanisms by which genotype F1b causes HCC are unclear. Here, we analyzed the clinical and virological significance of genotype F1b in long-term serial samples from 20 HCC patients with HBV infection. Complete sequence analyses revealed that all isolates were genotype F1b. In the HCC patients, T1938C and A2051C mutations in the core region had accumulated significantly with A1762T/G1764A mutations in the basal core promoter (BCP) region and G1896A mutation in the precore (PC) region. Several HBV clones containing the core mutations were examined for their replication efficiency and core stability in vitro. Clones containing the A2051C mutation replicated more efficiently than the wild type in association with enhanced stability of core protein dimerization. In chimeric mice with human hepatocytes carrying BCP/PC/2051 mutant but not with wild-type virus, liver fibrosis was induced in association with high levels of serum HBV DNA and hepatitis B surface antigen. Interestingly, microarray analysis and validation study showed that five genes associated with cell proliferation or carcinogenesis, v-myc avian myelocytomatosis viral oncogene homolog, Grb2-associated binding protein 2, bradykinin receptor B2, follistatin, and mitogen-activated protein kinase kinase kinase 8, were significantly up-regulated in human hepatocytes infected with genotype F1b, particularly the BCP/PC/2051 mutant, compared with other genotypes. Conclusion: We have identified an association between Alaska-specific core mutations and HCC development in AN people infected with genotype F1b; accumulation of these core mutations during the course of chronic infection with genotype F1b would contribute to HCC development in AN people earlier in life.

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 Indigenous populations of the circumpolar Arctic are considered to be endemically infected (>2% prevalence) with hepatitis B virus (HBV), with subgenotype B5 (formerly B6) unique to these populations. The distinctive properties of HBV/B5, including high nucleotide diversity yet no significant liver disease, suggest virus adaptation through long-term host-pathogen association. Methods To investigate the origin and evolutionary spread of HBV/B5 into the circumpolar Arctic, fifty-seven partial and full genome sequences from Alaska, Canada and Greenland, having known location and sampling dates spanning 40 years, were phylogeographically investigated by Bayesian analysis (BEAST 2) using a reversible-jump-based substitution model and a clock rate estimated at 4.1 × 10−5 substitutions/site/year. Results Following an initial divergence from an Asian viral ancestor approximately 1954 years before present (YBP; 95% highest probability density interval [1188, 2901]), HBV/B5 coalescence occurred almost 1000 years later. Surprisingly, the HBV/B5 ancestor appears to locate first to Greenland in a rapid coastal route progression based on the landscape aware geographic model, with subsequent B5 evolution and spread westward. Bayesian skyline plot analysis demonstrated an HBV/B5 population expansion occurring approximately 400 YBP, coinciding with the disruption of the Neo-Eskimo Thule culture into more heterogeneous and regionally distinct Inuit populations throughout the North American Arctic. Discussion HBV/B5 origin and spread appears to occur coincident with the movement of Neo-Eskimo (Inuit) populations within the past 1000 years, further supporting the hypothesis of HBV/host co-expansion, and illustrating the concept of host-pathogen adaptation and balance.