Rate and durability of the clearance of HBsAg in Alaska Native persons with long-term HBV infection: 1982-2019.

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.

Comparison of HBV DNA and RNA markers in Alaska Native people who did and did not clear hepatitis B surface antigen.

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.

HBV Genotype: A Significant Risk Factor in Determining Which Patients With Chronic HBV Infection Should Undergo Surveillance for HCC: The Hepatitis B Alaska Study.

BACKGROUND AND AIMS: Information is limited regarding HBV genotype and the outcome of chronic HBV (CHB) infection. We examined the effect of HBV genotype on 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 1,000 person-years of follow-up to determine which groups by age, sex, and genotype met current American Association for the Study of Liver Diseases (AASLD) 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 1,185 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 1,000 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% 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 and D. Among men < 40 years of age and women < 50 years of age, genotype F had the highest incidence (4.79/1,000 person-years). CONCLUSIONS: HBV genotype was strongly associated with HCC. HBV genotype should be considered in risk factor stratification.

Vaccination Status of Alaska Native Persons With Hepatitis A Virus Infection-Alaska, 1996-2018.

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.

Cascade of Care for Alaska Native People With Chronic Hepatitis C Virus Infection: Statewide Program With High Linkage to Care.

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%).

An Association Between Core Mutations in Hepatitis B Virus Genotype F1b and Hepatocellular Carcinoma in Alaskan Native People.

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.

Risk of end-stage liver disease, hepatocellular carcinoma, and liver-related death by fibrosis stage in the hepatitis C Alaska Cohort.

Long-term prospective studies of the outcomes associated with hepatitis C virus (HCV) infection are rare and critical for assessing the potential impact of HCV treatment. Using liver biopsy as a starting point, we analyzed the 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 no/mild fibrosis developed ESLD compared with 7.9% (95% CI, 4.0-15.2), 16.4% (95% CI, 9.6-27.2), and 49.0% (95% CI, 33.0-67.7) with moderate, severe fibrosis, and cirrhosis, respectively (P < 0.01). The 5-year outcome of HCC was 1.0% (95% CI, 0.1-7.0), 1.0% (95% CI, 0.1-6.6), 1.1% (95% CI, 0.2-7.7), and 13.4% (95% CI, 4.4-36.7) among persons with no/mild fibrosis, moderate fibrosis, severe fibrosis, and cirrhosis, respectively (P < 0.01). Five years after biopsy, 0.0% (95% CI, 0.0-14.8) of persons with no/mild fibrosis had suffered an LRD compared with 1.0% (95% CI, 0.2-7.5) of persons with moderate fibrosis, 4.7% (95% CI, 1.5-14.1) with severe fibrosis, and 16.3% (95% 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 individuals who have more than mild fibrosis. (Hepatology 2017;66:37-45).

Infection With Hepatitis C Virus Genotype 3 Is an Independent Risk Factor for End-Stage Liver Disease, Hepatocellular Carcinoma, and Liver-Related Death.

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% confidence intervals (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 up for 11,171 person-years (mean, 10.3 person-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), their aHR for HCC was 3.1 (95% CI, 1.4-6.6), and their aHR for liver-related death was 2.4 (95% CI, 1.5-4.0) compared with 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.

Persistence of seropositivity among persons vaccinated for hepatitis A during infancy by maternal antibody status: 15-year follow-up.

UNLABELLED: The effect of passively transferred maternal antibody to hepatitis A virus (anti-HAV) on the duration of seropositivity after hepatitis A vaccination during infancy and early childhood is unclear. We obtained levels of anti-HAV at intervals through age 15-16 years among three groups of Alaskan Native children who initiated a two-dose inactivated hepatitis A vaccination series at ages 6 months (group 1), 12 months (group 2), and 15 months (group 3), each group randomized according to maternal anti-HAV status. Seropositivity (anti-HAV ≥20 mIU/mL) 30 years after the second vaccine dose among the three groups was predicted using a random effects model. One hundred eighty-three children participated in the study; follow-up did not differ significantly by vaccine group or maternal anti-HAV status. Although the frequency of seropositivity among all participants through age 10 years was high (100% among groups 2 and 3 and >90% among group 1), there was a decrease thereafter through age 15-16 years among group 1 children, who initiated vaccination at age 6 months (50%-75%), and among maternal anti-HAV-positive children in groups 2 and 3 (67%-87%), who initiated vaccination at ages 12 months and 15 months, respectively. Nonetheless, the model indicated that anti-HAV seropositivity should persist for ≥30 years after vaccination in 64% of all participants; among those seropositive at age 15-16 years, 84% were predicted to remain so for ≥30 years. CONCLUSION: Most children vaccinated during early childhood available for sampling maintained seropositivity through age 15-16 years; however, seropositivity was less frequent among those starting vaccination at age 6 months and among maternal antibody-positive participants who started vaccination at age 12 months or 15 months; overall, our findings support current vaccine recommendations and continued follow-up of this cohort.

Prevalence and causes of elevated serum aminotransferase levels in a population-based cohort of persons with chronic hepatitis B virus infection.

BACKGROUND & AIMS: Information delineating the possible causes for elevated serum aminotransferase activity among persons with chronic hepatitis B virus (HBV) infection is limited. METHODS: We analysed data collected from a population-based cohort of persons with chronic HBV infection followed from 2001 to 2010 to determine the frequency and causes of elevated aminotransferase activity. Any elevation concurrent with an HBV DNA level ⩾2000 IU/ml was attributed to immune active hepatitis B. Participant medical charts were reviewed by expert clinical staff to determine the presence of additional or alternative attributable causes. For each participant, a serum aminotransferase elevation could be attributed to more than one cause. RESULTS: Among 1090 persons with chronic HBV infection, the mean follow-up was 7.7 years and the median age in 2001 was 39 (range 19-96) years; 634 (58.2%) had ⩾1 elevated aminotransferase level during follow-up and 438 (69.1%) of persons with ⩾1 elevation had at least one cause assigned for the elevation. The most common causes of aminotransferase elevations were immune active hepatitis B (48.4%), alcohol consumption (30.8%), and non-alcoholic fatty liver disease (NAFLD) (24.7%). Among participants with HBV DNA levels persistently less than 2000 IU/ml, the most common causes were NAFLD or alcohol consumption. CONCLUSIONS: In this population-based cohort of persons with chronic HBV infection, the prevalence of elevated aminotransferase activity was high and attributable to immune active chronic hepatitis B in approximately half of the cases; however, NAFLD or alcohol consumption were also common causes for enzyme elevations. These findings underscore the importance of monitoring HBV DNA levels, in addition to aminotransferase activity, among persons with chronic HBV infection so that appropriate interventions, including antiviral therapy, are utilised.

Relationship between level of hepatitis B virus DNA and liver disease: a population-based study of hepatitis B e antigen-negative persons with hepatitis B.

BACKGROUND & AIMS: There is little information on the proportion of persons with chronic hepatitis B virus (HBV) infection with active hepatitis. We aimed to determine the proportion of persons with hepatitis B e antigen-negative chronic HBV infection who develop immune-active HBV infection over time and the relationship between demographic and viral factors on severity of disease on liver biopsy. METHODS: We performed a longitudinal population-based cohort study of 754 Alaska Native patients with chronic HBV infection. Levels of alanine aminotransferase (ALT) were measured every 6 months, and levels of HBV DNA were measured at study entry and whenever ALT levels exceeded the upper limit of normal (ULN). Immune-active chronic HBV infection was defined as levels of ALT ≥ 30 U/L in men and >20 U/L in women and levels of HBV DNA >2000 IU/mL at 1 or more time points from 2001-2008. Liver biopsies were scored by using the modified histology activity index score of Knodell and the Ishak fibrosis score. RESULTS: Of the study participants, 186 (25%) met the criteria for immune-active HBV, 56% of these initially and 44% later during follow up. Of the 38 patients with liver biopsy results, only 1 of 16 with ALT levels consistently below twice the ULN and 1 of 19 with HBV DNA between 2000 and 20,000 IU/mL, vs 12 of 22 (55%) with ALT > twice ULN (P = .002) and 11 of 18 (61%) with 1 or more measurements of HBV DNA >20,000 IU/mL (P < .001), had moderate or severe hepatitis or fibrosis. CONCLUSIONS: In a cohort of Alaska Natives with chronic HBV infection, 25% met criteria for immune-active HBV. There is a low probability of advanced fibrosis if levels of HBV DNA never exceed 20,000 IU/mL.

Persistence of hepatitis A vaccine induced seropositivity in infants and young children by maternal antibody status: 10-year follow-up.

UNLABELLED: Persistence of seropositivity conferred by hepatitis A vaccine administered to children <2 years of age is unknown and passively transferred maternal antibodies to hepatitis A virus (maternal anti-HAV) may lower the infant's immune response to the vaccine. One hundred ninety-seven infants and young children were randomized into three groups to receive a two-dose hepatitis A vaccine: group 1 at 6 and 12 months, group 2 at 12 and 18 months, and group 3 at 15 and 21 months of age. Within each group, infants were randomized by maternal anti-HAV status. Anti-HAV levels were measured at 1 and 6 months and at 3, 5, 7, and 10 years after the second dose of hepatitis A vaccination. Children in all groups had evidence of seroprotection (>10 mIU/mL) at 1 month after the second dose. At 10 years, all children retained seroprotective anti-HAV levels except for only 7% and 11% of children in group 1 born to anti-HAV-negative and anti-HAV-positive mothers, respectively, and 4% of group 3 children born to anti-HAV-negative mothers. At 10 years, children born to anti-HAV-negative mothers in group 3 had the highest geometric mean concentration (GMC) (97 mIU/mL; 95% confidence interval, 71-133 mIU/mL) and children born to anti-HAV-positive mothers in group 1 had the lowest GMC (29 mIU/mL; 95% confidence interval, 20-40 mIU/mL). Anti-HAV levels through 10 years of age correlated with initial peak anti-HAV levels (tested at 1 month after the second dose). CONCLUSION: The seropositivity induced by hepatitis A vaccine given to children <2 years of age persists for at least 10 years regardless of presence of maternal anti-HAV.

Autoimmune hepatitis and overlap syndrome among Alaska Native people: Prevalence, clinical characteristics, and remission.

Background and Aim: High 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. Methods: We 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. Results: We 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. Conclusion: The 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.

Elimination of hepatocellular carcinoma and acute hepatitis B in children 25 years after a hepatitis B newborn and catch-up immunization program.

UNLABELLED: Alaska Native people experience the highest rates of acute and chronic hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC) in the United States. We examined the effect of a universal newborn immunization with hepatitis B vaccine and mass population screening immunization program initiated in 1984 on rates of HBV and HCC in children 25 years later. During this time, the population of Alaska Native people grew from an estimated 75,000 to 130,000 persons. A surveillance system to detect acute HBV infection in Alaska Native facilities was established in 1981. Cases of HCC in children under 20 years of age were identified using a National Cancer Institute (NCI)-funded Cancer Registry established in 1969 coupled with an active surveillance program of screening persons with chronic HBV semiannually for alpha-fetoprotein since 1982. The incidence of acute symptomatic HBV infection in persons <20 years of age fell from cases 19/100,000 in 1981-1982 to 0/100,000 in 1993-1994. No cases of acute HBV have occurred in children since 1992. The incidence of HCC in persons <20 years decreased from 3/100,000 in 1984-1988 to zero in 1995-1999 and no cases have occurred since 1999. The number of identified hepatitis B surface antigen-positive children <20 years in the Alaska Native population declined from 657 in 1987 to two in 2008. CONCLUSION: Universal newborn vaccination coupled with mass screening and immunization of susceptible Alaska Natives has eliminated HCC and acute symptomatic HBV infection among Alaska Native children and this approach is the best way to prevent HBV-related disease in children.

Adverse outcomes in Alaska natives who recovered from or have chronic hepatitis C infection.

BACKGROUND & AIMS: The factors associated with adverse outcome from hepatitis C virus (HCV) infection are incompletely understood. To determine the incidence and risk factors associated with the development of end-stage liver disease (ESLD) and liver-related death (LRD), we conducted a retrospective/prospective population-based study in a cohort of Alaska Native persons chronically infected with HCV from 1994 to 2005. METHODS: We followed 960 persons prospectively for an average of 7.2 years and retrospectively for 12.1 years with data from medical records and serum samples. We compared data from subjects that were chronically infected with those who recovered from HCV infection, stratified by alcohol use. Survival models were used to examine factors associated with ESLD and LRD in chronically infected patients. RESULTS: During prospective follow-up, 80 (8.8%) and 47 (5.2%) patients developed ESLD and LRD, respectively. In examining incidence per 100 person-years, no difference was found among heavy alcohol users in the incidence of LRD (2.28 versus 3.50; P = .34) or ESLD (3.21 versus 5.69; P = .13) in persons with chronic HCV compared with those recovered from HCV infection. In subjects that consumed <50 g alcohol/d, the incidences of LRD were 0.77 and 0.09 (P = .01) and of ESLD were 1.58 versus 0.36 (P = .002), respectively, in subjects with chronic infection versus those that recovered. Multivariate analysis showed that older age, heavy alcohol use, and HCV genotype 3 were associated with ESLD. CONCLUSIONS: A history of heavy alcohol use is associated with the highest incidence of LRD and ESLD, regardless of whether patients are chronically infected or recover from HCV infection.

Clearance of hepatitis B surface antigen and risk of hepatocellular carcinoma in a cohort chronically infected with hepatitis B virus.

UNLABELLED: Some individuals who are chronically infected with hepatitis B virus (HBV) eventually lose hepatitis B surface antigen (HBsAg). Hepatocellular carcinoma (HCC) has been demonstrated to occur in a few patients after loss of HBsAg. Neither factors associated with loss of HBsAg nor the incidence of HCC thereafter have been clearly elucidated. We performed a prospective population-based cohort study in 1,271 Alaska Native persons with chronic HBV infection followed for an average of 19.6 years to determine factors associated with loss of HBsAg and risk of developing HCC thereafter. HBsAg loss occurred in 158 persons for a rate of HBsAg clearance of 0.7%/year. Older age, but not sex, was associated with clearance of HBsAg, and loss of HBsAg was not associated with any particular HBV genotypes (A, B, C, D, and F) found in this population. Participants were followed for an average of 108.9 months after HBsAg loss. Six patients, two with cirrhosis and four without, developed HCC a mean of 7.3 years after HBsAg clearance (range, 2.0-15.5 years). The incidence of HCC after clearance of HBsAg was 36.8 per 100,000 per year (95% CI 13.5-80.0) which was significantly lower than the rate in those who remained HBsAg-positive (195.7 cases per 100,000 person-years of follow-up [95% CI 141.1-264.5; P < 0.001]). After loss of HBsAg, HBV DNA was detected in the sera of 28 (18%) of those who cleared a median of 3.6 years after clearance. CONCLUSION: HCC can occur in persons with chronic hepatitis B who have lost HBsAg, even in the absence of cirrhosis. These persons should still be followed with periodic liver ultrasound to detect HCC early.

The Alaska Native/American Indian experience of hepatitis C treatment with sofosbuvir-based direct-acting antivirals.

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.

Factors associated with the progression of fibrosis on liver biopsy in Alaska Native and American Indian persons with chronic hepatitis C.

BACKGROUND: Various factors influence the development and rate of fibrosis progression in chronic hepatitis C virus (HCV) infection. OBJECTIVES: To examine factors associated with fibrosis in a longterm outcomes study of Alaska Native/American Indian persons who underwent liver biopsy, and to examine the rate of fibrosis progression in persons with subsequent biopsies. METHODS: A cross-sectional analysis of the demographic, inflammatory and viral characteristics of persons undergoing liver biopsy compared individuals with early (Ishak fibrosis score of lower than 3) with those with advanced (Ishak score of 3 or greater) fibrosis. Persons who underwent two or more biopsies were analyzed for factors associated with fibrosis progression. RESULTS: Of 253 HCV RNA-positive persons who underwent at least one liver biopsy, 76 (30%) had advanced fibrosis. On multivariate analysis, a Knodell histological activity index score of 10 to 14 and an alpha-fetoprotein level of 8 ng/mL or higher were found to be independent predictors of advanced liver fibrosis (P<0.0001 for each). When surrogate markers of liver inflammation (alanine aminotransferase, aspartate aminotransferase/alanine aminotransferase ratio and alpha-fetoprotein) were removed from the model, type 2 diabetes mellitus (P=0.001), steatosis (P=0.03) and duration of HCV infection by 10-year intervals (P=0.02) were associated with advanced fibrosis. Among 52 persons who underwent two or more biopsies a mean of 6.2 years apart, the mean Ishak fibrosis score increased between biopsies (P=0.002), with progression associated with older age at initial biopsy and HCV risk factors. CONCLUSIONS: The presence of type 2 diabetes mellitus, steatosis and duration of HCV infection were independent predictors of advanced fibrosis in the present cohort, with significant fibrosis progression demonstrated in persons who underwent serial biopsies.

Chronic liver disease among Alaska-Native people, 2003-2004.

OBJECTIVES: A higher proportion of deaths among American-Indian/Alaska-Native (AI/AN) people has been attributed to chronic liver disease (CLD) compared with other racial/ethnic groups in the United States. The objectives of this study were to determine CLD prevalence and to define its etiologies and complications among AN and AI people, who received health care from an urban hospital center. METHODS: We conducted a retrospective, cross-sectional study of AN and AI people > or =18 years old who had at least one patient encounter at the Alaska Native Medical Center during January 2003-December 2004. RESULTS: A total of 1,886 (7.2%) of 26,166 AI/AN people met criteria for having CLD. The most commonly identified etiologies were alcohol-related liver disease (42%), nonalcoholic fatty liver disease (31%), chronic hepatitis C virus infection (26%), and chronic hepatitis B virus infection (8%). Compared with women, men had a higher overall prevalence of CLD (81.9 vs. 64.7 per 1,000), but were less likely to die from a CLD-related cause (1.5 vs. 2.7 per 1,000). These differences in the CLD deaths were mostly attributed to alcohol-related liver disease. CONCLUSIONS: This is the first known population-based study to examine the burden and etiology of CLD among AN people. Causes of CLD were similar among AI/AN people as those reported among other racial/ethnic groups in the United States. Identifying specific etiologies of CLD among populations can help target appropriate prevention and treatment strategies as they are specific to the causes of CLD.