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.

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.

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.

Clearance of hepatitis B e antigen in patients with chronic hepatitis B and genotypes A, B, C, D, and F.

BACKGROUND & AIMS: Persistence of hepatitis B e antigen (HBeAg) in chronic hepatitis B has been associated with increased risk for development of cirrhosis and hepatocellular carcinoma. Five hepatitis B virus genotypes were identified in Alaska Native persons; we analyzed clearance of HBeAg by age and genotype. METHODS: In this prospective cohort study, 1158 Alaska Native persons throughout Alaska were tested serially for HBeAg for a median of 20.5 years and were genotyped. Initial and final HBeAg-positive specimens, time to clearance, age at clearance, and subsequent HBeAg results were analyzed for persons initially HBeAg-positive. Subsequent HBeAg results were analyzed for persons initially negative. RESULTS: Genotypes A, B, C, D, and F were identified. Genotype C persons initially HBeAg-positive were more likely than those with other genotypes to be positive on initial and final specimens (P < .001 for each) and time to HBeAg clearance was longer (P < .001). Age at which 50% of persons cleared HBeAg was <20 years for those infected with genotypes A, B, D, and F and 47.8 years in genotype C (P < .001). After losing HBeAg, those with genotypes C and F were more likely to revert to the HBeAg-positive state (P < .001). CONCLUSIONS: Genotype may have a strong effect on mode of transmission and outcome. Genotype C may have been responsible for most perinatal transmission, given that seroconversion from HBeAg occurs decades later than in other genotypes.

Steatosis and hepatitis C in an Alaska Native/American Indian population.

OBJECTIVES: To determine the prevalence and characteristics of steatosis in Alaska Natives/American Indians (AN/AI) with chronic hepatitis C virus (HCV) infection. STUDY DESIGN: This outcomes study began in 1994, and 988 AN/AI have been enrolled, including 222 study patients with a positive HCV RNA who underwent liver biopsy. METHODS: Study patients were analyzed for sex, age at biopsy, estimated length of infection, body mass index (BMI), genotype, ethanol use, HCV RNA and alanine aminotransferase levels. A pathologist blinded to patient identity and clinical data reviewed all biopsy slides for histologic activity and fibrosis. RESULTS: Moderate to severe steatosis was found significantly more often in genotype 3 than in genotypes 1 and 2 (p = 0.008). On multivariate analysis, BMI > 30 and Ishak fibrosis score > or = 2 were significantly associated with steatosis (p = 0.0013 and 0.0002, respectively), but only genotype 3 was associated with presence of moderate to severe steatosis (p = 0.008). CONCLUSIONS: Our findings in a cohort of AN/AI are consistent with results of previous studies in other groups that steatosis is associated with fibrosis in HCV and infection with genotype 3 is associated with more severe steatosis.

Results of interferon-based treatments in Alaska Native and American Indian population with chronic hepatitis C.

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.

Treatment eligibility in Alaska Native and American Indian persons with hepatitis C virus infection.

OBJECTIVES: Treatment with pegylated interferon and ribavirin may prevent progression of liver disease among patients with chronic hepatitis C virus infection (HCV). Treatment initiation is based on published clinical eligibility criteria, patients' willingness to undergo treatment and likelihood of success. We examined treatment eligibility in a cohort of Alaska Native and American Indian persons with chronic HCV infection. STUDY DESIGN: Retrospective cohort study. METHODS: Medical records of all treatment naïve HCV RNA positive patients given an appointment by hepatology specialty clinic staff in 2003 and 2007 were evaluated by a hepatology provider to investigate documented reasons for treatment deferral. RESULTS: Treatment was initiated in 4 of 94 patients (4%) in 2003 and 14 of 146 patients (10%) in 2007. Major reasons for treatment deferral in 2003 versus 2007 included inconsistent appointment attendance (36% of deferrals vs. 18%), active substance abuse (17% vs. 22%), patient decision (17% vs. 27%), liver biopsy without fibrosis or normal ALT (8% vs. 3%), uncontrolled psychiatric condition (7% vs. 7%) and concurrent medical condition (6% vs. 9%). There was significant improvement in proportion of appointments attended in 2007 versus 2003 (76% vs. 67%, p = 0.04) and the percentage of patients attending at least 1 appointment (84% vs. 66%, p = 0.002). CONCLUSIONS: Multiple reasons for treatment deferral were documented. Despite a significant improvement in hepatology clinic attendance and an increase in the number of patients started on treatment in 2007 compared to 2003, the overall percentage of those treated remained low.

Hepatitis B-associated vasculitis in Alaska Natives: viral genotype, clinical and serologic outcome.

BACKGROUND: The highest incidence of hepatitis B virus (HBV)-associated vasculitis in the world has been reported in Alaska Natives. We examined the incidence of HBV-associated vasculitis before and after mass HBV vaccine immunization and the association between HBV genotype and vasculitis in a population-based cohort study in Alaska natives chronically infected with HBV. METHODS: Genotyping was performed in vasculitis cases and 644 hepatitis B-positive controls without vasculitis using polymerase chain reaction and sequencing of the S gene. Occurrence of HBV vasculitis from 1974 to 2004 was calculated. HBV vasculitis patients and controls were also tested for basal core promoter and precore mutations. RESULTS: Fifteen cases of HBV-associated vasculitis were identified: 13 (86%) had genotype D and one each genotype A and F. Genotype D was more commonly found in patients with vasculitis than controls [odd ratio (OR)=5.9, confidence interval (95% CI) 1.2, 21.8; P<0.015). CONCLUSIONS: HBV-associated vasculitis was associated with genotype D.

Hepatitis B virus genotypes in Alaska Native people with hepatocellular carcinoma: preponderance of genotype F.

BACKGROUND: The development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection has been associated with specific HBV genotypes and the presence of specific mutations. METHODS: From a cohort of Alaska Native people with chronic HBV infection, we genotyped 47 patients with HCC and 1129 patients without HCC, and we tested patients with HCC and control patients for mutations in the basal core promoter and precore regions. RESULTS: Genotype F was found in 68% of patients with HCC, versus 18% of those without HCC (P<.001). For patients with genotype F, the median age at diagnosis of HCC was lower than that for patients with other genotypes (22.5 vs. 60 years, respectively; P=.002). Overall, there were no significant differences in the number of basal core promoter and precore region mutations between patients with HCC and control patients. CONCLUSIONS: We found a significant association between genotype F and the development of HCC among Alaska Native people with chronic HBV infection but no significant association between HCC and basal core promoter or precore mutations in genotype F.