Chriss Homan

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.

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

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. (HEPATOLOGY 2010.)

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

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. (HEPATOLOGY 2011;)

Epidemiology and risk factors for hepatitis C in Alaska Natives

Large cohorts of persons infected with hepatitis C virus (HCV) that include patients with multiple risk exposures and behaviors have been rarely reported. We herein describe a population‐based cohort of 759 Alaska Natives (AN) with HCV who were recruited into a long‐term follow‐up study. History of injection drug use (IDU) was reported by 60.1% and blood transfusion by 14.0%. The most common genotype was 1a (42.0%), followed by 1b (20.3%), 2b (14.7%), 3a (14.3%), and 2a (7.8%). By multivariable analysis, risk exposures (blood transfusion vs. other; P < 0.01; odds ratio [OR], 2.87; 95% confidence interval [CI], 1.51–5.45) and year of infection (P < 0.01; OR, 3.47; 95% CI, 1.34–8.96) were significantly associated with HCV RNA‐positivity. Having an RNA concentration ≥2 million copies/mL was associated with male gender (OR, 1.94) and genotype (P < 0.01 overall; 1a vs. 3a: OR, 1.92; 2b vs. 3a: OR, 3.17) by multivariable analysis. In conclusion, the two principal risk exposures for AN infected with HCV (IDU and blood transfusion) are the same as the overall U.S. population. Persons with a history of blood transfusion were more likely to be HCV RNA positive than those without such history. Higher RNA levels found in males may explain the more severe disease previously reported in this group. (HEPATOLOGY 2004;39:325–332.)

High Rate of Spontaneous Negativity for Hepatitis C Virus RNA after Establishment of Chronic Infection in Alaska Natives

BACKGROUND Hepatitis C virus (HCV) leads to chronic infection in 70%-85% of exposed patients. Spontaneous clearance of the virus after chronic infection is believed to occur rarely. METHODS Alaska Natives who tested positive for HCV antibodies were enrolled in a prospective study that began in 1994 and were followed up on a regular basis. Individuals who tested positive for HCV RNA on 3 separate dates, each of which were at least 1 year apart, were included. Being negative for the virus was defined as having at least 1 negative HCV RNA test result after chronic viremia had been established. RESULTS Of the 815 patients enrolled in the cohort, 139 met entry criteria and were observed for a mean period of 7.0 years. Eleven (8%) of the persons had at least 1 test in which HCV RNA was undetectable; 7 were classified as having either possible or probable clearance of the virus, corresponding to an annualized clearance rate of 0.74% per person-year (95% CI, 0.30%-1.53%). Of 9 patients who underwent subsequent HCV RNA testing, 5 (56%) had negative test results. A low HCV RNA level was significantly associated with spontaneous nondetectability of HCV RNA. CONCLUSION Spontaneous HCV RNA negativity during chronic HCV infection is a surprisingly frequent event and is associated with low HCV RNA titers. Knowledge of immunologic determinants of clearance may open up avenues of novel therapy.

Hepatitis C Virus Dynamics during Natural Infection Are Associated with Long-Term Histological Outcome of Chronic Hepatitis C Disease

BACKGROUND The long-term dynamics of hepatitis C virus (HCV) infection and their association with hepatitis C disease are unknown. METHODS Fifty-two treatment-naive subjects with chronic HCV genotype 1 infection were selected from the Alaska Natives and American Indians cohort. Viral RNA levels were measured in 223 specimens (mean, 4.3 specimens/subject) over 457 patient-years. Viral quasispecies diversity was analyzed in 187 specimens (mean, 3.6 specimens/subject) over 365 patient-years. RESULTS Thirty-three subjects had minimal hepatic fibrosis, and 19 developed bridging fibrosis or cirrhosis. There was no significant difference in host variables, including alcohol consumption, between disease groups. Subjects with mild disease had higher serum RNA levels after 2 decades of infection (P=.013), greater fluctuations in RNA levels over time (P=.04), higher intraspecimen quasispecies diversity (P=.001), and higher rates of quasispecies diversification (P=.004) than did subjects with severe disease. On multivariate analysis, the odds of having severe disease were 15.3 (95% confidence interval, 2.3-99.6) times higher among persons with low quasispecies diversification rates compared with the odds among persons with high diversification rates. CONCLUSIONS Histological progression of hepatitis C is tightly associated with homogenization of HCV quasispecies, perhaps reflecting immune failure and/or selective outgrowth of aggressive viral variants.

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.

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 ≥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.

Clinical significance of elevated alpha‐fetoprotein in Alaskan Native patients with chronic hepatitis C

Summary.  The clinical significance of elevated serum alpha‐fetoprotein (AFP) in patients with chronic hepatitis C virus (HCV) infection is not well defined. We analysed data from a population‐based cohort of patients with HCV infection to assess the prevalence of elevated serum AFP, to determine its association with clinical and virologic parameters and with clinical outcomes. We defined a slightly elevated serum AFP level as 8 to <15 and a high‐AFP level as ≥15 μg/L. Among 541 HCV‐RNA‐positive persons, 61 (11%) had a slightly elevated or high AFP at the time of consent. AFP ≥8 μg/L was associated with the older age, aspartate aminotransferase/alanine aminotransferase ratio >1, and higher alkaline phosphatase levels, but not with heavy alcohol use, IV drug use, genotype, viral load or duration of HCV infection. Among 192 persons with an AFP at liver biopsy, 17% had an AFP ≥8 μg/L. The sensitivity/specificity of an AFP level ≥8 in detecting Ishak 3–6 fibrosis was 39%/95%. Among 372 persons with a minimum of four AFP measurements over 6 years, 5% had persistently elevated AFP >8 μg/L, 19% had both elevated and normal AFP measurements, and 76% had persistently normal AFP. Elevated AFP at consent was associated with hepatocellular carcinoma (HCC) and end‐stage liver disease. Over 6 years of follow‐up, persistently elevated AFP was associated with the development of HCC; no person with AFP persistently <8 μg/mL developed HCC. Serial AFP measurements appear to be useful in identifying persons with advanced fibrosis and help to determine who needs periodic screening with liver ultrasound to detect HCC.

Estimating the Date of Hepatitis C Virus Infection from Patient Interviews and Antibody Tests on Stored Sera

OBJECTIVES:Studies on the natural history and outcome of chronic hepatitis C virus (HCV) infection differ regarding the proportion of persons who develop serious sequelae over time. Most of these studies use an estimated date of HCV infection based on risk factor data obtained from patient interviews. The date of HCV infection is often estimated using the year of a pre-1992 blood transfusion (BT), or the first year of injecting drug use (IDU). We sought to determine the accuracy of these dates obtained by interview.METHODS:We compared BT dates reported by patients in a long-term HCV outcome study to dates confirmed in a BT-Lookback project, and also compared the reported first year of IDU to seroconversion dates estimated from HCV tests on historical sera.RESULTS:Of 28 BT recipients who were interviewed in the HCV outcome study and identified in the Lookback project, 14 (50%; 95% CI: 31–69%) were unaware they had received a BT. Of 25 persons identified in the BT-Lookback project with historical sera available, 9 (36%; 95% CI: 19–57%) had anti-HCV results that did not correlate with their confirmed BT date. Of 216 persons with a history of IDU and historical serum samples available, 66 (31%; 95% CI: 25–37%) had anti-HCV results that did not correlate with their reported first year of IDU.CONCLUSIONS:Inaccuracies in the length of HCV could occur in outcome studies that rely on patient recall of risk-factor history. Statistical methods that incorporate the uncertainty in assigning infection date are needed.