Brenna C. Simons

Advancing the High Throughput Identification of Liver Fibrosis Protein Signatures Using Multiplexed Ion Mobility Spectrometry

Rapid diagnosis of disease states using less invasive, safer, and more clinically acceptable approaches than presently employed is a crucial direction for the field of medicine. While MS-based proteomics approaches have attempted to meet these objectives, challenges such as the enormous dynamic range of protein concentrations in clinically relevant biofluid samples coupled with the need to address human biodiversity have slowed their employment. Herein, we report on the use of a new instrumental platform that addresses these challenges by coupling technical advances in rapid gas phase multiplexed ion mobility spectrometry separations with liquid chromatography and MS to dramatically increase measurement sensitivity and throughput, further enabling future high throughput MS-based clinical applications. An initial application of the liquid chromatography - ion mobility spectrometry-MS platform analyzing blood serum samples from 60 postliver transplant patients with recurrent fibrosis progression and 60 nontransplant patients illustrates its potential utility for disease characterization.

Incidence of diabetes mellitus in a population-based cohort of persons with chronic hepatitis B virus infection.

To investigate the effect of hepatitis B virus (HBV) infection on the development of diabetes mellitus (DM), we compared DM incidence and characteristics of Alaska Native persons with and without HBV infection. From 1990 to 2010, there were 52 incident DM cases among 1309 persons with infection vs 4557 DM cases among 85 698 persons without infection (log‐rank test, P = 0.20). Compared to infected persons without DM, those with DM were significantly older (57.0 vs 47.4 years, P < 0.001) and had higher body mass index (34.5 vs 28.4 kg/m2, P < 0.001). Genotype, immune active disease and the presence of cirrhosis were not associated with DM. In this population‐based cohort with over 20 years of follow‐up, there was no effect of HBV infection on DM development.

Alaska Native and rural youth views of sexual health: a focus group project on sexually transmitted diseases, HIV/AIDS, and unplanned pregnancy.

BACKGROUND The disparity in rates of sexually transmitted diseases (STDs), HIV/AIDS, and unplanned pregnancy between Alaska Native (AN) and non-AN populations, particularly among young adults and females, is significant and concerning. Focus groups were conducted to better understand the knowledge, attitudes, and beliefs of rural Alaska youth (both AN and non-AN) and communities regarding STDs, HIV/AIDS, and unplanned pregnancy and to determine the best methods to educate and facilitate behavior change in AN youth regarding these issues. METHODS A convenience sample of AN and rural youth (n = 105) from 5 communities in Alaska, ages 15-24 years, participated in 21 focus groups. Focus group participants were divided by sex and age. We assessed themes related to knowledge, attitudes, and beliefs about STDs, HIV/AIDS, and unplanned pregnancy, as well as perceptions of how youth prefer to learn about sexual health issues. RESULTS The major themes identified were: (1) sexual health is not viewed only in relation to a physical act; (2) there is a basic understanding of sexual health, but youth have a lot of unanswered questions pertaining to STDs and HIV/AIDS; (3) sexual health messages should be delivered via the Internet and school; (4) youth want to hear messages promoting STD/HIV testing and condom use; (5) easier access to condoms is needed; (6) alcohol and drug use affect sexual behavior and risk taking; and (7) issues of confidentiality and embarrassment affect health care-seeking behaviors for sexual health issues. CONCLUSIONS One of the fundamental principles of public health practice is community participation, which asserts that success in achieving change is enhanced by the active participation of the intended audience in defining their own high-priority solutions. Our findings-driven by youth themselves-are critical in designing and implementing future sexual health interventions and promoting greater community involvement and acceptance.

Nested Case-Control Study: Hepatocellular Carcinoma Risk After Hepatitis B Surface Antigen Seroclearance

Hepatocellular carcinoma (HCC) risk after resolving chronic hepatitis B virus (HBV) infection is unclear.

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.

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.

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).

Distribution of viral hepatitis in indigenous populations of North America and the circumpolar Arctic.

The burden of viral hepatitis among indigenous populations of the United States, Canada and Greenland is greater than in non-indigenous populations. In particular, throughout the circumpolar Arctic regions, chronic hepatitis B infection is highly prevalent, although incidence rates have declined considerably in certain regions due to infant HBV vaccination. Unique HBV (sub)genotypes having distinct clinical outcomes and distribution patterns are also observed within this region. In conjunction with hepatitis B infection, hepatitis delta infection is also apparent within North American indigenous peoples, particularly with outbreaks in Greenlandic Inuit communities. Incidence rates for hepatitis C infection are higher for indigenous populations within the United States and Canada; however, some hepatitis C antibody-positive indigenous patients are more likely to be HCV RNA-negative compared to non-indigenous patients. Thus, an increased understanding of the epidemiology, clinical consequences and pathogenicity of viral hepatitis affecting the indigenous populations will help to address and balance the burden of infection.

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.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.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.