- Hepatology (Liver)
Director, Fellowship in GI & Hepatology, Stanford (2004 - Present)
Chief of Hepatology, VAPAHCS (1999 - Present)
Associate Director, Fellowship in GI & Hepatology, Stanford (2002 - 2004)
Director of Endoscopy, VAPAHCS (1997 - 1998)
Chief of Gastroenterology, VA-Livermore (1993 - 1995)
Honors & Awards
Teaching Award, Department of Medicine (2002, 2004, 2006, 2007)
Residency:UCI College of Medicine (1985) CA
Fellowship:Stanford University School of Medicine (1991) CA
Internship:UCI College of Medicine (1983) CA
Medical Education:University of Chicago School of Medicine (1982) IL
Board Certification: Gastroenterology, American Board of Internal Medicine (1991)
Board Certification: Internal Medicine, American Board of Internal Medicine (1986)
Current Research and Scholarly Interests
Dr. Cheung's past research utilized the duck animal model to study the mechanism of viral neutralization of hepatitis B virus at the molecular level. In collaboration with basic scientists, he is interested in using molecular biology approaches to study clinical samples from chronic hepatitis C patients and investigate the host-virus interaction. The ultimate goal is to understand the pathogenesis of HCV and mechanism of anti-viral therapy. Dr. Cheung is also investigating the healthcare model of hepatitis C care among infected veterans, interaction between hepatitic C infection and alcoholic cirrhosis, and impact of comorbid conditions on the health related quality of life. He is investigating methods to improve care of veterans with chronic hepatitis C, including use of the novel experimental anti-viral therapies as part of clinical trails. Dr. Cheung also used VA and other database to study various healthcare issues in patients with chronic hepatitis C.
Study of Nitazoxanide, Peginterferon Alfa-2a and Ribavirin in Treatment-Naive Hepatitis C Patients
The purpose of this study is to determine if nitazoxanide in combination with peginterferon alfa-2a and ribavirin is safe and effective in treating chronic hepatitis C in treatment-naive patients.
Stanford is currently not accepting patients for this trial. For more information, please contact Shawna Thunen, (650) 723 - 5512.
Risk Factors and Molecular Genomics of U.S. Patients With Chronic Liver Disease &Hepatocellular CA
To identify risk factors for the development and diagnosis of hepatocellular CA in patients with chronic hepatitis C and to use the data to ultimately develop an effective screening program.
Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, (650) 725 - 4047.
Study of Nitazoxanide, Peginterferon Alfa-2a and Ribavirin for the Treatment of Hepatitis C
The purpose of this study is to determine if nitazoxanide in combination with peginterferon alfa-2a and ribavirin is safe and effective in treating chronic hepatitis C in patients that have previously failed to respond to treatment with peginterferon and ribavirin.
Stanford is currently not accepting patients for this trial. For more information, please contact Shawna Thunen, (650) 723 - 5512.
Graduate and Fellowship Programs
Gastroenterology & Hepatology (Fellowship Program)
The impact of chronic hepatitis C and co-morbid illnesses on health-related quality of life
QUALITY OF LIFE RESEARCH
2008; 17 (5): 715-724
Determine the relative impact of chronic hepatitis C (CHC) and co-morbid illnesses on health-related quality of life (HRQoL) in 3023 randomly selected veterans with known hepatitis C virus antibody (anti-HCV) status who previously completed a veteran-specific HRQoL questionnaire (SF-36V).Multiple regression analyses were performed to measure the relative contribution of anti-HCV status, four demographic variables, and ten common medical and six psychiatric co-morbidities to HRQoL between 303 anti-HCV(+) and 2720 anti-HCV(-) patients.Anti-HCV(+) veterans were younger, reported a lower HRQoL on seven of eight 36-Item Short Form Health Survey for Veterans (SF-36V) subscales (P < or = 0.001) and the mental component summary (MCS) scale (P < 0.001). The ten medical and six psychiatric co-morbidities had variable impact on predicting lower HRQoL in both groups. After adjusting for demographic variables and co-morbid illnesses, we found that anti-HCV(+) patients reported a significantly lower MCS score (P < 0.001) and a trend toward a lower physical component summary (PCS) score (P < 0.07) compared to anti-HCV(-) veterans. Among the anti-HCV(+) veterans, co-morbid medical illnesses contributed to impaired PCS but not to MCS.Veterans with CHC were younger than HCV(-) veterans and hence less likely to have other co-morbid medical illnesses. Medical co-morbidities seen in those veterans with CHC contribute to impaired PCS but not MCS. Anti-HCV(+) status negatively affects HRQoL, particularly MCS, independently of medical and psychiatric co-morbidities.
View details for DOI 10.1007/s11136-008-9344-3
View details for Web of Science ID 000256522600007
View details for PubMedID 18427949
A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C
2007; 46 (2): 297-306
Clinical factors such as age, gender, alcohol use, and age-at-infection influence the progression to cirrhosis but cannot accurately predict the risk of developing cirrhosis in patients with chronic hepatitis C (CHC). The aim of this study was to develop a predictive signature for cirrhosis in Caucasian patients. All patients had well-characterized liver histology and clinical factors; DNA was extracted from whole blood for genotyping. We validated all significant markers from a genome scan in the training cohort, and selected 361 markers for the signature building. Using a "machine learning" approach, a signature consisting of markers most predictive for cirrhosis risk in Caucasian patients was developed in the training set (N = 420). The Cirrhosis Risk Score (CRS) was calculated to estimate the risk of developing cirrhosis for each patient. The CRS performance was then tested in an independently enrolled validation cohort of 154 Caucasian patients. A CRS signature consisting of 7 markers was developed for Caucasian patients. The area-under-the-ROC curves (AUC) of the CRS was 0.75 in the training cohort. In the validation cohort, AUC was only 0.53 for clinical factors, increased to 0.73 for CRS, and 0.76 when CRS and clinical factors were combined. A low CRS cutoff of <0.50 to identify low-risk patients would misclassify only 10.3% of high-risk patients, while a high cutoff of >0.70 to identify high-risk patients would misclassify 22.3% of low-risk patients. Conclusion: CRS is a better predictor than clinical factors in differentiating high-risk versus low-risk for cirrhosis in Caucasian CHC patients. Prospective studies should be conducted to further validate these findings.
View details for DOI 10.1002/hep.21695
View details for Web of Science ID 000248501600005
View details for PubMedID 17461418
Incidence of statin hepatotoxicity in patients with hepatitis C
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
2006; 4 (7): 902-907
Statins are considered contraindicated in patients with chronic liver disease. Our objective was to determine the risk of developing hepatotoxicity from statin therapy in hyperlipidemic patients with hepatitis C.Changes in liver biochemistry values within 12 months compared with baseline were determined in 3 cohorts matched for age, sex, and body mass index: (I) 166 anti-hepatitis C virus (HCV)-positive hyperlipidemic veterans who were initiated on statin therapy; (II) 332 anti-HCV-positive veterans who had not received statin therapy; and (III) 332 anti-HCV-negative hyperlipidemic veterans who were initiated on statin therapy. An increase in liver biochemistry values was defined as mild-moderate or severe as proposed in a previous study on statin hepatotoxicity in a non-hepatitis C population.In patients with hepatitis C, statin therapy (cohort I) was associated with a higher incidence of mild-moderate liver biochemistry value increases compared with those not on statin therapy (cohort II) (22.9% vs 13.3%, respectively, P = .009), but a lower incidence of severe increases (1.2% vs 6.6%, respectively, P = .015). Among patients started on statin therapy (cohorts I and III), the incidence of mild-moderate liver biochemistry value increases (22.9% vs 16.3%, respectively, P = .094), severe increases (1.2% vs 1%, respectively, P = .874), or discontinuation of statin therapy as a result of hepatotoxicity (21.6% vs 9.2%, respectively, P = .147) were similar in hepatitis C-positive and hepatitis C-negative patients.Statin therapy was not associated with a higher risk of severe hepatotoxicity in patients with chronic hepatitis C and appeared safe.
View details for DOI 10.1016/j.cgh.2006.03.014
View details for Web of Science ID 000239202600018
View details for PubMedID 16697272
Epidemiology of hepatitis C virus infection in American Veterans
AMERICAN JOURNAL OF GASTROENTEROLOGY
2000; 95 (3): 740-747
This study reports the findings of hepatitis C virus (HCV) infection in a large Department of Veterans Affairs Health Care System in suburban Northern California.All veterans who had anti-HCV (EIA II) tested during a 6-yr period (7/92 to 6/98) were included in this study. To estimate the seroprevalence of anti-HCV among our population, 126 consecutive bloodborne pathogen exposure accidents were studied.Of 8558 veterans tested for anti-HCV (EIA II), 2985 (35%) veterans were positive with a mean age of 48.4 yr (range, 28-89 yr). Sixty percent were between the age of 41 and 50 yr. Risk factors for HCV infection identified in 409 consecutive veterans were intravenous drug abuse (81%), unknown (11%), blood transfusion (3%), sexual/household contact (2%), transfusion and intravenous drug use (2%), and tattoo (1%). Of 215 consecutive anti-HCV-positive veterans whose sera were tested by polymerase chain reaction, 96% were viremic. The most common HCV genotypes were 1a (50.5%), 1b (22.8%), 3a (12.1%), 2b (9.7%), 2a (1.9%), undetermined (1.9%), and mixed infection (1%). Veterans infected with genotype 1b were significantly older. Among 126 consecutive bloodborne pathogen exposure accidents, hepatitis C serology was available for 72 index veterans involved in the accidents and 18% were positive.We found the epidemiology of hepatitis C infection was different in the veteran population when compared to other published data on nonveterans. Hepatitis C infection was much more common among veteran, within a very narrow age distribution and intravenous drug use was the major risk factor.
View details for Web of Science ID 000085605200030
View details for PubMedID 10710068
Increased Long-term Survival Among Patients With Hepatocellular Carcinoma After Implementation of Model for End-stage Liver Disease Score.
Clinical gastroenterology and hepatology
2014; 12 (9): 1534-1540 e1
Assignment of model for end-stage liver disease (MELD) exception points to patients with hepatocellular carcinoma (HCC) who fall within Milan criteria, which began in 2003, increases their priority on liver transplantation waitlists. However, little is known about how this change affected survival of all patients with HCC (transplant eligible and ineligible). We compared long-term survival of HCC patients before and after this change.We performed a large population-based cohort study using the Surveillance, Epidemiology, and End Results cancer registry to investigate survival times of patients with HCC before those who met the Milan criteria were given MELD exception points (1998-2003) and afterward (2004-2010), using Kaplan Meier methods. Multivariate Cox proportional hazards models evaluated independent predictors of survival.During 2004-2010, a significantly higher percentage of patients with HCC survived for 5 years compared to 1998-2003 (21.9% vs 13.0%, P<.001). This difference remained significant among all treatment groups (no therapy: 15.2% vs 10.2%, P<0.001; local tumor destruction: 37.6% vs 22.1%, P<0.001; resection: 55.5% vs 39.2%, P<0.001; transplantation: 77.2% vs 73.1%, P =0.12). Multivariate Cox proportional hazards models, inclusive of sex, age, ethnicity, Milan criteria, number and stage of tumor, and time period, showed increased survival of patients during 2004-2010 (hazard ratio [HR], 0.87; 95% confidence interval, 0.83-0.91; P<.001). Compared to non-Hispanic whites, Asians (HR, 0.81; 95% CI, 0.77-0.86; P<.001) and Hispanics (HR, 0.89, 95% CI, 0.84-0.95; P<.001) had longer survival times, whereas blacks had a trend toward shorter survival times (HR, 1.05; 95% CI 0.98-1.13; P=.16).Patients with HCC who met Milan criteria had significantly longer survival times after implementation of the MELD exception points, regardless of sex or ethnicity. Blacks continued to have the lowest rates of 5 year survival.
View details for DOI 10.1016/j.cgh.2013.12.008
View details for PubMedID 24361414
Ethnic disparities and liver transplantation rates in hepatocellular carcinoma patients in the recent era: Results from the surveillance, epidemiology, and end results registry
2014; 20 (5): 528-535
Hepatocellular carcinoma (HCC) is a leading cause of morbidity and mortality. Following implementation of the model for end stage liver disease (MELD) system, rates of liver transplantation (LT) for HCC patients increased. However, it is not clear if this trend continued into the recent time period. Utilizing the Surveillance, Epidemiology, and End Results 1998-2010 registry, we retrospectively analyzed trends in LT among HCC patients using three time periods: 1998-2003, 2004-2008, and 2009-2010). A total of 60,772 HCC patients were identified. With more recent time periods, the proportion of localized stage HCC increased (45.0% in 1998-2003 vs. 50.4% in 2004-2008 vs. 51.7% in 2009-2010, p<0.001). While the proportion of HCC patients within Milan criteria also increased with time (22.8% vs. 31.8% vs. 37.1%, p<0.001), the proportion of these patients receiving LT increased from 1998-2003 to 2004-2008, but decreased in 2009-2010. However, the actual frequency of LT was similar in 2004-2008 (208.2/year) and 2009-2010 (201.5/year). Multivariate logistic regression, inclusive of sex, age, ethnicity, Milan criteria, tumor stage, tumor size and number, and time periods, demonstrated a lower likelihood of LT in 2009-2010 compared to 1998-2003 (OR 0.63, 95% CI 0.57-0.71). Blacks (OR 0.48, 95% CI 0.41-0.56), Asians (OR 0.65, 95% CI 0.57-0.73), and Hispanics (OR 0.76, 95% CI 0.68-0.85) were all less likely to receive LT compared to non-Hispanic whites. Despite increasing proportion of earlier staged HCC diagnosed, LT rates are declining in the recent era. In addition, ethnic minorities were significantly less likely to receive LT. The growing imbalance between the number of transplant-eligible HCC patients and the shortage of donor livers emphasizes the need to improve donor availability and curative alternatives to LT. Liver Transpl , 2014. © 2014 AASLD.
View details for DOI 10.1002/lt.23820
View details for Web of Science ID 000334953000004
View details for PubMedID 24415542
Nonalcoholic Steatohepatitis Is the Second Leading Etiology of Liver Disease Among Adults Awaiting Liver Transplantation in the United States.
Nonalcoholic steatohepatitis (NASH) has been predicted to become the leading indication for liver transplantation (LT) in the United States. However, few studies have evaluated changes in the etiology of liver diseases among patients awaiting LT, and none have focused on the effects of NASH on liver transplant waitlists in the United States.We collected data from the United Network for Organ Sharing and Organ Procurement and Transplantation Network registry from 2004 through 2013, on liver transplant waitlist registrants with hepatitis C virus (HCV) infection, NASH, alcoholic liver disease (ALD), or a combination of HCV infection and ALD. We compared differences in survival within 90 days of registration (90-day survival) and probability of LT among patients with different diseases using Kaplan-Meier and multivariate logistic regression models.Between 2004 and 2013, new waitlist registrants with NASH increased by 170% (from 804 to 2174), with ALD increased by 45% (from 1400 to 2024), and with HCV increased by 14% (from 2887 to 3291); registrants with HCV and ALD decreased by 9% (from 880 to 803). In 2013, NASH became the second-leading disease among liver transplant waitlist registrants, after HCV. Patients with ALD had a significantly higher mean Model for End-Stage Liver Disease score at time of waitlist registration than other registrants. However, after multivariate adjustment, patients with ALD were less likely to die within 90 days when compared with patients with NASH (odds ratio [OR] = 0.77; 95% confidence interval [CI]: 0.67-0.89; P < .001); patients with HCV infection or HCV and ALD had similar odds for 90-day survival compared with NASH patients. Compared with patients with NASH, patients with HCV (OR = 1.45; 95% CI: 1.35-1.55; P < .001), ALD (OR = 1.15; 95% CI: 1.06-1.24; P < .001), or HCV and ALD (OR = 1.29; 95% CI: 1.18-1.42; P < .001) had higher odds for 90-day survival.Based on data from US adult LT databases, since 2004 the number of adults with NASH awaiting LTs has almost tripled. However, patients with NASH are less likely to undergo LT and less likely to survive for 90 days on the waitlist than patients with HCV, ALD, or HCV and ALD.
View details for DOI 10.1053/j.gastro.2014.11.039
View details for PubMedID 25461851
Comparative effectiveness of the hepatitis C virus protease inhibitors boceprevir and telaprevir in a large US cohort
ALIMENTARY PHARMACOLOGY & THERAPEUTICS
2014; 39 (1): 93-103
Limited data exist on the effectiveness of boceprevir and telaprevir in routine practice.To assess the comparative effectiveness of boceprevir and telaprevir regimens.In this observational, intent-to-treat cohort analysis of hepatitis C genotype 1-infected veterans initiated on peginterferon/ribavirin and boceprevir (n = 661) or telaprevir (n = 198), we determined sustained virological response (SVR), treatment discontinuation rates and adverse haematological events. Inverse probability-of-treatment weighting (IPTW) was used to estimate the effect of one drug over the other, with matched pairs and unweighted logistic regression on the entire cohort for comparison.Of 835 veterans, SVR occurred in 50% and 52% receiving boceprevir- and telaprevir-based treatment, respectively (P = 0.72). No significant differences occurred among subgroups: cirrhotics (37% vs. 39%, P = 0.94), null responders (23% vs. 18%, P = 0.81), partial responders (39% vs. 58%, P = 0.15) and relapsers (60% vs. 77%, P = 0.11). Early discontinuation rates for boceprevir and telaprevir, respectively, were 31% and 28% by week 24 (P = 0.46) and 54% and 45% by 48 weeks (in those completing at least 28 weeks) (P = 0.14). Choice of telaprevir over boceprevir was significantly associated with SVR in multivariate models (IPTW OR: 1.57, 95% CI: 1.10-2.25, P = 0.01; matched-pairs OR: 1.91, 95% CI: 1.23-3.00, P = 0.004; unweighted OR: 1.50 95% CI: 1.05-2.14, P = 0.02). Rates of haematological adverse events in boceprevir- and telaprevir-treated patients were as follows: anaemia 59% vs. 51%, P = 0.30, thrombocytopenia 41% vs. 48%, P = 0.26, neutropenia 41% vs. 27%, P = 0.04.Sustained virological response was more likely with telaprevir-based regimens compared with boceprevir-based regimens in routine medical practice, after accounting for patient differences. Early discontinuation and haematological events, however, were similar.
View details for DOI 10.1111/apt.12546
View details for Web of Science ID 000327659000009
View details for PubMedID 24206566
Increasing antiviral treatment through integrated hepatitis C care: a randomized multicenter trial.
Contemporary clinical trials
2013; 35 (2): 97-107
Most individuals infected with the hepatitis C have not received antiviral treatment, with mental health and substance abuse problems being the primary barrier. Interventions have been developed to address these barriers among HCV patients considered "high-risk" for antiviral treatment. We present the design and methods of a prospective, randomized controlled multisite trial being conducted in the Veterans Affairs Healthcare System. The study employed a parallel design and the three study sites randomized a total of 364 VA patients with HCV to either Integrated Care (IC) or Usual Care (UC). The IC intervention consisted of a mental health provider (MHP) performing a) brief interventions to address risk factors; b) collaborative consultation with the HCV treatment clinicians; and c) case management prior to and during antiviral treatment. Clinical outcomes were abstracted from patient medical records and self-report questionnaires were completed at baseline, 4-months, 16-months, and 22-months after enrollment. The primary outcome of the study was sustained viral response (SVR). Secondary clinical outcomes were HCV treatment initiation and completion rates. Other secondary outcomes included substance use, depression, PTSD symptoms, quality of life, healthcare satisfaction, and healthcare utilization. The Integrated Care intervention has the potential to transform HCV antiviral treatment by increasing the number of HCV-infected individuals that can be successfully treated.
View details for DOI 10.1016/j.cct.2013.05.002
View details for PubMedID 23669414
Assessment and Utilization of Rapid Virologic Response in US Veterans With Chronic Hepatitis C Evaluating Provider Adherence to Practice Guidelines
JOURNAL OF CLINICAL GASTROENTEROLOGY
2013; 47 (3): 264-270
There are limited data on the extent to which medical providers adhere to practice guidelines for the antiviral treatment of patients with chronic hepatitis C virus (HCV) infection. As representative of overall provider adherence to practice guidelines, provider adherence to specific recommendations regarding rapid virologic response (RVR) was assessed.From the Department of Veterans Affairs' Clinical Case Registry, all patients with HCV genotype 1 who initiated peginterferon and ribavirin between January 1, 2007 and December 31, 2008 were identified. The rate of testing for RVR was determined. Patient, provider, and facility characteristics were assessed to determine the factors that predicted improved provider adherence. For patients who achieved RVR, the overall treatment duration was calculated as a secondary measure of provider adherence.About one half of the cohort (54%) had HCV RNA testing for RVR. Among several significant predictors, testing for RVR was more likely in gastroenterology/hepatology specialty clinics, by midlevel providers such as nurse practitioners and physician assistants, and in facilities with a higher volume of HCV patients. Most patients who achieved RVR completed a treatment course within the recommended range. However, 27% of the cohort received more or less than the recommended duration of treatment, thereby unnecessarily increasing their risk for adverse events or decreasing their potential for cure.More aggressive education is needed to improve provider adherence to HCV antiviral treatment guidelines and optimize the outcomes of HCV patients, especially with the recent approval of complicated direct-acting antiviral regimens.
View details for DOI 10.1097/MCG.0b013e31827035cf
View details for Web of Science ID 000314863800016
View details for PubMedID 23269309
Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S.
Hepatology (Baltimore, Md.)
Nonalcoholic steatohepatitis (NASH) is currently the third leading indication for liver transplantation (LT) in the U.S. and is predicted to become the leading indication for LT in the near future. The trends in NASH-related hepatocellular carcinoma (HCC) among LT recipients in the U.S. remain undefined. We performed a retrospective cohort study to evaluate trends in the etiology of HCC among adult LT recipients in the U.S. from 2002 to 2012, utilizing national data from the United Network for Organ Sharing registry. From 2002-2012, there were 61,868 adults who underwent LT in the U.S., including 10,061 patients HCC. The total number and proportion of HCC LT recipients demonstrated a significant increase following the implementation of the model for end stage liver disease (MELD) scoring system in 2002 (3.3%, n=143 in 2000 vs. 12.2%, n=714 in 2005 vs. 23.3%, n=1336 in 2012). The proportion of HCV-related HCC increased steadily from 2002 to 2012, and HCV remained the leading etiology of HCC throughout the MELD era (43.4% in 2002 vs. 46.3% in 2007 vs. 49.9% in 2012). NASH-related HCC also increased significantly, and NASH is the second leading etiology of HCC-related LT (8.3% in 2002 vs. 10.3% in 2007 vs. 13.5% in 2012). From 2002 to 2012, the number of patients undergoing LT for HCC secondary to NASH increased by nearly 4-fold, and the number of LT patients with HCC secondary to HCV increased by 2-fold. Conclusion: NASH is the second leading etiology of HCC leading to LT in the U.S. More importantly, NASH is currently the most rapidly growing indication for LT in patients with HCC in the U.S. (Hepatology 2013;).
View details for DOI 10.1002/hep.26986
View details for PubMedID 24375711
Acute exacerbation among chronic hepatitis C patients: Tip of the iceberg that deserves more attention.
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
View details for PubMedID 23735449
Tenofovir Monotherapy and Tenofovir Plus Entecavir Combination as Rescue Therapy for Entecavir Partial Responders
DIGESTIVE DISEASES AND SCIENCES
2012; 57 (11): 3011-3016
Despite high potency, a significant proportion of patients treated with entecavir achieve only partial viral suppression. Our goal was to examine the complete viral suppression rate (undetectable HBV DNA PCR levels) with alternative therapies in such patients.We retrospectively studied 42 consecutive patients with partial response to entecavir (detectable HBV DNA at ?12 months of therapy) who were treated at three clinics with rescue therapies: entecavir + adefovir (n = 5), tenofovir (n = 6), and entecavir + tenofovir (n = 31). Antiviral resistance was excluded by negative mutation analysis and/or absence of virologic breakthrough (increase >1 log(10)IU/mL from nadir).All patients were Asian and 57 % were male with a median age of 36 (22-64) years. Only a few patients had prior exposure to lamivudine (7 %) or adefovir (7 %). Almost all patients (95 %) had positive HBeAg. Overall, the complete viral suppression rate was 79 %, and the alanine aminotransferase normalization rate was 83 % in entecavir partial responders after 6 months on rescue therapies. Cumulative complete viral suppression rates were significantly different (P = 0.0164) among the entecavir + adefovir, tenofovir, and entecavir + tenofovir treatment groups at 6 months (20 vs. 83 vs. 83 %, respectively) and 12 months (20 vs. 100 vs. 97 %). All three patients without complete viral suppression on entecavir + adefovir became aviremic 6 months after switching to entecavir + tenofovir.Virologic response to entecavir + tenofovir combination therapy and tenofovir monotherapy appeared to be similar in most patients, but not with the entecavir + adefovir combination.
View details for DOI 10.1007/s10620-012-2402-2
View details for Web of Science ID 000309867800051
View details for PubMedID 23010744
The water exchange method for colonoscopy-effect of coaching.
Journal of interventional gastroenterology
2012; 2 (3): 122-125
The growing popularity of water immersion is supported by its long history as an adjunct to air insufflation; after facilitating colonoscope passage, the infused water is conveniently removed during withdrawal. Water exchange, a modification of water immersion to minimize discomfort in scheduled unsedated patients in the U.S. is new. Even though it may be superior in reducing pain and increasing adenoma detection, the paradigm shift to complete exclusion of air during insertion necessitates removal of infused water containing residual feces, a step often perceived as laborious and time-consuming. The nuances are the efficient steps to remove infused water predominantly during insertion to maintain minimal distension and deliver salvage cleansing. Mastery of the novel maneuvers with practice returns insertion time towards baseline. In this observational study the impact of direct verbal coaching on the primary outcome of intention-to-treat cecal intubation was assessed. The results showed that 14 of 19 (74%) experienced colonoscopists achieved 100% intention-to-treat cecal intubation. Initiation of the examination with water exchange did not preclude completion when conversion to the more familiar air insufflation method was deemed necessary to achieve cecal intubation (total 98%). The overall intention-to-treat cecal intubation rate was 88%, 90% in male and 87% in female. Only 2.7% of bowel preparation was rated as poor during withdrawal. The mean volume of water infused and cecal intubation time was 1558 ml and 18 min, respectively. Direct coaching appears to facilitate understanding of the nuances of the water exchange method. Studies of individual learning curves are necessary.
View details for DOI 10.4161/jig.23732
View details for PubMedID 23805391
Implications of rapid virological response in hepatitis C therapy in the US veteran population
ALIMENTARY PHARMACOLOGY & THERAPEUTICS
2012; 35 (1): 105-115
Early predictors of response to hepatitis C virus (HCV) therapy, such as rapid virological response, are valuable for the identification of patients with a higher likelihood of treatment success.To identify predictors of rapid virological response in a real world setting.Using the VA Clinical Case Registry, we identified patients with HCV mono-infection, without liver transplantation, who initiated peginterferon (PEG-IFN) and ribavirin (RBV) in 2007 or 2008 and had HCV RNA testing for RVR. Significant baseline characteristics from genotype specific univariate analyses were used in backwards stepwise models to identify significant independent predictors of RVR.The final cohort consisted of 2424 patients with genotype 1 (G1), 666 patients with genotype 2 (G2), and 419 patients with genotype 3 (G3). Rapid virological response rates were 15% for G1, 71% for G2 and 57% for G3. Sustained virological response rates were significantly higher in patients with rapid virological response than without, increasing from 18% to 52% in G1, 39% to 71% in G2, and 40% to 60% in G3 (P < 0.0001). A baseline HCV RNA < 500,000 IU/mL positively predicted RVR across all genotypes studied. In addition, for G1, Black race, Hispanic ethnicity, aspartate aminotransferase/alanine aminotransferase (AST/ALT) ? 0.6, ferritin ? 350 ng/mL, LDL< 100 mg/dL and diabetes; for G2, BMI ? 30 kg/m(2), platelets < 150 K/?L, LDL< 100 mg/dL and the use of PEG-IFN alfa-2b; and for G3, AST/ALT ? 1.0, all negatively predicted rapid virological response.We found several novel independent predictors of rapid virological response, including BMI, AST/ALT ratio, ferritin, platelets, LDL, diabetes and type of PEG-IFN prescribed, which may be useful in guiding treatment decisions in routine medical practice.
View details for DOI 10.1111/j.1365-2036.2011.04903.x
View details for Web of Science ID 000297922600011
View details for PubMedID 22060887
Utilization and Antiviral Therapy in Patients with Chronic Hepatitis C: Analysis of Ambulatory Care Visits in the US
DIGESTIVE DISEASES AND SCIENCES
2010; 55 (6): 1744-1751
Studies on mostly veterans found the majority of chronic hepatitis C (CHC) patients were not treated. Little information exists on a broad-based population.To determine the national trend of ambulatory visits with a diagnosis of hepatitis C and the prescription of antiviral therapy associated with such visits.Retrospective analysis of national cross-sectional databases, the National Ambulatory Medical Care Survey (NAMCS), and the National Hospital Ambulatory Medical Care Survey (NHAMCS) encompassing all ambulatory visits from 2000 to 2006.During the study period, 16.5 million visits (0.21% of all visits) carried a diagnosis of hepatitis C and the number initially increased. Characteristics of the hepatitis C patients were: 65% male; 71% white, 22% black; 69% >or=45 years old. Overall, 47% had private insurance, 24% had Medicaid, and 12% had Medicare. Only 9.1% of these patients were prescribed antiviral treatment for CHC. There was no significant difference between those who received treatment and those who did not in terms of age, gender, race, and insurance status. HIV infection, mood, substance-use disorders, and anemia were more common in the CHC group.Less than 10% of the ambulatory visits for hepatitis C were associated with a prescription for antiviral therapy, independent of demographic and insurance status. Purposes of the clinic visits were different in the CHC group compared to the general population. The reason for the low treatment rate is not clear but deserves further investigation.
View details for DOI 10.1007/s10620-010-1147-z
View details for Web of Science ID 000278578800036
View details for PubMedID 20186486
Multiple variants in toll-like receptor 4 gene modulate risk of liver fibrosis in Caucasians with chronic hepatitis C infection
JOURNAL OF HEPATOLOGY
2009; 51 (4): 750-757
Seven genomic loci, implicated by single nucleotide polymorphisms (SNPs), have recently been associated with progression to advanced fibrosis (fibrosis risk) in patients with chronic hepatitis C virus. Other variants in these loci have not been examined but may be associated with fibrosis risk independently of or due to linkage disequilibrium with the original polymorphisms.We carried out dense genotyping and association testing of additional SNPs in each of the 7 regions in Caucasian case control samples.We identified several SNPs in the toll-like receptor 4 (TLR4) and syntaxin binding protein 5-like (STXBP5L) loci that were associated with fibrosis risk independently of the original significant SNPs. Haplotypes consisting of these SNPs in TLR4 and STXBP5L were strongly associated with fibrosis risk (global P=3.04 x 10(-5) and 4.49 x 10(-6), respectively).Multiple variants in TLR4 and STXBP5L genes modulate risk of liver fibrosis. These findings are of relevance for understanding the pathogenesis of HCV-induced liver disease in Caucasians and may be extended to other ethnicities as well.
View details for DOI 10.1016/j.jhep.2009.04.027
View details for Web of Science ID 000270749000022
View details for PubMedID 19586676
- Adenovirus-Induced Acute Liver Failure DIGESTIVE DISEASES AND SCIENCES 2009; 54 (2): 218-221
Can we predict the degree of fibrosis in chronic hepatitis C patients using routine blood tests in our daily practice?
JOURNAL OF CLINICAL GASTROENTEROLOGY
2008; 42 (7): 827-834
To determine the validity of fibrosis indexes based on simple laboratory tests in daily practice.Fibrosis indexes were developed in referral centers using high-quality data.We compared the performance characteristics of several such indexes with liver biopsies in a cohort of 490 diverse veterans with chronic hepatitis C from 24 centers. All laboratory tests including interpretation of the liver biopsy were done locally. The following indexes were calculated and correlated with a 5-point fibrosis stage (F0-F4) on liver biopsies: platelet counts (<100 or <150x10(9)/L), aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio (AAR), Pohl score, AST-to-platelet ratio index (APRI) and "Lok's model."Our cohort was predominantly male with 24% blacks, and fibrosis stages of 0, 1, 2, 3, and 4 in 11%, 24%, 28%, 24%, and 13%, respectively. All indexes performed better in predicting advanced (F3-4) than significant (F2-4) fibrosis. When patients with F3-4 were compared to those with F0-2, the area under the receiver operating characteristics curve were 0.534 and 0.641 for platelet count <100 and <150x10(9)/L, respectively, 0.524 for AAR, 0.534 for Pohl score, 0.693 for Lok's model, and 0.765 for APRI. The sensitivity, specificity, and predictive values of APRI and Lok's model were only slightly lower than those reported by the authors using the recommended cutoffs in clinical trial settings. Alcohol use within 12 months, normalization of AST, ALT, and race (blacks/non-blacks) had minimal impact on the performance.AAR, Pohl, and platelet counts <100x10(9)/L have limited ability to predict significant/advanced fibrosis with area under the receiver operating characteristics curve similar to 0.5. However, platelet counts <150x10(9)/L, Lok's model and APRI performed well for advanced fibrosis in our daily practice setting.
View details for Web of Science ID 000258389800012
View details for PubMedID 18285716
Monitoring of epithelial cell caspase activation via detection of durable keratin fragment formation
JOURNAL OF PATHOLOGY
2008; 215 (2): 164-174
Keratins 18 and 19 (K18/K19) are epithelial-specific intermediate filament proteins. Apoptosis induces caspase cleavage at the highly conserved K18 or K19 Asp237, which in K18 is preceded by cleavage at Asp396. We characterized the keratin N-terminal fragments that are generated upon caspase digestion of K18/K19 at Asp237 in order to study keratin dynamics during apoptosis. This was carried out by generating and characterizing antibodies selective to K18/K19 Asp237. K18 or K19 peptides that expose Asp237 in 234VEVD were used for rabbit immunization. The generated antibodies recognized cleaved but not intact K18/K19, exclusively, as determined by blotting or immunofluorescence staining of apoptotic human HT29 cells or livers isolated from Fas-Ab-injected mice. Antibodies to K18/K19 Asp237 recognized the common VEVD-motif as determined by immunoblotting of cells transfected with K18, K19 or K20. The K18/K19 VEVD-directed antibodies demonstrated sequential Asp396 then Asp237 K18 cleavage during apoptosis. Specific-keratin selectivity of the anti-Asp237 antibodies was confirmed by their inability to recognize K14 after UV-induced apoptosis in transfected cells. The Asp237-containing apoptotic keratin fragments are secreted into the medium of cultured HT29 cells and are stable up to 96 h after inducing apoptosis. Furthermore, the generated antibodies recognize keratin apoptotic fragments in sera of mice undergoing hepatocyte apoptosis and sera of patients with cirrhosis, and also recognize apoptotic cells in various epithelial human tumours. Therefore, the N-terminal caspase-generated K18 fragment is stable in tissues and biological fluids. The Asp237-directed antibodies provide a powerful tool to study apoptosis in human and mouse tissues, cells and serum, using a broad range of detection modalities.
View details for DOI 10.1002/path.2344
View details for Web of Science ID 000256456900009
View details for PubMedID 18393369
Persistence with hepatitis C therapy in the Department of Veterans Affairs
JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS
2008; 33 (3): 251-261
Persistence with Hepatitis C therapy has been identified as a key variable for predicting treatment success. The primary purpose of this study was to assess the persistence with therapy for patients undergoing hepatitis C treatment in the VA healthcare system with two forms of combination therapies: peginterferon alfa-2a with Ribavirin (peg-IFN alpha-2a/Rib) and peginterferon alpha-2b with Ribavirin (peg-IFN alpha-2b/Rib).A retrospective cohort study design was used to analyse persistence in VA patients undergoing hepatitis C therapy during FY 2003-2004 using a large national VA data set. Stringent inclusion and exclusion criteria along with various defining variables were used to identify the inception cohort. Persistence rates were calculated for each of the two treatment groups at 3, 6, 9 and 11 months using the Kaplan-Meier method. Likelihood ratio test of equality between the two treatment groups was performed to detect any differences in persistence rates.A total of 5816 hepatitis C patients formed the inception cohort. Persistence rates for the overall duration showed significantly higher rates for patients on peg-IFN alpha-2a/Rib than peg-IFN alpha-2b/Rib. Cox regression analysis also showed favourable hazard ratio of persistence (0.88) for peg-IFN alpha-2a/Rib over peg-IFN alpha-2b/Rib.Peg alfa-2A/Rib showed slightly higher persistence rates for the overall duration of treatment as compared to Peg alfa-2B/Rib. However the differences, even though statistically significant, are small and not likely to translate into any substantial clinical advantage. Further research involving other approaches is required to confirm these findings.
View details for Web of Science ID 000255485400006
View details for PubMedID 18452412
Diagnostic markers for hepatitis virus infection.
Expert opinion on medical diagnostics
2008; 2 (3): 303-314
Background: Accurate diagnosis and characterization of hepatitis viruses are essential from a public health perspective and for clinical management. Objective: To review recent advances in the diagnosis of viral hepatitis A - D and their clinical utilities. Methods: Review of the literature published up to 2007. Result/conclusion: Recent advances in the sensitivity and ease of serologic and molecular diagnostics have improved our understanding of the natural history of viral hepatitis, are helpful in the pretreatment evaluation and provide guidance to antiviral therapy. As the technology improves, this will be reflected in an increased reliance and expanded role of these tests in clinical management and improved safety of the blood supply.
View details for DOI 10.1517/17530059.2.3.303
View details for PubMedID 23495660
Treatment eligibility and outcomes in elderly patients with chronic hepatitis C: Results from the VA HCV-001 study
DIGESTIVE DISEASES AND SCIENCES
2008; 53 (3): 809-814
We undertook this study to determine if treatment candidacy and outcomes were similar between elderly and non-elderly patients.This was a prospective cohort study that screened 4,025 patients with chronic hepatitis C for HCV antiviral treatment at 24 Veterans Affairs Medical Centers throughout the country. We used multivariable logistic regression to determine whether there was an independent association between being elderly (age > 60 vs.
View details for DOI 10.1007/s10620-007-9926-x
View details for Web of Science ID 000253570700033
View details for PubMedID 17823868
- Diagnostic markers for hepatitis virus infection Expert Opinion Med Diagnostics 2008; 2: 303-314
Positive CAGE screen correlates with cirrhosis in veterans with chronic hepatitis C
DIGESTIVE DISEASES AND SCIENCES
2007; 52 (10): 2564-2569
The current study examines the relationship between problem alcohol use and severity of liver disease by self-administered questionnaires using both the CAGE questionnaire and beverage-specific quantity-frequency questions. The cohort consisted of 38 patients with cirrhosis (10 with decompensated liver disease) and 62 with mild fibrosis (stage 0-1), of comparable mean age and estimated duration of infection. Although mean alcohol consumption was similar in both groups, a positive CAGE screen (defined as two or more affirmative answers) was significantly more common among cirrhotics (OR = 5.24; 95% CI, 1.78-15.39) and tended to be associated with decompensated liver disease (OR = 13.3; 95% CI, 0.67-256) among cirrhotics. In multivariate analysis, only inflammatory grade on liver biopsy (OR = 67.7; 95% CI, 10.6-431) and positive CAGE score (OR = 8.09; 95% CI, 1.15-57.1) were independent predictors of cirrhosis. These findings suggest that the CAGE questionnaire predicts advanced liver disease better than daily or lifetime drinking measures.
View details for DOI 10.1007/s10620-006-9668-1
View details for Web of Science ID 000249300100016
View details for PubMedID 17415636
Hepatitis C treatment candidacy and outcomes among 4318 US veterans with chronic hepatitis C virus infection - Does a history of injection drug use matter?
JOURNAL OF CLINICAL GASTROENTEROLOGY
2007; 41 (2): 199-205
Many patients with a history of injection drug use (IDU) are excluded from hepatitis C virus (HCV) treatment. This prospective multicenter study aimed to determine the impact of IDU history on HCV treatment candidacy and outcomes.Between 1999 and 2001, 4318 HCV-infected patients seen at 24 VA Medical Centers were evaluated for HCV treatment candidacy and followed prospectively. Univariate and multivariate logistic regression analyses were used to determine whether an IDU history was associated with HCV treatment candidacy, HCV treatment acceptance, early treatment discontinuation, and virologic response.Of 4318 participants, 2611 (61%) reported an IDU history. IDU history was not significantly associated with HCV treatment candidacy, acceptance, early discontinuation of therapy, or virologic response (all P values nonsignificant). Instead, reduced HCV treatment candidacy was independently associated with low-income [odds ratio (OR)=1.46, 95% confidence interval (CI)=1.22-1.74), education < or = 12 years (OR=1.23, 95% CI=1.03-1.46), and alcohol consumption > or = 3 drinks/d (OR=2.08, 95% CI=1.68-2.57), whereas early discontinuation of HCV therapy was independently associated with low-income and consuming > or = 3 alcoholic drinks/d.A history of IDU was not associated with HCV treatment candidacy or outcomes, supporting national guidelines to evaluate former IDUs on a case-by-case basis for HCV treatment.
View details for Web of Science ID 000244133400014
View details for PubMedID 17245220
Clinical implications of hepatic steatosis in patients with chronic hepatitis C: A multicenter study of US Veterans
DIGESTIVE DISEASES AND SCIENCES
2007; 52 (2): 570-578
Studies have indicated a high prevalence of hepatic steatosis in patients with chronic hepatitis C (CHC). To address the impact of steatosis on the clinical course of CHC and treatment response requires large multicenter studies. The present study analyzed hepatitis C virus (HCV)-infected veterans enrolled in a U.S. Veteran Administration multicenter study of the epidemiology and response to interferon alpha-2b and ribavirin treatment. Of the 357 patients, 97.1% were males, with a mean age of 48.7+/-6.4 years, and 184 (51.5%) had hepatic steatosis. The mean body mass index (BMI) was 29.3+/-5.2 kg/m(2), including 37.1% who were obese (BMI, > or =30 kg/m(2)). Stage III-IV fibrosis was present in 111 of 334 (33.3%) of the patients. After adjusting for age, race, and history of alcohol use in the past 12 months, only stage III-IV fibrosis was independently and significantly associated with hepatic steatosis (P=0.03). There was a trend of association between obesity and steatosis independent of the other factors. Only HCV genotype was independently associated with a sustained virological response (SVR) to interferon alpha-2b and ribavirin treatment after adjusting for age, alcohol use, steatosis, BMI, stage III-IV fibrosis, serum AFP, and HCV load. In conclusion, analyses of our multicenter trial data demonstrated that the prevalence of hepatic steatosis is 51.5% in HCV-infected U.S. veterans. We found that steatosis is independently associated with stage III-IV fibrosis. However, only HCV genotype, and not steatosis, obesity, or stage III-IV fibrosis, was associated with SVR to interferon alpha-2b and ribavirin treatment.
View details for DOI 10.1007/s10620-006-9418-4
View details for Web of Science ID 000243904600046
View details for PubMedID 17226072
- Screening for esophageal varices in cirrhotic patients: endoscope, platelet count, or both? GASTROINTESTINAL ENDOSCOPY 2006; 64 (6): 865-867
Phenotypic and functional status of intrahepatic T cells in chronic hepatitis C
JOURNAL OF INFECTIOUS DISEASES
2006; 194 (8): 1068-1077
Polychromatic flow-cytometric assays were used to analyze paired intrahepatic and peripheral lymphocyte samples from 37 patients with chronic hepatitis C. Compared with peripheral cells, intrahepatic T cells were selectively enriched with CD45RO+ memory T cells but had a lower percentage of CD4+ T cells expressing the differentiation markers CD27 and CD28. The percentage of intrahepatic CD45RO+ and CD28+ T cells correlated with the degree of liver inflammation, which suggests that memory T cells at relatively early stages of differentiation are directly involved in liver inflammation. Despite their memory phenotype, intrahepatic T cells were defective in proliferation capability, produced less interferon- gamma in response to stimulation by T cell receptor, and contained less perforin but expressed higher levels of Fas and Fas ligand, compared with their counterparts in peripheral blood. The distinct characteristics of intrahepatic T cells suggest that they play an important role in the immunopathogenesis of chronic hepatitis C.
View details for Web of Science ID 000240548500007
View details for PubMedID 16991081
Global transcriptional response to interferon is a determinant of HCV treatment outcome and is modified by race
2006; 44 (2): 352-359
Interferon (IFN)-alpha-based therapy for chronic hepatitis C is effective in fewer than 50% of all treated patients, with a substantially lower response rate in black patients. The goal of this study was to investigate the underlying host transcriptional response associated with interferon treatment outcomes. We collected peripheral blood mononuclear cells from chronic hepatitis C patients before initiation of IFN-alpha therapy and incubated the cells with or without IFN-alpha for 6 hours, followed by microarray assay to identify IFN-induced gene transcription. The microarray datasets were analyzed statistically according to the patients' race and virological responses to subsequent IFN-alpha treatment. The global induction of IFN-stimulated genes (ISGs) was significantly greater in sustained virological responders compared with nonresponders and in white patients compared with black patients. In addition, a significantly greater global induction of ISGs was observed in sustained virological responders compared with nonresponders within the group of white patients. The level of IFN-induced signal transducer and activator of transcription (STAT) 1 activation, a key component of the Janus kinase (JAK)-STAT signaling pathway, correlated with the global induction of ISGs and was significantly higher in white patients than in black patients. In conclusion, both treatment outcome and race are associated with different transcriptional responses to IFN-alpha. Because this difference is evident in the global induction of ISGs rather than a selective effect on a subset of such genes, key factors affecting the outcome of IFN-alpha therapy are likely to act at the JAK-STAT pathway that controls transcription of downstream ISGs.
View details for DOI 10.1002/hep.21267
View details for Web of Science ID 000239523200009
View details for PubMedID 16871572
The impact of chronic hepatitis C and comorbid psychiatric illnesses on health-related quality of life
JOURNAL OF CLINICAL GASTROENTEROLOGY
2006; 40 (6): 528-534
To determine the relative impact of chronic hepatitis C (CHC) and comorbid psychiatric illness on the health-related quality of life (HRQoL).Psychiatric conditions are more common among patients with CHC but their relative influence on HRQoL is not well understood.We identified 864 veterans who had previously completed a veteran-specific HRQoL questionnaire (SF-36V) as part of the 1999 VA Large Health Survey with known HCV antibody (anti-HCV) status before the survey. For 201 anti-HCV(+) and 663 anti-HCV(-) patients, we compared the HRQoL status and the prevalence of 6 major psychiatric diagnoses. We conducted multiple regression analyses to measure the effect of anti-HCV status and psychiatric comorbidity.Compared with the anti-HCV(-) group, anti-HCV(+) veterans were more likely to have alcohol dependence (P<0.001), depression (P=0.01), or posttraumatic stress disorder (PTSD) (P<0.004). The anti-HCV(+) group also reported lower HRQoL on 4 of the 8 SF-36V subscales (P<0.01) and the mental component summary scale (P<0.001). Even after adjusting for demographic variables and comorbid psychiatric illness, anti-HCV(+) patients reported a significantly lower mental component summary score (P<0.01) than did anti-HCV(-) patients. Multiple regression analysis found that depression and PTSD predicted lower HRQoL scores for all 8 HRQoL subscales (P<0.01) and both the physical (P<0.001) and mental component (P<0.03) summary scales independent of anti-HCV status.The HRQoL is significantly impaired in veterans with CHC, particularly the mental health components of HRQoL. In contrast, comorbid depression and PTSD are associated with both lower physical and mental components of HRQol, independent of CHC.
View details for Web of Science ID 000239136700012
View details for PubMedID 16825936
Effectiveness of a screening program for hepatitis C
DIGESTIVE DISEASES AND SCIENCES
2006; 51 (5): 976-981
We sought to determine the outcomes of a screening program for hepatitis C virus (HCV) infection. Of 536 veterans initially screened between July 2000 and June 2001 for risk factors and then tested positive for antibody for HCV, only 260 (48.5%) kept their initial appointments for further evaluation; 51 were not viremic and only 19 (9.1%) were treatment eligible. Of the 276 who did not keep their initial appointments, 92 were subsequently evaluated over the next 2 years and 23 (25%) were treatment eligible, along with another 15 from the first group. Thus, with appropriate intervention and long-term follow-up, there were 57 treatment candidates. In conclusion, most veterans who tested positive either failed to keep their appointment or were ineligible for treatment when first evaluated. Over the following 2 years, some were lost to follow-up, many continued to have contraindication(s) to antiviral therapy, and relatively few were treatment candidates.
View details for DOI 10.1007/s10620-006-9100-x
View details for Web of Science ID 000238847600027
View details for PubMedID 16642419
Alcohol use and treatment of hepatitis C virus: Results of a national multicenter study
2006; 130 (6): 1607-1616
Patients with hepatitis C virus (HCV) infection who use alcohol have been excluded from clinical trials; therefore, outcomes with antiviral therapy are unknown. The aim of the study was to determine the impact of alcohol use on HCV treatment outcomes.Subjects using alcohol were categorized as follows: no alcohol versus regular alcohol use, quantity consumed (none, <6 drinks/day, >/=6 drinks/day), CAGE score <2 or >/=2, and recent alcohol use (past 12 months). Patients were treated with interferon plus ribavirin.A total of 4061 subjects were enrolled, and 726 (18%) received treatment. Alcohol use (past and within 12 months) reduced treatment candidacy. Past alcohol use did not affect the end-of-treatment response, sustained virologic response (SVR), and treatment discontinuation rates. However, recent alcohol use resulted in higher treatment discontinuation (40% vs 26%; P = .0002) and tended to reduce the SVR (14% vs 20%; P = .06), but when patients who discontinued treatment were excluded from analysis, the trend in favor of nondrinkers for SVR disappeared (25% vs 23%). These findings were also consistent in subgroup analyses on race and genotype.Eligibility for anti-HCV treatment was reduced in past and recent drinkers. Recent alcohol use was associated with increased treatment discontinuation and lower SVR. However, patients who use alcohol and completed the treatment had a response comparable to that of nondrinkers. Patients with a history of alcohol use should not be excluded from HCV therapy. Instead, additional support should be provided to these patients to ensure their ability to complete treatment.
View details for DOI 10.1053/j.gastro.2006.02.023
View details for Web of Science ID 000237686700011
View details for PubMedID 16697724
Identification of two gene variants associated with risk of advanced fibrosis in patients with chronic hepatitis C
2006; 130 (6): 1679-1687
Previously identified clinical risk factors such as sex, alcohol consumption, and age at infection do not accurately predict which patients with chronic hepatitis C (CHC) will develop advanced fibrosis (bridging fibrosis and cirrhosis). The aim of this study was to identify genetic polymorphisms that can predict the risk of advanced fibrosis in patients with CHC.A total of 916 subjects with CHC was enrolled from 2 centers. A gene-centric disease association study of 24,832 putative functional, single nucleotide polymorphisms (SNPs) was performed. Of the 1609 SNPs that were significantly associated (P = .05) with advanced fibrosis in the discovery cohort (University of California San Francisco [UCSF], N = 433), the first batch of 100 SNPs were selected for validation in the replication cohort (Virginia Commonwealth University [VCU], N = 483).A missense SNP in the DEAD box polypeptide 5 (DDX5) gene was significantly associated with an increased risk of advanced fibrosis in both the UCSF and the VCU cohorts (OR, 1.8 and 2.2, respectively). Two diplotype groups, carrying the haplotypes composed of the DDX5 SNP and 2 neighboring POLG2 SNPs were also significantly associated with an increased risk of advanced fibrosis and had comparable or better risk estimates. In addition, a missense SNP in the carnitine palmitoyltransferase 1A (CPT1A) gene was associated with a decreased risk of advanced fibrosis in both the UCSF and the VCU cohorts (OR, 0.3 and 0.6, respectively).Subjects with CHC carrying DDX5 minor allele or DDX5-POLG2 haplotypes are at an increased risk of developing advanced fibrosis, whereas those carrying the CPT1A minor allele are at a decreased risk.
View details for DOI 10.1053/j.gastro.2006.02.032
View details for Web of Science ID 000237686700019
View details for PubMedID 16697732
Black patients with chronic hepatitis C have a lower sustained viral response rate than non-Blacks with genotype 1, but the same with genotypes 2/3, and this is not explained by more frequent dose reductions of interferon and ribavirin
JOURNAL OF VIRAL HEPATITIS
2006; 13 (4): 242-249
In previous hepatitis C virus (HCV) treatment studies, Black patients not only had a lower sustained viral response (SVR) rate to interferon and ribavirin (RBV) than non-Black patients but also a higher frequency of HCV genotype 1 (GT-1) infection. The aim of this community-based study was to determine whether Black patients have a lower SVR rate independent of genotype. We prospectively enrolled 785 patients (24.8% Black, 71.5% White, 3.7% others) who received interferon alpha-2b 3 MU three times weekly + RBV 1000-1200 mg/day for 24 weeks (GT-2/3) or 48 weeks (GT-1). Black patients were more commonly infected with GT-1 (86.8%vs 64.8%, P < 0.001) and less frequently had an SVR compared with non-Black patients (8.4%vs 21.6%, P < 0.001). Within GT-1, Black patients had a lower SVR rate than non-Black patients (6.1%vs 14.1%, P = 0.004) but not within GT-2/3 (50.0%vs 36.5%, P = 0.47). Black patients had lower baseline haemoglobin levels (14.8 vs 15.3 g/dL, P < 0.001) and neutrophil counts (2900 vs 4100/mm(3), P < 0.001) and required more frequent dose reductions of RBV (29.8%vs 18.5%, P < 0.001) and interferon (4.7%vs 1.6%, P = 0.012). However, dose reductions were not associated with lower SVR rates while early treatment discontinuations were (2.9%vs 25.7%, P < 0.001). Independent predictors of SVR were GT-1 [odds ratio (OR) 0.33; 95% confidence interval (CI) 0.20-0.55; P < 0.001], Black race (OR 0.45; 95% CI 0.22-0.93; P = 0.030), and advanced fibrosis, stages 3 + 4 (OR 0.53; 95% CI 0.31-0.92; P = 0.023). In conclusion, Black patients infected with HCV GT-1 (but not GT-2/3) have a lower SVR rate than non-Black patients. This is not explained by their lower baseline haemoglobin levels and neutrophil counts that lead to higher rates of ribavirin and interferon dose reductions.
View details for DOI 10.1111/j.1365-2893.2005.00682.x
View details for Web of Science ID 000236065100005
View details for PubMedID 16611190
Hepatitis B vaccines
INFECTIOUS DISEASE CLINICS OF NORTH AMERICA
2006; 20 (1): 27-?
Immunization is the most effective way to prevent transmission of HBV and, hence, the development of acute or chronic hepatitis B. The national strategy to eliminate transmission of the virus in the United States includes vaccination of all newborn infants, children, adolescents, and high-risk adults. Postexposure prophylaxis is also advocated, depending on the vaccination and anti-HBs status of the exposed person. Seroprotection after vaccination, defined as anti-HBs > or = 10 mIU/mL, is achieved in over 95% of all vaccinees. The hepatitis B vaccines are very well tolerated with usually minimal adverse effects. Predictors of non-response include increasing age, male gender, obesity, tobacco smoking, and immunocompromising chronic dis-ease. For those who remain nonresponders after the second series of vaccination, adjuvants such as GM-CSF may be considered, but their results are variable.
View details for DOI 10.1016/j.idc.2006.01.004
View details for Web of Science ID 000236520400003
View details for PubMedID 16527647
Chronic hepatitis C in Latinos: Natural history, treatment eligibility, acceptance, and outcomes
AMERICAN JOURNAL OF GASTROENTEROLOGY
2005; 100 (10): 2186-2193
The natural history of chronic hepatitis C and treatment response are different between blacks and Caucasians, but little comparable data is available about Latinos.A cross-sectional secondary analysis to investigate differences between 421 anti-HCV-positive, treatment-naïve, HCV-viremic Latinos and 2,510 Caucasians in 24 VA medical centers enrolled in a prospective study.Latinos were infected at a younger age and were less likely to have blood contact during combat, surgery, and needle stick injury, but were more frequently HIV coinfected (20.4%vs 3.9%, p < 0.0001) and prior HAV infection (39.9%vs 26.4%, p= 0.0001). Latinos were more likely to be treatment candidates, but less likely to actually initiate treatment. Liver histology (123 Latinos, 743 Caucasians) showed no difference in fibrosis or fibrosis rate, but steatosis (54.7%vs 43.2%, p= 0.038) was more common in Latinos. Eighty-eight Latinos and 481 Caucasians were subsequently treated with interferon-ribavirin: body mass index (BMI), duration of infection, baseline tests, liver histology and genotype distribution were similar. Compared with Caucasians, Latinos discontinued treatment prematurely more often (39.8%vs 28.9%, p= 0.043) and tended to have lower sustained virological response (SVR) rates (14.8%vs 22.5%, p= 0.10). Multivariate analysis found Latino race and history of recent alcohol use to be associated with early treatment discontinuation, whereas genotype and viral load but not ethnicity to be associated with SVR.Latinos were infected younger, more frequently HIV coinfected, more likely to meet criteria for antiviral therapy yet less likely to initiate treatment and had a trend toward lower SVR rates than Caucasians, but not in severity of liver disease. Latino ethnicity was associated with early discontinuation but not as an independent predictor of SVR.
View details for DOI 10.1111/j.1572-0241.2005.00240.x
View details for Web of Science ID 000231950500009
View details for PubMedID 16181367
Amantadine in treatment of chronic hepatitis C virus infection?
JOURNAL OF VIRAL HEPATITIS
2005; 12 (5): 445-455
Treatment of chronic hepatitis C (CHC) continues to be an important and growing challenge. As the response rate to FDA-approved treatment improved over the past decade, we are facing increasing number of difficult-to-treat patients such as those who have failed prior anti-viral therapy. The role of amantadine in the treatment of CHC remains unclear. Studies thus far have produced conflicting results, and type II error could not be excluded. This review summarized results published in the literature from 1997 to 2003, and reviewed the existing questions and controversies regarding the use of amantadine. Current literature suggests that amantadine is ineffective as monotherapy. Amantadine increased the sustained virologic response of certain treatment naïve patients when used in combination with interferon, and may be effective as an adjunct to interferon-based combination therapy in some patients who have failed or relapsed on prior therapy. Factors such as small sample size, patient characteristics, and differences in treatment protocols including amantadine preparation and duration of therapy might explain the conflicting observations of various studies. Further investigations are needed to define optimal dosing and formulation of amantadine, and its appropriate role in management of CHC infection.
View details for DOI 10.1111/j.1365-2893.2005.00622.x
View details for Web of Science ID 000231223400001
View details for PubMedID 16108758
Prospective multicenter study of eligibility for antiviral therapy among 4,084 US veterans with chronic hepatitis C virus infection
AMERICAN JOURNAL OF GASTROENTEROLOGY
2005; 100 (8): 1772-1779
Many veterans may not be candidates for hepatitis C virus (HCV) treatment due to contraindications to therapy. The aims of this study were to determine the proportion of HCV-infected veterans who were eligible for interferon alfa and ribavirin therapy and to evaluate barriers to HCV treatment.We prospectively enrolled 4,084 veterans who were referred for HCV treatment over a 1-yr period at 24 Veterans Affairs (VA) Medical Centers. Treatment candidacy was assessed using standardized criteria and the opinion of the treating clinician.Overall, 32.2% (95% CI, 30.8-33.7%) were candidates for HCV treatment according to standardized criteria, whereas 40.7% (95% CI, 39.2-42.3%) were candidates in the opinion of the treating clinician. Multivariable analysis identified ongoing substance abuse (OR = 17.68; 95% CI, 12.24-25.53), comorbid medical disease (OR = 9.62; 95% CI, 6.85-13.50), psychiatric disease (OR = 9.45; 95% CI, 6.70-13.32), and advanced liver disease (OR = 8.43; 95% CI, 4.42-16.06) as the strongest predictors of not being a treatment candidate. Among patients who were considered treatment candidates, 76.2% (95% CI, 74.0-78.3%) agreed to be treated and multivariable analysis showed that persons >/=50 yr of age (OR = 1.37; 95% CI, 1.07-1.76) and those with >50 lifetime sexual partners (OR = 1.44; 95% CI, 1.08-1.93) were more likely to decline treatment.The majority of veteran patients are not suitable candidates for HCV treatment because of substance abuse, psychiatric disease, and comorbid medical disease, and many who are candidates decline therapy. Multidisciplinary collaboration is needed to overcome barriers to HCV therapy in this population.
View details for DOI 10.1111/j.1572-0241.2005.41860.x
View details for Web of Science ID 000230992100021
View details for PubMedID 16086714
High mortality rate in patients with advanced liver disease independent of exposure to general anesthesia
JOURNAL OF CLINICAL ANESTHESIA
2005; 17 (3): 172-176
To evaluate the survival of patients with advanced liver disease to determine if known exposure to general anesthesia within a 5-year period has a measurable effect on mortality.Retrospective survival analysis of male veterans with advanced liver disease.Tertiary referral VA Medical Center and university-affiliated teaching hospital.One hundred twenty-seven patients with a history of alcoholic cirrhosis and documented hepatitis C infection and stable platelet counts were identified and then divided into 3 groups. The 5-year survival rates in all 3 groups were compared using Kaplan-Meier survival curves.Ninety patients had marked thrombocytopenia (<100000/mm3). Their survival rates with and without known exposure to general anesthesia were compared with those of control subjects with alcoholic cirrhosis and hepatitis C infection but with platelet counts greater than 100000/mm3. The 5-year survival rate of 57% in the group that received general anesthesia was comparable to the 58% rate observed in the group without this exposure. Both groups' rates were statistically lower than the 5-year survival rate of 77% in the group with advanced liver disease but without thrombocytopenia.Comparably high mortality rates were observed in patients with advanced liver disease with or without exposure to general anesthesia. Higher survival rates were noted in patients with advanced liver disease who were not thrombocytopenic.
View details for DOI 10.1016/j.jclinane.2004.06.016
View details for Web of Science ID 000229688100005
View details for PubMedID 15896582
A randomized, double-blind, placebo-controlled dose-escalation trial of merimepodib (VX-497) and interferon-alpha in previously untreated patients with chronic hepatitis C
2005; 10 (5): 635-643
Inhibition of inosine monophosphate dehydrogenase (IMPDH) is one of several proposed mechanisms of action for ribavirin (RBV), a critical component of the current treatment for chronic hepatitis C (CHC). This study was a double-blind, placebo-controlled dose-escalation study of a novel, selective, orally active small molecule inhibitor of IMPDH, merimepodib (VX-497 or MMPD) in combination with standard interferon-alpha (IFN-alpha). Fifty-four treatment-naive patients with genotype-1 CHC were randomized to receive IFN-alpha 3 MIU subcutaneously three times a week, alone or in combination with 100 mg or 300 mg (every 8 h) of MMPD for 4 weeks. At the end of 4 weeks, all patients were offered 48 weeks of treatment with IFN-alpha/RBV. The objectives of the study were to evaluate the tolerability of the IFN-alpha/MMPD combination and to evaluate whether MMPD had an on-treatment effect on HCV-RNA, similar to RBV when added to IFN-alpha. The drug combination was generally well tolerated; one patient at the higher dose discontinued because of elevated alanine aminotransferase levels. No pharmacokinetic interactions were evident between the two drugs. Analysis of covariance that adjusted for a baseline imbalance in HCV-RNA in the intent-to-treat population did not show any significant differences between the treatment groups, or between MMPD plus IFN-alpha compared with IFN-alpha alone. However, the per-protocol primary efficacy analysis based on treatment-compliant patients demonstrated a greater reduction in mean HCV-RNA in the combination of 100 mg MMPD plus IFN-alpha compared with IFN-alpha alone (-1.78 log vs -0.86 log, P=0.037). In conclusion, the addition of a selective IMPDH inhibitor to IFN-alpha was well tolerated. In a low-dose range, the addition of MMPD may have the potential to add to the antiviral efficacy of IFN-alpha. Larger, longer duration trials incorporating pegylated IFN would be required to determine whether this combination, alone or with RBV, would increase either early or sustained virological response rates.
View details for Web of Science ID 000231963400006
View details for PubMedID 16152757
Expression of chemokine receptors on intrahepatic and peripheral lymphocytes in chronic hepatitis C infection: Its relationship to liver inflammation
JOURNAL OF INFECTIOUS DISEASES
2004; 190 (5): 989-997
Intrahepatic lymphocytes are believed to be directly involved in the immunopathogenesis of chronic liver diseases. Little is known about the trafficking of lymphocytes into the liver and their role in chronic hepatitis C infection.The expression of 4 chemokine receptors and an activation marker on multiple lymphocyte subsets in paired liver biopsy and peripheral blood specimens from 23 patients with chronic hepatitis C infection were analyzed by a 6-color flow-cytometric assay.CCR5, CXCR3, and CXCR6 were expressed on intrahepatic CD4+ and CD8+ T cells, natural killer (NK) T cells, NK cells, and B cells at significantly higher frequencies than on peripheral lymphocyte subsets. The expression of these receptors and the activation marker CD38 tended to increase with the severity of liver inflammation. This increase was significant for several intrahepatic lymphocytes subsets. Correlations in expression differed among pairs of these extralymphoid homing receptors on the intrahepatic T cells.The homing program for intrahepatic lymphocytes involves multiple extralymphoid chemokine receptors that are regulated by >1 pathway. The expression of homing receptors on intrahepatic lymphocytes is associated with the immunopathogenesis of chronic hepatitis C disease. These preliminary results indicate that confirmational studies with larger sample sizes are warranted.
View details for Web of Science ID 000223114800018
View details for PubMedID 15295707
Hepatitis B vaccines.
Clinics in liver disease
2004; 8 (2): 283-300
Immunization is the most effective way to prevent transmission of HBV and, hence, the development of acute or chronic hepatitis B. The national strategy to eliminate transmission of the virus in the United States includes vaccination of all newborn infants, children, adolescents, and high-risk adults. Postexposure prophylaxis is also advocated, depending on the vaccination and anti-HBs status of the exposed person. Seroprotection after vaccination, defined as anti-HBs > or = 10 mIU/mL, is achieved in over 95% of all vaccinees. The hepatitis B vaccines are very well tolerated with usually minimal adverse effects. Predictors of non-response include increasing age, male gender, obesity, tobacco smoking, and immunocompromising chronic disease. For those who remain nonresponders after the second series of vaccination, adjuvants such as GM-CSF may be considered, but their results are variable.
View details for PubMedID 15481341
The use of class-I HLA tetramers for the detection of hepatitis C virus NS3-specific CD8+ T cells in patients with chronic infection
JOURNAL OF IMMUNOLOGICAL METHODS
2004; 287 (1-2): 91-99
New methods to detect virus-specific T-cell responses have recently been developed. Several human leukocyte antigen (HLA)-peptide tetramers for the detection of hepatitis C virus (HCV)-specific CD8(+) T cells are under evaluation.Evaluation of one HLA class I-tetramer (HCVNS3-2) for the detection of HCV NS3-specific CD8(+) T cells in a series of 38 HLA-A2(+) chronically infected patients.Almost half (42%) of the patients had detectable NS3-specific CD8(+) T cells. The frequencies of such cells ranged from 0.01% to 0.22% of total CD8(+) T cells. No significant differences in clinical features or mean viral load were detected between patients with or without tetramer + CD8(+) T cells.The tetramer HCVNS3-2 may be very useful for the study of the HCV-specific CD8(+) immune response. Combination of this reagent with other tetramers based on other HCV peptides may help in the understanding of the immune response to the virus. However, a panel of tetramers based on several parts of the HCV polyprotein may be a mandatory requirement to explore the whole breadth of the CD8(+) T-cell response against HCV and to detect that response in the majority of patients with chronic infection.
View details for DOI 10.1016/j.jim.2004.01.023
View details for Web of Science ID 000221148800008
View details for PubMedID 15099758
Genetic variability of hepatitis C virus non-structural protein 3 and virus-specific CD8+response in patients with chronic hepatitis C
JOURNAL OF MEDICAL VIROLOGY
2004; 72 (4): 575-585
Hepatitis C virus (HCV) variation in specific T-cell epitopes may represent a mechanism of viral persistence in chronic infection. We examined the HCV non-structural protein 3 (NS3), including the immunologically relevant epitopes HCV NS3-2 KLVALGINAV (human leukocyte antigen [HLA]-A2-restricted) and HCV NS3-1391 LIFCHSKKK (HLA-A3-restricted), in 22 HLA-A2+ patients with chronic infection. Significant amino acid variation was found in HCV NS3-2 epitope sequences when compared to the HCV-1 prototype virus. Six of the nine different HCV NS3-2 peptide variants were identified in patients with HCV NS3-2-specific CD8+ cells, detected with an HLA-A2 tetramer made with the HCV-1 prototype peptide. Phylogenetic analysis, including HCV reference sequences other than HCV-1, suggested however that most of the variations in the HCV NS3-2 epitope could be related to genetic heterogeneity between HCV reference subtypes. Variation was less common when comparing HCV NS3-2 epitope sequences from the clinical isolates to the most-closely related HCV reference subtype in each case. Some subtype-independent variations were found in epitopic residues probably important for T-cell receptor interaction. In contrast, no significant variation was found in HLA primary anchor sites, flanking regions, or in the contiguous HLA A3-restricted CD8+ T-cell epitope. Ongoing variation was not evident in two selected patients with follow-up. In conclusion, (i) the HCV NS3-2 epitope is not conserved between different HCV strains/subtypes, and (ii) an HLA-A2 tetramer loaded with the HCV-1 prototype NS3-2 peptide may still detect NS3-specific CD8+ cells in some patients with variant viruses. These data may be useful to improve T-cell assays using HCV NS3 peptides, taking into account the genetic diversity of this virus.
View details for DOI 10.1002/jmv.20036
View details for Web of Science ID 000220046100010
View details for PubMedID 14981760
The impact of hepatitis C status on postoperative outcome
ANESTHESIA AND ANALGESIA
2003; 97 (2): 550-554
The impact of the hepatitis C virus (HCV) infection on the postoperative complication rate is unknown. We identified a population of surgical patients (n = 2457) for whom the HCV antibody (anti-HCV) had been measured and compared after surgical complications and mortality between those who were positive (17.9%) versus negative. The complication rates were 10% in the anti-HCV positive and 13% in the negative group (P = 0.125), whereas the mortality rates were 0.7% and 2.5%, respectively (P = 0.017). The anti-HCV positive patients were younger, had lower ASA physical status, and underwent shorter procedures. In the univariate analysis, emergent surgery and high ASA physical status but not anti-HCV positivity were associated with a more frequent complication. In the multivariate analysis, the urgency of surgery, age, ASA physical status, length of surgery, and preoperative hematocrit (but not platelet count) were associated with complications. Anti-HCV positivity was associated with an odds ratio for having a complication of 1.08 (95% confidence interval, 0.90-1.30), which was not statistically significant (P = 0.405). In conclusion, we were unable to show HCV antibody status to be an independent risk factor for postoperative complications when other co-factors were considered.In this large study at a Veterans Administration medical center, the urgency of surgery, age, ASA physical status, length of surgery, and preoperative hematocrit were all independently associated with postoperative complications. However, hepatitis C infection was not an independent risk factor for postoperative complications.
View details for DOI 10.1213/01.ANE.0000068984.22840.FE
View details for Web of Science ID 000184354600044
View details for PubMedID 12873952
Determination of hepatitis C virus genotype by Pyrosequencing
JOURNAL OF VIROLOGICAL METHODS
2003; 109 (2): 171-176
A simple sequencing-based assay is described for genotyping of hepatitis C virus (HCV). RT-PCR was employed to amplify a 237-nucleotide-long fragment from the 5' untranslated region (UTR) of the genome using one biotinylated and one normal primer. Subsequent to capture of the PCR products on streptavidin-coated beads, single-stranded DNA separation, and hybridization of sequencing primer, Pyrosequencing was performed. The genotype of 98 samples out of which 77 samples were from American veterans and 21 samples were from Iran was determined. The samples from the American veterans contained six different subtypes, while five subtypes were found in Iranian samples. For rapid population-specific HCV subtyping, a multiplex assay was developed. This study demonstrates the suitability of this technology for low-cost, high throughput and accurate microbial genotyping.
View details for DOI 10.1016/S0166-0934(03)00068-5
View details for Web of Science ID 000183092800009
View details for PubMedID 12711060
Interferon alfa regulated gene expression in patients initiating interferon treatment for chronic hepatitis C
2003; 37 (3): 610-621
Interferon alfa (IFN-alpha) is an approved therapeutic agent for chronic hepatitis C. To directly characterize the effects of IFN-alpha in humans, we used microarrays to profile gene expression in peripheral blood mononuclear cells (PBMCs) from hepatitis C patients treated with IFN-alpha. Seven patients were studied using two strategies: (1) in vivo: PBMCs were collected immediately before the first dose of IFN-alpha, and 3 and 6 hours after the dose; (2) ex vivo: PBMCs that were collected before the first IFN-alpha dose were incubated with IFN-alpha for 3 and 6 hours. The microarray datasets were analyzed with significance analysis of microarrays (SAM) to identify genes regulated by IFN-alpha. We identified 516 named genes up-regulated at least 2-fold, at a false discovery rate (FDR) of less than 1%. In vivo and ex vivo studies generated similar results. No genes were identified as regulated differently between these 2 experimental conditions. The up-regulated genes belonged to a broad range of functional pathways and included multiple genes thought to be involved in the direct antiviral effect of IFN-alpha. Of particular interest, 88 genes directly relating to functions of immune cells were up-regulated, including genes involved in antigen processing and presentation, T-cell activation, lymphocyte trafficking, and effector functions, suggesting that IFN-alpha up-regulates multiple genes involving different aspects of immune responses to enhance immunity against hepatitis C virus. In conclusion, IFN-alpha-inducible genes can be identified in human PBMCs in vivo as well as ex vivo. Signature changes associated with different treatment outcomes may be found among these genes.
View details for DOI 10.1053/jhep.2003.50105
View details for Web of Science ID 000181276800017
View details for PubMedID 12601359
Depression, anxiety, post-traumatic stress, and alcohol-related problems among veterans with chronic hepatitis C
AMERICAN JOURNAL OF GASTROENTEROLOGY
2002; 97 (10): 2640-2646
The aim of this study was to determine the incidence of psychiatric comorbidities among veterans with chronic hepatitis C.Depression, anxiety sensitivity, post-traumatic stress symptoms, and alcohol use were assessed using standardized questionnaires in 120 consecutive veterans with chronic hepatitis C referred to the Liver Clinic.Using well-established scoring criteria of the questionnaires, clinically significant levels of depression (44.2%), anxiety (38.1%), post-traumatic stress disorder (20.8%), and alcohol-related problems (26.7%) were observed. The majority of patients had a clinically significant score for at least one questionnaire, whereas 37.2% had significant scores in two or more questionnaires. Positive correlations were found between post-traumatic symptoms and depressive symptoms, anxiety sensitivity, and alcohol use problems. Depressive symptoms were also correlated with anxiety. Responses to the questionnaires, in general, correlated poorly with psychiatric histories documented in the medical record. Overall, 79 (65.8%) patients had one or more possible contraindications to antiviral therapy: coexisting unstable psychiatric disorders and/or recent substance use was found in 73.4% of these patients.Psychiatric comorbidities were very common among veterans with chronic hepatitis C and correlated poorly with diagnoses documented in the medical record. We recommend a multidisciplinary approach that includes psychological assessment using standardized questionnaires in the evaluation of these patients for antiviral therapy.
View details for Web of Science ID 000178504800028
View details for PubMedID 12385453
Viral hepatitis and other infectious diseases in a homeless population
JOURNAL OF CLINICAL GASTROENTEROLOGY
2002; 34 (4): 476-480
To determine the prevalence of four common infectious diseases-hepatitis B, hepatitis C, human immunodeficiency virus (HIV), and tuberculosis-as well as co-infection rates and risk factors in a homeless population.The prevalence of infectious diseases, especially viral hepatitis, among the homeless population is largely unknown.This study consists of a retrospective analysis of the history and laboratory data collected from all homeless veterans admitted to a Veterans Administration (VA) domiciliary from May 1995 to March 2000.Of the homeless veterans admitted to a VA domiciliary program, 597 of 829 were screened for markers of all four infectious diseases. The overall prevalence of anti-hepatitis C virus (HCV) antibody, and positive result for purified protein derivative (PPD), anti-HIV antibody, and hepatitis B surface antigen (HbsAg) were 41.7%, 20.6%, 1.84% and 1.17%, respectively. At least one of the four markers was positive in 52.6% and more than one in 12%. Co-infection with HCV occurred commonly in veterans who were positive for anti-HIV (72.7%) and HBsAg (57.1%). Four self-reported major risk factors (intravenous drug use, alcohol abuse, previous imprisonment, and prior stay in a shelter) were evaluated. Multivariate analysis indicates that intravenous drug use and anti-HBs reactivity are independent risk factors for HCV infection, HCV infection for anti-hepatitis B surface antibody reactivity, and older age for PPD positivity.Chronic hepatitis C and co-infections are common among the homeless population. Patients infected with HIV and hepatitis B virus frequently are co-infected with HCV. Infections frequently are associated with certain identifiable risk factors.
View details for Web of Science ID 000174716100021
View details for PubMedID 11907367
- Treating chronic hepatitis C patients with psychiatric disorders: An uphill battle AMERICAN JOURNAL OF GASTROENTEROLOGY 2001; 96 (1): 3-4
Endoscopic gastrointestinal manifestations of liver disease.
Gastrointestinal endoscopy clinics of North America
2001; 11 (1): 15-44
Esophageal and gastric varices are common manifestations of advanced chronic liver disease, but other endoscopic gastrointestinal manifestations of portal hypertension may occur. In the upper gastrointestinal tract, portal hypertensive gastropathy, particularly when severe, and gastric antral vascular ectasias are important alternative causes of gastrointestinal bleeding. Portal hypertensive enteropathy is an uncommon source of gastrointestinal bleeding, and its overall clinical significance remains unknown. In the lower gastrointestinal tract, portal hypertension may be associated with hemorrhoids, anorectal varices, and portal hypertensive colopathy, all of which are occasional causes of gastrointestinal bleeding.
View details for PubMedID 11175973
Delayed fatal hemorrhage from pseudoaneurysm of the hepatic artery after percutaneous liver biopsy
AMERICAN JOURNAL OF GASTROENTEROLOGY
2001; 96 (1): 233-237
Hemorrhage is the most common serious complication of percutaneous liver biopsy. Liver biopsy is usually done in an outpatient setting because most significant hemorrhage is evident within a few hours after biopsy. Delayed hemorrhage occurs much less frequently but carries a much higher mortality. We present a 41-yr-old man with chronic hepatitis C who underwent a percutaneous liver biopsy uneventfully but was found to have a pseudoaneurysm of the hepatic artery 5 days later. Shortly after admission, the patient experienced bleeding into the liver from the pseudoaneurysm, which was controlled initially by angiographic embolization. However, recurrent bleeding could not be controlled by repeat angiography and surgical intervention, and the patient expired. The diagnosis and management of pseudoaneurysm of the hepatic artery complicating liver biopsy is reviewed.
View details for Web of Science ID 000166435400039
View details for PubMedID 11197259
Management of gallstones and their complications
AMERICAN FAMILY PHYSICIAN
2000; 61 (6): 1673-1680
The accurate differentiation of gallstone-induced biliary colic from other abdominal disease processes is the most crucial step in the successful management of gallstone disease. Despite the availability of many imaging techniques to demonstrate the presence of gallstones, clinical judgment ultimately determines the association of symptoms with cholelithiasis and its complications. Adult patients with silent or incidental gallstones should be observed and managed expectantly, with few exceptions. In symptomatic patients, the intervention varies with the type of gallstone-induced complication. In this article, we review the salient clinical features, diagnostic tests and therapeutic options employed in the management of gallstones and their complications.
View details for Web of Science ID 000086196400009
View details for PubMedID 10750875
Quantitative analysis of hepatitis C virus-specific CD8(+) T cells in peripheral blood and liver using peptide-MHC tetramers
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
1999; 96 (10): 5692-5697
It is believed that the hepatitis C virus (HCV)-specific CD8(+) cytotoxic T lymphocytes (CTLs) play a role in the development of liver cell injury and in the clearance of the virus. To develop a direct binding assay for HCV-specific CTLs, we generated two peptide-MHC tetramers by using the recombinant HLA A2.1 molecule and A2-restricted T cell epitopes of the HCV NS3 protein. With these reagents we are able to detect specific CD8(+) cells in the blood of 15 of 20 HLA-A2(+), HCV-infected patients, at a frequency ranging from 0.01% to 1.2% of peripheral CD8(+) T cells. Phenotypic analysis of these specific cells indicated that there is a significant variation in the expression of the CD45 isoforms and CD27 in different patients. A 6-hour incubation of one patient's blood with NS3 peptides resulted in the activation of the epitope-specific CD8(+) cells, as indicated by their expression of CD69 and IFN-gamma. We also detected NS3-specific CD8(+) T cells in the intrahepatic lymphocyte population isolated from liver biopsies of two HCV-infected patients. The frequency of these specific CD8(+) cells in the liver was 1-2%, at least 30-fold higher than in the peripheral blood. All of the intrahepatic NS3-specific CD8(+) T cells were CD69(+), suggesting that they were activated CTLs. Direct quantitation and characterization of HCV-specific CTLs should extend our understanding of the immunopathogenesis and the mechanism of clearance or persistence of HCV.
View details for Web of Science ID 000080246500068
View details for PubMedID 10318946
- Finding the iron in the melting pot - Practical use of a new genetic assay for hereditary hemochromatosis WESTERN JOURNAL OF MEDICINE 1998; 168 (6): 525-527
- Hepatitis G virus: Clinical relevance and responsiveness to interferon AMERICAN JOURNAL OF GASTROENTEROLOGY 1997; 92 (11): 1957-1959
Hepatitis G virus: Is it a hepatitis virus?
WESTERN JOURNAL OF MEDICINE
1997; 167 (1): 23-33
Hepatitis G virus (HGV) and GB virus C (GBV-C) are two newly discovered viral agents, different isolates of a positive-sense RNA virus that represents a new genus of Flaviviridae. The purpose of this review is to analyze new data that have recently been published on the epidemiology and associations between HGV and liver diseases such as posttransfusion hepatitis, acute and chronic non-A-E hepatitis, fulminant hepatitis, cryptogenic cirrhosis, and hepatocellular carcinoma. The role of HGV in coinfection with other hepatitis viruses, the response to antiviral therapy, and the impact of HGV on liver transplantation are also discussed. HGV is a transmissible blood-borne viral agent that frequently occurs as a coinfection with other hepatitis viruses due to common modes of transmission. The prevalence of HGV ranges from 0.9 to 10% among blood donors throughout the world and is found in 1.7% of volunteer blood donors in the United States. The majority of patients infected with HGV by blood transfusion do not develop chronic hepatitis, but hepatitis G viremia frequently persists without biochemical evidence of hepatitis. Serum HGV RNA has been found in 0 to 50% of patients with fulminant hepatitis of unknown etiology and 14 to 36% of patients with cryptogenic cirrhosis. The association between HGV and chronic non-A-E hepatitis remains unclear. Although HGV appears to be a hepatotrophic virus, its role in independently causing acute and chronic liver diseases remains uncertain.
View details for Web of Science ID A1997XQ01100004
View details for PubMedID 9265860
Hepatitis C virus detection by single-round PCR specific for the terminal 3' noncoding region
JOURNAL OF CLINICAL MICROBIOLOGY
1996; 34 (10): 2552-2558
A single-round PCR method with primers specific for the 3' noncoding region (NCR) of hepatitis C virus (HCV) has been developed. Using a double RNAzol-B extraction, a high-temperature reverse-transcription step with SuperScript II reverse transcriptase, and a 40-cycle two-temperature PCR with a TaqStart antibody hot-start procedure, we were able to detect a 92-nucleotide fragment of the recently discovered 98-nucleotide highly conserved sequence at the 3' terminus of the HCV genome. Direct sequencing of the PCR products confirmed the specificity of the PCR and demonstrated conservation in this region. Only one nucleotide change in 14 specimens was found. End point dilution titration of sera with known viral RNA titers showed the sensitivity of the single-round 3' NCR PCR to be comparable to those of the established nested 5' NCR assays (fewer than 25 HCV genome equivalents). To evaluate specificity and sensitivity, a panel of 116 serum samples characterized by nested 5'-end PCR, genotyping, and quantitative assays was tested. A high degree of concordance (96%) between the 3' NCR and 5' NCR PCR results was found. The sequence conservation at the 3' end of the HCV genome among common genotypes and the savings in time, labor, and reagents from a single-round PCR make this assay a useful addition to the detection systems available to identify and monitor HCV infection.
View details for Web of Science ID A1996VK78700043
View details for PubMedID 8880519
RAPID AND SENSITIVE METHOD FOR DETECTION OF HEPATITIS-C VIRUS-RNA BY USING SILICA PARTICLES
JOURNAL OF CLINICAL MICROBIOLOGY
1994; 32 (10): 2593-2597
We describe a rapid, sensitive, and economic method for detection of hepatitis C virus (HCV) RNA. This method uses silica particles for purification of nucleic acid and then a modified reverse transcription-PCR that minimizes the risk of contamination and reduces the amount of reagents used. We found purification by silica particles to be at least as sensitive and in certain circumstances more sensitive than that by traditional phenol-chloroform extraction. This improved sensitivity may be due to more efficient recovery of HCV RNA by silica particles. HCV RNA appears to bind to silica particles in a saturable fashion, and the addition of extraneous nucleic acids (salmon sperm DNA or tRNA) decreases the binding in a dose-related fashion. The reverse transcription-PCR is performed by using a modified single tube method which further simplifies and reduces the cost of this assay. Finally, this method may be applied to clinical specimens such as liver tissue.
View details for Web of Science ID A1994PG91200050
View details for PubMedID 7529243
FORMATION AND INTRACELLULAR-LOCALIZATION OF HEPATITIS-C VIRUS ENVELOPE GLYCOPROTEIN COMPLEXES EXPRESSED BY RECOMBINANT VACCINIA AND SINDBIS VIRUSES
JOURNAL OF VIROLOGY
1994; 68 (10): 6147-6160
Hepatitis C virus (HCV) encodes two putative virion glycoproteins (E1 and E2) which are released from the polyprotein by signal peptidase cleavage. In this report, we have characterized the complexes formed between E1 and E2 (called E1E2) for two different HCV strains (H and BK) and studied their intracellular localization. Vaccinia virus and Sindbis virus vectors were used to express the HCV structural proteins in three different cell lines (HepG2, BHK-21, and PK-15). The kinetics of association between E1 and E2, as studied by pulse-chase analysis and coprecipitation of E2 with an anti-E1 monoclonal antibody, indicated that formation of stable E1E2 complexes is slow. The times required for half-maximal association between E1 and E2 were 60 to 85 min for the H strain and more than 165 min for the BK strain. In the presence of nonionic detergents, two forms of E1E2 complexes were detected. The predominant form was a heterodimer of E1 and E2 stabilized by noncovalent interactions. A minor fraction consisted of heterogeneous disulfide-linked aggregates, which most likely represent misfolded complexes. Posttranslational processing and localization of the HCV glycoproteins were examined by acquisition of endoglycosidase H resistance, subcellular fractionation, immunofluorescence, cell surface immunostaining, and immunoelectron microscopy. HCV glycoproteins containing complex N-linked glycans were not observed, and the proteins were not detected at the cell surface. Rather, the proteins localized predominantly to the endoplasmic reticular network, suggesting that some mechanism exists for their retention in this compartment.
View details for Web of Science ID A1994PG54100002
View details for PubMedID 8083956
SCREENING AND CONFIRMATORY TESTING OF CADAVER ORGAN DONORS FOR HEPATITIS-C VIRUS-INFECTION - A US NATIONAL COLLABORATIVE STUDY
1994; 46 (3): 886-892
Hepatitis C virus (HCV) can be transmitted by organ transplantation. Cadaver organ donors are screened for HCV infection by testing for antibodies to HCV (anti-HCV). The prevalence of HCV infection and performance of anti-HCV tests in detecting HCV infection in organ donors are unknown. Sera from 3078 cadaver organ donors were tested for anti-HCV by a first generation enzyme-linked immunosorbent assay (ELISA1). Sera from all 137 ELISA1 positive donors and a random sample of 92 ELISA1 negative donors were tested for anti-HCV by a second generation ELISA (ELISA2) and for HCV RNA by the polymerase chain reaction. Organ bank records were reviewed for risk factors associated with HCV infection. Follow-up was available on 70 recipients of organs from 42 ELISA2 positive donors. The prevalence of HCV RNA, extrapolated to all 3078 donors, was 2.4%. Liver disease, anti-HCV and HCV RNA were detected more frequently among recipients of organs from ELISA2 positive donors with HCV RNA than from ELISA2 positive donors without HCV RNA. Among donors, the sensitivity and negative predictive value of the ELISA2 for HCV RNA were 100%. However, despite a specificity of 98.1%, the positive predictive value was only 55.1%. Clinical and laboratory characteristics did not distinguish ELISA2 positive donors with and without HCV RNA. The presence of serum HCV RNA in organ donors predicts the risk of transmission of HCV infection. Discarding organs from ELISA2 positive donors would eliminate transmission, but organs from 1.88 percent of donors would be wasted.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1994PC21700036
View details for PubMedID 7527878
A CELL-SURFACE PROTEIN THAT BINDS AVIAN HEPATITIS-B VIRUS-PARTICLES
JOURNAL OF VIROLOGY
1994; 68 (4): 2091-2096
We have identified a 180-kDa cellular glycoprotein (gp180) that binds with high affinity to duck hepatitis B virus (DHBV) particles. The protein was detected by coprecipitating labeled duck hepatocyte proteins with virions or recombinant DHBV envelope proteins, using nonneutralizing monoclonal antibodies to the virion envelope. Binding of gp180 requires only the pre-S region of the viral large envelope protein, since recombinant fusion proteins bearing only this region efficiently coprecipitate gp180. The DHBV-gp180 interaction is blocked by two independent neutralizing monoclonal antibodies. The protein is found on both internal and surface membranes of the cell, and the species distribution of gp180 binding activity mirrors the known host range of DHBV infection. Functional gp180 is expressed in a wide variety of tissues in susceptible ducks.
View details for Web of Science ID A1994NA30700007
View details for PubMedID 8138993
LONGITUDINAL-STUDY OF HEPATITIS-C VIREMIA IN CHRONIC HEPATITIS-C
JOURNAL OF MEDICAL VIROLOGY
1993; 41 (4): 338-342
Serial serum samples from 20 untreated patients with chronic hepatitis C virus (HCV) infection were tested for HCV RNA by a nested polymerase chain reaction assay using primers from the highly conserved 5' noncoding region to determine the relationship between hepatitis C viremia and the activity of liver disease during the natural course of chronic HCV infection. Semiquantitation of serum HCV RNA level was achieved by testing serial 10-fold dilutions of RNA extracts to determine the end-point titer. All the patients were HCV RNA positive at presentation. There was a poor correlation between the initial HCV RNA titer and serum transaminase levels. All patients except one were persistently HCV RNA positive during a follow-up period of 1.5-15 years, although 17 (85%) had periods of normal or near-normal transaminase levels. There was no correlation between changes in the serum transaminase levels and HCV RNA titer. Patients with chronic HCV infection have persistent viremia despite fluctuations in ALT levels.
View details for Web of Science ID A1993MJ71700014
View details for PubMedID 8106870
HEPATITIS-C VIREMIA IN PATIENTS WITH HEPATITIS-C VIRUS-INFECTION
1992; 15 (6): 1007-1012
Sera from 103 patients were tested for hepatitis C virus RNA by nested polymerase chain reaction assay. Using primers from the highly conserved 5'-untranslated region, we detected hepatitis C virus RNA in 67 (88.2%) of 76 patients positive for antibody to hepatitis C virus by both second-generation and neutralization enzyme immunoassays. Hepatitis C virus RNA was detected in 93% of patients who had been infected for 10 yr or less and in 89% of those who had been infected for longer than 10 yr. Hepatitis C virus RNA was detected in all patients with chronic hepatitis, active cirrhosis or hepatocellular carcinoma and in 50% of those with nonspecific reactive hepatitis or inactive cirrhosis. Hepatitis C virus RNA was not detected in sera from 22 patients negative for antibody to hepatitis C virus or in 5 patients positive for antibody to hepatitis C virus by second-generation but not by neutralization enzyme immunoassay. Using primers from the less conserved nonstructural region 4, we detected hepatitis C virus RNA at a lower frequency, in 66% of patients who were positive for antibody to hepatitis C virus by both second-generation and neutralization enzyme immunoassays. The detection rate was higher in patients with frequent parenteral exposure. Our study showed that hepatitis C viremia can be detected in most patients with hepatitis C virus infection, including those with long-standing infection or advanced liver disease.
View details for Web of Science ID A1992HX53200005
View details for PubMedID 1317337
PEPTIDE-MAPPING OF NEUTRALIZING AND NONNEUTRALIZING EPITOPES OF DUCK HEPATITIS-B VIRUS PRE-S POLYPEPTIDE
1991; 181 (1): 14-21
Antibodies to the envelope proteins of duck hepatitis B virus neutralize viral infection in vitro. Using a library of murine monoclonal antibodies (Mabs) against the envelope proteins, we previously identified four neutralizing and two non-neutralizing epitopes on the pre-S region of the large envelope proteins. In this study we report the localization of all but one of these epitopes at the amino acid level. All but 28 nucleotides of the pre-S and S genes were cloned in pUC vectors and expressed in Escherichia coli. All Mabs in this study reacted with the expressed gene products in Western blots. Deletion mutants of the pre-S region were generated and their expressed products tested on Western blots for reactivity with the Mabs. Of the three epitopes involved in neutralization, the epitope found to be immunodominant in convalescent ducks was localized to nine amino acids of the middle portion of the pre-S gene product, while a second epitope was mapped to nine amino acids upstream of the immunodominant epitope and the third epitope to seven amino acids adjacent to the S gene. One of the two non-neutralizing epitopes was located between the two groups of neutralizing epitopes while the other mapped to the same region as one of the neutralizing epitopes. Our data indicate that several regions of the pre-S polypeptide may play a role in neutralization of hepadnaviruses.
View details for Web of Science ID A1991EW94200002
View details for PubMedID 1704654
EPITOPE-SPECIFIC ANTIBODY-RESPONSE TO THE SURFACE-ANTIGEN OF DUCK HEPATITIS-B VIRUS IN INFECTED DUCKS
1990; 176 (2): 546-552
In order to investigate the immune response to duck hepatitis B virus (DHBV) infection, newly hatched DHBV DNA negative ducklings were injected with infectious serum of sufficiently low DHBV-DNA titer to allow clearance of viremia. Of 20 injected ducklings, 13 (65%) became viremic. Of these, 6 (46%) cleared virus from the serum 3 to 22 weeks postinjection. The convalescent sera of these 6 animals were tested for an epitope-specific antibody response in a highly specific competitive inhibition assay using a panel of monoclonal antibodies against duck hepatitis B surface antigen (DHBsAg) that had been well-characterized. All 6 animals recovering from DHBV infection developed antibodies to epitopes on the preS and S proteins of DHBV. Antibody responses were highly variable with marked differences between animals in the extent and specificity of the antibody response. The humoral response to DHBsAg was prolonged in some animals but transient in others. No antibody to preS or S was detected in either preimmune sera or sera of control animals from an uninfected flock. Infected animals that did not clear viremia also remained antibody negative. The humoral responses to neutralizing preS epitopes III and V were weak but antibodies to two immunodominant epitopes on the preS region (II and B) were present in all 6 animals. The humoral response to the two epitopes in the S region was transient and of lower titer when compared to the two immunodominant preS epitopes. The two immunodominant preS epitopes may play an important role in clearance of DHBV infection in ducks.
View details for Web of Science ID A1990DF12300025
View details for PubMedID 1693247
EPITOPE MAPPING OF NEUTRALIZING MONOCLONAL-ANTIBODIES AGAINST DUCK HEPATITIS-B VIRUS
JOURNAL OF VIROLOGY
1989; 63 (6): 2445-2451
In this article we report the first topological mapping of neutralizing epitopes of a hepadnavirus. Duck hepatitis B virus is the only hepadnavirus that can replicate and spread from cell to cell in tissue culture. As a result, it is possible to study hepadnaviral neutralization in vitro with this system. To accomplish this goal, we produced a library of monoclonal antibodies against duck hepatitis B virus and identified 12 neutralizing monoclonal antibodies by using an in vitro neutralization assay. The characteristics of six of the neutralizing monoclonal antibodies were further studied by epitope mapping. From the results of competitive binding studies, three distinct neutralizing epitopes were identified on the pre-S polypeptides and one was identified on the S polypeptide. Our findings suggest that antibodies to both the pre-S and S gene products of duck hepatitis B virus can neutralize viral infection in vitro. The pre-S gene product is at least as important as the S gene product in eliciting neutralizing antibodies.
View details for Web of Science ID A1989U609600005
View details for PubMedID 2470915
Quantitative analysis of hepatitis C virus in peripheral blood and liver: Replication detected only in liver
UNIV CHICAGO PRESS. 2001: 827-835
Prior studies seeking evidence of viral replication in peripheral lymphocytes of hepatitis C virus (HCV)-infected patients have yielded conflicting results. This study sought to quantitatively determine whether a permissive HCV cell interaction could be detected in leukocytes from infected patients. Peripheral leukocytes from chronically infected patients were purified and were tested for HCV RNA. The results show that virus load is highest in B cells. Other subsets of peripheral leukocytes consistently had very low levels of viral RNA or were negative. Negative-strand HCV was found only in hepatocytes. To determine whether HCV replication could be induced by activation, B cells from HCV-infected patients were stimulated in vitro. No HCV replicating in peripheral leukocytes was detected by a highly sensitive assay. If HCV replication occurs in the leukocyte subsets analyzed here, it is at extremely low levels or occurs under alternate physiological conditions.
View details for Web of Science ID 000171228400003
View details for PubMedID 11550124