Vincent G. Nguyen

Reduction of chronic hepatitis B-related hepatocellular carcinoma with anti-viral therapy, including low risk patients

Anti‐viral therapy in chronic hepatitis B (CHB) is associated with a reduced risk of hepatocellular carcinoma (HCC) primary described in patients with cirrhosis.

Hepatocellular carcinoma incidence in noncirrhotic patients with chronic hepatitis B and patients with cirrhosis of all etiologies.

Background: Hepatocellular carcinoma (HCC) causes approximately a half million deaths annually with the majority related to chronic hepatitis B (CHB) and cirrhosis. Results on HCC incidence in CHB patients without cirrhosis are conflicting. Goals: This study aimed to examine HCC incidence in 2 high-risk groups: (1) patients with noncirrhotic CHB and 45 years of age or older; and (2) patients with cirrhosis of all etiologies and any age. Results: Through electronic query using ICD-9 diagnosis codes for CHB and cirrhosis (070.32 and 571.5, respectively) between January 2001 and January 2008, a total of 949 patients with 12 months of follow-up or longer were identified and reviewed. Over 4231.5 person-years of observation, HCC developed in 15 of the 741 noncirrhotic CHB patients and 30 of the 208 cirrhotic patients. Male and female noncirrhotic CHB patients had significantly lower annual HCC incidences than those found in male and female patients with cirrhosis regardless of etiologies (0.7% vs. 4.1%, P<0.0001 and 0.1% vs. 2.7%, P<0.0001). Annual HCC incidence increased significantly with age in both sexes of noncirrhotic CHB patients. In noncirrhotic CHB patients, annual HCC incidence was very low in young females, but increased to 0.3% to 0.4% in females 55 years of age or older. An HCC incidence rate of 1.1% per year was seen in noncirrhotic CHB men aged 55 or older. Conclusions: Although annual HCC incidence in cirrhotic patients did not differ significantly among different age groups, rates among noncirrhotic patients were significantly higher in older patients and up to 1.1% in males above 55 years.

Treatment Eligibility of Patients With Chronic Hepatitis B Initially Ineligible for Therapy

BACKGROUND & AIMS Chronic hepatitis B (CHB) is a dynamic disease, therefore patients initially ineligible for treatment, based on current guidelines, often become eligible at some point during their follow-up evaluation. We investigated the reasons for this change and developed a timeline for treatment eligibility for this population. METHODS We performed a retrospective cohort study of 245 consecutive treatment-naive, community-based patients with CHB who were not eligible for treatment when they first presented, from March 2007 through June 2010 (mean age, 44 y, almost all Asian). The patients were followed up for a median period of 26 months, receiving standard laboratory tests. They were treated according to US panel 2008 and American Association for Liver Disease (AASLD) 2009 guidelines. RESULTS Fifty-four patients (22%) became eligible for treatment during the follow-up period; most of these (n = 47; 87%) were based on only the US Panel algorithm and the rest were based on AASLD guidelines (n = 7; 13%). Six percent of patients met the treatment criteria at 1 year, 18% at 2 years, and 29% at 3 years. Among hepatitis B e antigen-positive patients with levels of hepatitis B virus (HBV) DNA greater than 3 log IU/mL at baseline, 11% met treatment criteria at 1 year, 52% at 2 years, and 80% at 3 years. Based on Cox multivariate analysis, which included age; sex; and levels of hepatitis B e antigen, alanine aminotransferase, and HBV DNA, an increase in HBV DNA level was the only factor from the US panel associated with treatment eligibility (hazard ratio, 1.43; P < .001), and an increase in alanine aminotransferase was the only factor associated with treatment eligibility from the AASLD guidelines (hazard ratio, 1.03; P = .001). CONCLUSIONS Although most patients with CHB who initially are not eligible for treatment remain ineligible, almost 30% become eligible within 3 years. These findings indicate the importance of carefully following disease status in patients with CHB.

Lower liver cancer risk with antiviral therapy in chronic hepatitis B patients with normal to minimally elevated ALT and no cirrhosis

Abstract For chronic hepatitis B (CHB), alanine aminotransferase (ALT) ≥2 × upper limit of normal (ULN) is often used as a major criteria to initiate treatment in absence of cirrhosis, though patients with lower ALT may not be free from future risk of hepatocellular carcinoma (HCC). We aimed to examine the effect of antiviral therapy on HCC incidence based on ALT levels. We performed a retrospective study on 3665 patients consisting of United States and Taiwanese REVEAL-HBV cohort who were consecutive, treatment-naïve, noncirrhotic CHB patients aged ≥40 years. Patients were categorized by ALT cutoffs (≥2 × ULN vs <2 × ULN) and subgrouped by treatment status. Kaplan–Meier and Cox proportional hazards models were used to calculate cumulative incidence and hazard ratio (HR) of HCC adjusting for REACH-B scores. A total of 202 patients developed HCC. Antiviral treatment significantly reduced HCC risk: HR 0.24, 95% confidence interval 0.10–0.58; P = 0.001. HCC incidence per 100,000 person-years was significantly higher in untreated versus treated patients, even for those with ALT < 2 × ULN: 314.46 versus 0 per 100,000 person-years, P = 0.0042. For patients with Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) ≥ 2000 IU/mL, the number-needed-to-treat (NNT) were 15 and 14 to prevent 1 incident HCC at year 10 for patients with ALT < 2 × ULN and ≥2 × ULN, respectively. After adjustment by REACH-B score, antiviral treatment significantly decreased HCC incidence even in patients with ALT < 2 × ULN. NNT to prevent 1 incident HCC after 10 years of therapy was low (14–15) in patients with mildly elevated HBV DNA ≥ 2000 IU/mL regardless of ALT levels.

Chronic hepatitis B treatment eligibility and actual treatment rates in patients in community gastroenterology and primary care settings.

Goals: This study aims to compare the eligibility and treatment rates of patients evaluated by gastroenterology [gastrointestinal (GI)] specialists for chronic hepatitis B (CHB) and patients followed by their primary care physicians (PCPs) only. Background: Guidelines have been devised to direct the care of patients with CHB but data on the application of these guidelines, especially in primary care settings, has been limited to date. Study: Consecutive CHB patients were enrolled retrospectively from several community clinics in the San Francisco Bay Area: 2 GI referral clinics, 3 primary care clinics, and a multispecialty medical center. Patients were classified as group 1 if they saw a gastroenterologist for CHB within 6 months of presentation or as group 2 if they only saw PCPs. Eligibility according to AASLD 2009 and US Panel 2008 guidelines was determined using clinical and laboratory data available within 6 months of presentation. Results: Patients in group 2 had lower eligibility rates according to both US Panel 2008 (32% vs. 51%, P<0.001) and AASLD 2009 (8% vs. 24%, P<0.001) guidelines. GI specialists treated US Panel–eligible patients more readily than PCPs (45% vs. 25%, P<0.001), and treatment rates in AASLD-eligible patients suggested a similar trend (68% vs. 50%, P=0.080). Conclusions: GI specialists were more likely than PCPs to see patients who were treatment eligible, and also more likely to initiate antiviral therapy. However, there are still a considerable number of patients from both settings who did not receive treatment despite being eligible.

Su1286 Differences Between Community and Academic Cohorts of Patients With Chronic Hepatitis B (CHB) in the Development of Hepatocellular Carcinoma (HCC)

G A A b st ra ct s CI = 19%-27%) for patients receiving only supportive care, 39% (95% CI = 32%-46%) for those receiving liver-directed palliative therapy, 61% (95%CI = 51%-70%) for those undergoing partial hepatectomy, and 77% (95% CI = 71%-82%) for those having a liver transplantation. In multivariate analysis (Table), independent predictors for improved survival were non-White/non-Black race, palliative as well as surgical treatment. Independent predictors for poorer survival were age older than 65 and Black race (compared toWhites). Conclusions: In spite of improved opportunity for both effective palliative and curative therapies in the recent years, almost half of patients meeting Milan criteria are still not undergoing any therapy. In addition to assessing the efficacy and survival impact of current therapies, it is also important to focus on why so many patients diagnosed with HCC are not undergoing any treatment and reasons for continued existence of racial disparities. Early diagnosis through better screening protocols together with patient and physician education is crucial to achieve better outcomes. Multivariate Cox Proportional Hazards Model Assessing Factors Associated with Survival

Sa1005 Antiviral Treatment Eligibility and Treatment Rates in Patients With Chronic Hepatitis B (CHB) At Primary Care, Community and University Referral Clinics: A Comparative Study

Background: Liver cirrhosis is inevitable outcome triggered by consistent chronic inflammation. Recent studies have implied that liver cirrhosis accompanied with angiogenesis. Our previous studies demonstrated that celecoxib could reduce angiogenesis in hepatocellular carcinoma and gastric adenocarcinoma. However, the effect of celecoxib on the antiangiogenesis of cirrhotic liver is still controversial. Objective: To investigate the effect of celecoxib on angiogenesis of cirrhotic liver. Methods: Peritoneal injection of thiacetamide (TAA) was employed to induce liver cirrhosis (200 mg/kg every three days × 16 weeks). 36 male Sprague-Dawley rats were assigned to three groups: group 1 (TAA + celecoxib, n = 12) received TAA plus celecoxib (20 mg/kg/day) by gavage from the initiation of TAA administration on, group 2 (TAA, n = 12) received TAA plus placebo and group 3 (Control, n = 12) received injections of 0.9% saline (1mL i.p., every three days). Serum biochemistry for liver and kidney function parameters and serum prostaglandin E2 (PGE2) were determined. Portal pressure and mean artery pressure were also measured. Histopathological study and vascular casting by scanning electron microscope (SEM) of liver vascular were performed. Additionally, immunohistochemistry (IHC), quantitative real-time PCR (qRT-PCR) and western blot for CD31, vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR2), and Cyclooxygenase-2 (COX-2) were determined. Results: Compared with TAA group, the fibrotic areas of liver tissues in TAA+celecoxib group were significantly decreased by one fold (20.8 ± 1.5% vs. 10.6 ± 0.9%, p , 0.001). Histological sections, vascular casts of hepatic portal vein by SEM, IHC and qRT-PCR for CD31 showed that hepatic fibrosis was accompanied with significant neoangiogenesis in TAA group when compared with Control group (0.1502 ± 0.0143 vs. 0.0325 ± 0.0086 mm2, p , 0.001). Impressively, the increased vascular areas were greatly reduced after celecoxib treatment (0.0485 ± 0.0097 vs. 0.1502 ± 0.0143 mm2, p , 0.001). The up-regulation of VEGF and VEGFR-2, COX-2 and PGE2 induced by TAA administration were significantly inhibited after celecoxib treatment. Compared with TAA group, the portal pressure in TAA+celecoxib group was significantly decreased by 17.8% (14.88 ± 0.84 vs. 12.23 ± 1.09 mmHg, p , 0.001). No significant differences in arterial pressure, heart rate and liver and kidney function parameters were observed among three groups (p . 0.05). Conclusions: Anti-angiogenesis therapy with celecoxib ameliorated hepatic angiogenesis, portal pressure as well as fibrosis. This result suggested that celecoxib would be beneficial for the treatment of liver cirrhosis.

Sa1006 Effectiveness of Oral Antiviral Therapy for Treatment-Naive Chronic Hepatitis B (CHB) in Routine Clinical Practice

Background: Liver cirrhosis is inevitable outcome triggered by consistent chronic inflammation. Recent studies have implied that liver cirrhosis accompanied with angiogenesis. Our previous studies demonstrated that celecoxib could reduce angiogenesis in hepatocellular carcinoma and gastric adenocarcinoma. However, the effect of celecoxib on the antiangiogenesis of cirrhotic liver is still controversial. Objective: To investigate the effect of celecoxib on angiogenesis of cirrhotic liver. Methods: Peritoneal injection of thiacetamide (TAA) was employed to induce liver cirrhosis (200 mg/kg every three days × 16 weeks). 36 male Sprague-Dawley rats were assigned to three groups: group 1 (TAA + celecoxib, n = 12) received TAA plus celecoxib (20 mg/kg/day) by gavage from the initiation of TAA administration on, group 2 (TAA, n = 12) received TAA plus placebo and group 3 (Control, n = 12) received injections of 0.9% saline (1mL i.p., every three days). Serum biochemistry for liver and kidney function parameters and serum prostaglandin E2 (PGE2) were determined. Portal pressure and mean artery pressure were also measured. Histopathological study and vascular casting by scanning electron microscope (SEM) of liver vascular were performed. Additionally, immunohistochemistry (IHC), quantitative real-time PCR (qRT-PCR) and western blot for CD31, vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR2), and Cyclooxygenase-2 (COX-2) were determined. Results: Compared with TAA group, the fibrotic areas of liver tissues in TAA+celecoxib group were significantly decreased by one fold (20.8 ± 1.5% vs. 10.6 ± 0.9%, p , 0.001). Histological sections, vascular casts of hepatic portal vein by SEM, IHC and qRT-PCR for CD31 showed that hepatic fibrosis was accompanied with significant neoangiogenesis in TAA group when compared with Control group (0.1502 ± 0.0143 vs. 0.0325 ± 0.0086 mm2, p , 0.001). Impressively, the increased vascular areas were greatly reduced after celecoxib treatment (0.0485 ± 0.0097 vs. 0.1502 ± 0.0143 mm2, p , 0.001). The up-regulation of VEGF and VEGFR-2, COX-2 and PGE2 induced by TAA administration were significantly inhibited after celecoxib treatment. Compared with TAA group, the portal pressure in TAA+celecoxib group was significantly decreased by 17.8% (14.88 ± 0.84 vs. 12.23 ± 1.09 mmHg, p , 0.001). No significant differences in arterial pressure, heart rate and liver and kidney function parameters were observed among three groups (p . 0.05). Conclusions: Anti-angiogenesis therapy with celecoxib ameliorated hepatic angiogenesis, portal pressure as well as fibrosis. This result suggested that celecoxib would be beneficial for the treatment of liver cirrhosis.

Tu1018 Chronic Hepatitis B (CHB) Management Based on Standard Guidelines: Primary Care Physicians (Pcp) and Specialist Care Examined

Purpose: Prior studies have underlined the need for increased hepatitis B screening and awareness, especially in certain high-risk populations, but few examine the prevalence of adequate evaluation and management of CHB between PCP and specialists according to standard guidelines. Our goal was to examine adherence to current guidelines on the management of CHB between primary care physicians (PCP) and specialists. Methods: We retrospectively studied 253 CHB patients who were evaluated by PCP only (n=63) or by specialist (n=190) for CHB at a community multispecialty medical center between March 2007 and June 2009. Criteria for CHB management and treatment eligibility were based on AASLD 2009 guideline and US Panel 2008 algorithm. Adequate evaluation for CHB was defined as having done testing for hepatitis B e antigen (HBeAg), HBV DNA PCR and alanine aminotransferase (ALT) six months from initial presentation. First-line antiviral agents for CHB include pegylated interferon, entecavir and tenofovir. Due to high rates of antiviral resistance, lamivudine is not a recommended first-line therapy for CHB. Results: The majority of patients were Asians (90%) and male (54%) with a mean age of 43±11.6 years. As shown in Figure 1, more patients underwent more thorough laboratory testing for CB evaluation by specialists than those seen by their PCP only. Adequate laboratory evaluation (≥3 tests) was significantly higher among specialists (62% vs. 33%, p<0.0001) (Figure 1). Compared to PCPs, specialist were more likely to order laboratory testing for ALT (94% vs. 86%, p= 0.05), HBeAg (67% vs. 41%, p<0.0001) and HBV DNA (83% vs. 52%, p<0.0001). Of those who were started on treatment by specialists (n=56, 30%) and PCPs (n=8, 13%), lamivudine was prescribed much more often by PCPs compared to specialists (33% vs. 2%, p=0.05). Conclusion: Patients evaluated by specialists for CHB are more likely to undergo more complete laboratory evaluation and if eligible, they were also more likely to be treated with newer first-line agents for CHB than those evaluated by PCP only. Long-term clinical significance of this lack of adequate evaluation in patients not evaluated by specialists should be further studied.

Mo1904 Treatment Evaluation of Chronic Hepatitis B (CHB) Patients at Tertiary Care and Community Centers

Background/Aims: Hepatitis B virus (HBV) genotypes B and C are common in Japan and have been demonstrated as one of the predictive factors associated with the progression of liver diseases. The aim of this study was to examine the changes over time in genotypes of HBV carriers in the hyperendemic area for HBV genotype B infection in Japan as well as in genotypes responsible for acute hepatitis B. Methods: We evaluated HBV genotypes in 430 HBsAg-positive HBV carriers and 34 patients with acute hepatitis B who had a medical examination at our university hospital between 1990 and 2010. The subjects were divided into two time-period groups (1990-1999 and 2000-2010) and analyzed the distribution of genotypes. In addition, the clinical and virological characteristics; ALT value, HBeAg, antiHBe antibody, IgM-HBc antibody, HBVDNA, were compared between subjects with genotype A infection and those with non-genotype A infection. Results: Of the 430 HBsAg-positive carriers, 45% had genotype B and 35% had genotype C in both time-period groups, indicating no changes in genotypes over time. Among 34 acute hepatitis B patients, the prevalence of genotype B was lower in the 2000-2009 group (1/17; 5.9%) than in the 1990-1999 group (10/17; 58.8%, p=0.012), while that of genotype A tended to have increased from 11.8% (2/17) to 29.4% (5/17) in the last 10 years. One of 7 patients with acute HBV genotype A infection did not clear HBsAg and developed to chronic infection. When Kaplan-Meier analysis was used to compare HBsAg clearance phase between the patients with or without genotype A infection, the phase was significantly longer in the genotype A patients (49 wks vs. 8 wks; p < 0.05). HBV DNA negative phase was also significantly longer in the genotype A patients (45 wks vs. 4.9 wks; p < 0.05), while the both groups showed no difference in HBeAg negative phase, anti-HBe positive phase, IgM-HBc antibody negative phase, and ALT normalization period. Conclusion: In a hyperendemic area for HBV genotype B infection in Japan, there was no large change of HBV genotypic distribution in carriers, while genotype A infection was increased in acute hepatitis B in the last 10 years. Compared to patients with acute HBV non-genotype A infection, patients with genotype A infection took a longer duration for HBsAg clearance and for achievement of HBV DNA negative status. Infection became chronic in some of the patients with infected with genotype A, suggesting that genotype distribution in HBV carriers will change in Japan in the future. It is necessary to re-examine the nation-wide study of clinical course of acute hepatitis B patients, especially infected with genotype A.