Yi-g Chen

Age-specific prognosis following spontaneous hepatitis B e antigen seroconversion in chronic hepatitis B.

Hepatitis B e antigen (HBeAg) seroconversion in chronic hepatitis B virus infection confers a favorable prognosis, but untoward outcomes may develop in some patients. The impact of the age of HBeAg seroconversion on prognosis is not clearly known. HBeAg‐positive patients with biopsy‐proven chronic hepatitis B were followed up long‐term. Follow‐up studies included liver biochemistry, alpha‐fetoprotein, and ultrasonography every 3 to 6 months or more frequently if clinically indicated. Of the patients who underwent spontaneous HBeAg seroconversion, the incidences of HBeAg‐negative hepatitis, cirrhosis, hepatocellular carcinoma (HCC), and hepatitis B surface antigen seroclearance were compared between patient groups with different ages at the time of HBeAg seroconversion using Kaplan–Meier survival analysis and Poisson regression model. Spontaneous HBeAg seroconversion was documented in 508 patients. Of the 483 patients who had no evidence of cirrhosis or HCC at the time of HBeAg seroconversion, HBeAg seroconversion occurred before age 30 in 218 patients (group A), between age 31 and 40 in 199 patients (group B), and after age 40 in 66 patients (group C). The 15‐year cumulative incidences of HBeAg‐negative hepatitis, cirrhosis, and HCC increased with increasing age of HBeAg seroconversion, the lowest being in group A (31.2%, 3.7%, and 2.1%, respectively) and highest being in group C (66.7% [P < 0.0001], 42.9% [P <0.0001], and 7.7% [P = 0.29], respectively). The hazard ratio of HBeAg‐negative hepatitis, cirrhosis, and HCC was 2.95, 17.6, and 5.22, respectively, in group C compared with group A. Conclusion: Patients with HBeAg seroconversion before age 30 have excellent prognosis, whereas patients with delayed HBeAg seroconversion after age 40 have significantly higher incidences of HBeAg‐negative hepatitis, cirrhosis, and HCC. (HEPATOLOGY 2010.)

Natural course following the onset of cirrhosis in patients with chronic hepatitis B: a long-term follow-up study

PurposeTo elucidate the long-term natural course following the onset of cirrhosis in patients with chronic hepatitis B.MethodsNinety-three patients with chronic hepatitis B who had developed cirrhosis during regular follow-up were included in this long-term follow-up study. At the time of cirrhosis detection, 30% of the patients were seropositive for hepatitis B e antigen (HBeAg) and 73% had a HBV-DNA level >104xa0copies/ml. Follow-up studies included liver biochemistry, viral markers, α-fetoprotein and ultrasonography every 3–6xa0months.ResultsDuring a mean follow-up period of 102xa0±xa060 (12–246; median 97) months, 32 patients (34.4%) experienced 55 episodes of hepatitis flare (7.0%/year), 15 (53.6%) of 28 HBeAg-positive patients seroconverted to anti-HBe (6.3%/yr) and 12 (12.9%) lost HBsAg (1.5%/year). Overall disease progression was observed in 25 (26.9%, 3.2%/year) patients: 12 (12.9%, 1.5%/year) hepatic decompensation, 21 (22.6%, 2.7%/year) hepatocellular carcinoma and 11 (11.8%, 1.4%/year) died. Multivariate analysis showed that age at onset of cirrhosis (Pxa0=xa00.015) and persistent HBeAg seropositivity (Pxa0=xa00.019) were the independent factors for overall disease progression.ConclusionsThese results suggest that patients with older age at onset of cirrhosis and persistent HBeAg seropositivity following the onset of cirrhosis were independent factors for the disease progression in the first 10-year after the development of cirrhosis in patients with chronic hepatitis B.

Decreasing Levels of HBsAg Predict HBsAg Seroclearance in Patients With Inactive Chronic Hepatitis B Virus Infection

BACKGROUND & AIMSnSerum levels of hepatitis B surface antigen (HBsAg) decrease gradually during chronic hepatitis B virus infection. We investigated the association between levels of HBsAg and HBsAg seroclearance.nnnMETHODSnWe studied data from 46 patients who underwent spontaneous seroclearance of HBsAg (median age at seroclearance, 48 y; 87% male; 76% infected with genotype B). There were 46 controls matched for age, sex, and hepatitis B virus genotype, and e antigen status with persistently normal levels of alanine aminotransferase and seropositive for HBsAg. Levels of HBsAg were assessed in serum specimens collected 5 years 3 years, and 1 year before HBsAg seroclearance (or before the last examination, for controls).nnnRESULTSnThe decrease in HBsAg level was significant and accelerated within the 3 years before HBsAg seroclearance; there was no significant decrease in serum level of HBsAg among controls (P < .0001). The positive predictive value (PPV) for HBsAg seroclearance within 1 year was 36% among patients with HBsAg levels of 200 IU/mL, increasing to 44%, 54%, and 67% among patients with HBsAg levels of 100 IU/mL, 50 IU/mL, or 10 IU/mL, respectively; the negative predictive value (NPV) for these levels was 96% or greater. The combination of HBsAg level less than 200 IU/mL and a decrease of 1 or more log(10) IU/mL in a preceding 2-year period had PPVs of 97% and 100% for HBsAg seroclearance at 1 and 3 years, respectively; the NPVs were 100% and 92%, respectively.nnnCONCLUSIONSnThe decrease in the level of HBsAg accelerates during the 3 years before HBsAg seroclearance. Levels of HBsAg of 200 IU/mL or less have high NPVs for HBsAg seroclearance; PPVs increase to 97% to 100% when combined with a 1 log IU/mL or more decrease in level of HBsAg over a 2-year period.

Blockade of TNF-α signaling benefits cancer therapy by suppressing effector regulatory T cell expansion

Effector but not naive regulatory T cells (Treg cells) can accumulate in the peripheral blood as well as the tumor microenvironment, expand during tumor progression and be one of the main suppressors for antitumor immunity. However, the underlying mechanisms for effector Treg cell expansion in tumor are still unknown. We demonstrate that effector Treg cell-mediated suppression of antitumor CD8+ T cells is tumor-nonspecific. Furthermore, TNFR2 expression is increased in these Treg cells by Affymetrix chip analysis which was confirmed by monoclonal antibody staining in both hepatocellular carcinoma (HCC) and colorectal cancer (CRC) patients and murine models. Correspondingly, increased levels of TNF-α in both tissue and serum were also demonstrated. Interestingly, TNF-α could not only expand effector Treg cells through TNFR2 signaling, but also enhanced their suppressive activity against antitumor immunity of CD8+ T cells. Furthermore, targeting TNFR2 signaling with a TNF-α inhibitor could selectively reduce rapid resurgence of effector Treg cells after cyclophosphamide-induced lymphodepletion and markedly inhibit the growth of established tumors. Herein, we propose a novel mechanism in which TNF-α could promote tumor-associated effector Treg cell expansion and suggest a new cancer immunotherapy strategy using TNF-α inhibitors to reduce effector Treg cells expansion after cyclophosphamide-induced lymphodepletion.

Level of Hepatitis B Virus DNA in Inactive Carriers With Persistently Normal Levels of Alanine Aminotransferase

BACKGROUND & AIMSnLittle is known about the level of hepatitis B virus (HBV) DNA in individuals with chronic, inactive HBV infections. Patients who test positive for the antibody to hepatitis B e antigen (anti-HBe) and have normal levels of alanine aminotransferase for more than 10 years have a low risk of HBV reactivation and are considered to be inactive carriers. We investigated HBV DNA levels in inactive carriers and identified factors that correlated with this state among anti-HBe-positive carriers with HBV DNA levels of 10(4) copies/mL or greater (5.26 copies/mL = 1 IU/mL).nnnMETHODSnHBV DNA levels were assayed in 250 inactive carriers with persistently normal alanine aminotransferase levels for more than 10 years. Clinical and virologic features were compared between inactive carriers (with HBV DNA levels > or =10(4) copies/mL) and age-matched patients with HBe antigen-negative chronic hepatitis (controls, n = 90).nnnRESULTSnThe median level of HBV DNA among inactive carriers was 3.70 log(10) copies/mL (range, undetectable to 5.98 log(10) copies/mL). Ninety (36%) had levels of 10(4) copies/mL or greater. Compared with control patients, significant differences of inactive carriers included sex (more female patients), lower HBV DNA levels, and lower prevalence of genotype C virus and the basal core promoter mutation T1762/A1764. The prevalence of the precore mutation A1896 was similar between groups. Multiple logistic regression analyses identified male sex, HBV DNA levels greater than 10(5) copies/mL, and the basal core promoter mutation as independent factors that correlated with active disease.nnnCONCLUSIONSnNearly 40% of inactive carriers had HBV DNA levels of 10(4) copies/mL or greater. Female sex, HBV DNA levels of 10(4) to 10(5) copies/mL, and wild-type basal core promoter correlated with inactive carrier state.

Fine-needle aspiration cytology to distinguish dysplasia from hepatocellular carcinoma with different grades

Background:u2002 Distinguishing dysplasia from hepatocellular carcinoma (HCC) by fine‐needle aspiration (FNA) cytology is difficult. The aim of this study was to diagnose HCC and the distinction of liver cell dysplasia from HCC with different grades by interpreting and scoring the cyto‐morphological features.

Treatment of Hepatocellular Carcinoma Using Internally Cooled Electrodes

Objectives: To compare the effectiveness of modified automated and manual pulsed radiofrequency (RF) algorithms using internally cooled electrodes for hepatocellular carcinoma (HCC). Methods: Seventy-seven treatment-naive cirrhotic patients with 102 HCC (≤4 cm) underwent 109 sessions of ultrasound-guided percutaneous RF ablation using a 17-gauge, 20-cm-long, single internally cooled electrode. Patients were assigned alternatively: 40 patients to the modified automated algorithm group and 37 patients to the manual algorithm group. The mean tumor diameters were 2.34 ± 0.9 and 2.25 ± 0.7 cm in the automated and manual groups, respectively (p = 0.56). Primary technique effectiveness and local tumor progression were compared between the two groups. Results: More overlapping ablations (n = 112) were required in the manual than in the automated group (n = 82) to achieve similar primary technique effectiveness rates of 96.1 and 94.1%, respectively. After a mean follow-up period of 26.7 ± 1.1 months, the local tumor progression rates at 12 and 18 months were 4 and 20% in the manual group and 12 and 24% in the modified automated group (p = 0.3). Only tumors >3 cm were independently associated with local tumor progression (odds ratio 1.25; 95% CI 1.06–2.34, p = 0.03). Conclusions: The manual algorithm requires more overlapping ablations and treatment sessions in order to achieve similar primary technique effectiveness and local tumor progression rates compared with the modified automated algorithm.

α-Fetoprotein level-dependent early hepatitis B surface antigen decline during entecavir therapy in chronic hepatitis B with hepatitis flare

OBJECTIVESnHepatitis B surface antigen (HBsAg) reduction during nucleos(t)ide analogue therapy is related to ALT level. ALT reflects hepatocytolysis while α-fetoprotein (AFP) ≥100 ng/mL during hepatitis flare reflects more extensive hepatocytolysis (bridging hepatic necrosis). The impact of AFP levels on early HBsAg kinetics during entecavir therapy was investigated.nnnMETHODSnHBsAg level was measured at baseline and months 6 and 12 of entecavir therapy in 149 chronic hepatitis B patients with hepatitis flare, defined as ALT ≥5× upper limit of normal (ULN), and 58 patients with ALT <5× ULN.nnnRESULTSnThere was a significantly greater HBsAg reduction in an ALT (<5, 5-10, 10-20 and ≥20× ULN, Pu200a=u200a0.001) and AFP (<20, 20-99 and ≥100 ng/mL, Pu200a=u200a0.000) level-dependent manner. In hepatitis flares with a peak AFP level ≥20 ng/mL, the differences in HBsAg reduction across all ALT levels became non-significant. HBsAg reduction was greater in genotype B- than genotype C-infected patients with baseline ALT ≥20× ULN, but the difference became non-significant in those with peak AFP ≥100 ng/mL. Multivariate linear regression analysis showed that AFP level ≥100 ng/mL, baseline HBsAg level and genotype B were independent significant factors for greater HBsAg decline at month 6 of entecavir therapy.nnnCONCLUSIONSnDuring entecavir therapy, early HBsAg reduction increased in an AFP and ALT level-dependent manner, suggesting the impact of hepatocytolysis rather than nucleos(t)ide analogue per se. Notably, a higher AFP level during hepatitis flare, reflecting more extensive hepatic necrosis, was a more powerful factor than ALT and genotype for greater HBsAg decline.

Pharmacotherapeutic options for hepatitis B

ABSTRACT Introduction: Hepatitis B virus (HBV) is the driving force of disease progression in chronic hepatitis B. Patients with active HBV replication and/or significant liver disease require timely treatment. Currently, pegylated interferon-α (PEG IFN), entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are the preferred first-line drugs.Areas covered: A finite course IFN-based therapy has modest response and may reduce cirrhosis or hepatocellular carcinoma development. Nucleos(t)ide analogs (Nuc) have excellent safety profile, cumulative or maintained response and long-term efficacy in terms of reduction or reversal of fibrosis, decrease in development of cirrhosis and its adverse sequalae. The optimal duration of Nuc therapy is unknown and a feasible stopping rule with off-therapy monitoring plan has been developed.Expert opinion: Choosing a drug to initiate therapy in a right patient at a right time should be primarily based on the prospect and likelihood for improved outcomes. Nuc is the only choice for patients with hepatic decompensation, pregnant women and those about to receive immune/chemotherapy or organ transplantation. IFN-based therapy is preferred in patients with compensated liver disease, particularly in young patients, females of childbearing age. The development of new drugs and new strategies is the highest priority in further improving the outcomes of treatment.

Durability of Telbivudine-Associated Improvement of Renal Function Following Withdrawal or Switching of Antivirals in Chronic Hepatitis B Patients

Abstract Background Besides antiviral activities against hepatitis B virus (HBV), telbivudine has an extrahepatic pharmaceutical effect: to improve renal function assessed by estimated glomerular filtration rate (eGFR). However, the durability of this effect after withdrawal of telbivudine or switching to other antivirals has never been investigated. Methods We conducted a postmarketing, real-world observation study for telbivudine treatment. The durability of telbivudine-associated renal function improvement was examined following withdrawal/switching of antivirals. Results Of 160 telbivudine-treated, chronic hepatitis B patients, 21, 6, and 2 patients were loss to follow-up, dead, and pregnant during the study, respectively. Of the remaining 131 patients, 26, 47, 28, and 30 patients experienced telbivudine withdrawal, continuous use of telbivudine, switching to entecavir, or switching to tenofovir, respectively. During the first 2 years, eGFR in telbivudine-treated patients significantly improved before withdrawal/switching of antivirals (P = .009). Thereafter, eGFR remained unchanged for >1 year in the withdrawal (P = .100) and continuous use (P = .517) subgroups, but decreased significantly in the switching to entecavir (P = .002) and switching to tenofovir (P < .001) subgroups. Multivariate logistic regression analysis revealed that switching to tenofovir and poor liver functional reserve were predictors for eGFR deterioration. Conclusions Telbivudine-associated renal function improvement was durable after withdrawal or continuous use of telbivudine. However, renal function deteriorated if patients were switched to entecavir or tenofovir.