Hepatitis B virus (HBV) core antigen-specific regulatory T cells confer sustained remission to anti-HBV therapy in chronic hepatitis B with acute exacerbation.

Acute exacerbations (AEs) of chronic hepatitis B (CH-B) are thought to be the result of breakdown of immune tolerance on the natural history of chronic hepatitis B virus (HBV) infection. Immune tolerance to HBV maintained in CH-B patients without hepatitis is under the control of the host's forkhead box p3-expressing regulatory T cells (Tregs). Its breakdown mimics the occurrence of autoimmune diseases. Severe AEs may lead to liver decompensation and mortalities. Consequently, AEs are currently the major therapeutic targets in patient treatment. In this study, we employed the SYFPEITHI scoring system to identify epitopes on HBV core antigen (HBcAg) for the construction of human leukocyte antigen class II tetramers to measure HBcAg-specific Treg frequencies (Tregf). Upregulation of Treg gene profiling accompanied by increased HBcAg-specific Tregf was detected in AE patients with sustained remission (SR) to anti-HBV therapy. Depletion of Tregs from peripheral blood mononuclear cells enhanced proliferation to HBcAg. HBcAg-specific Treg clones inhibited the killing capacity of cytotoxic T lymphocyte clones in an antigen-independent manner. A greater posttherapy increase in HBcAg-specific Tregf correlated with a higher SR rate to anti-HBV therapy. These results suggest that HBcAg-specific Tregs function as suppressor effectors and confer SR to anti-HBV therapy.

Acute hepatitis E virus infection in Taiwan 2002-2006 revisited: PCR shows frequent co-infection with multiple hepatitis viruses.

Sporadic cases of acute hepatitis E virus (HEV) infection with production of anti-HEV IgM have been reported occasionally in Taiwan despite no reported outbreaks in the past. This study was undertaken to determine whether serological markers correlated with virus detection. From 2002 to 2006, 72 reported cases of acute hepatitis E seropositive for anti-HEV IgM in Taiwan were enrolled for investigation. Acute phase serum samples were collected for detection of HEV RNA, HBV DNA, HCV RNA, and GBV-C RNA by PCR. The results showed that viral sequences of HEV, HBV, HCV and GBV-C were detected in 54 (75%), 21 (29.2%), 9 (12.5%), and 22 (30.6%) of cases, respectively. Acute hepatitis A co-infection was excluded in all patients because none were seropositive for anti-HAV IgM and, nine patients (12.5%) did not seroconvert to anti-HEV IgG. These results suggest that serum markers did not correlate completely with viremia in the diagnosis of acute HEV infection. Multiple viruses may co-infect with acute hepatitis E virus in Taiwan. Detection of hepatitis E viremia together with seropositivity for anti-HEV IgM and followed by seroconversion to anti-HEV IgG should be included in the diagnostic criteria for HEV infection.

Wnt-1 protein as a prognostic biomarker for hepatitis B-related and hepatitis C-related hepatocellular carcinoma after surgery.

BACKGROUND: Up-regulation of Wnt-1 protein has been reported in hepatitis B virus (HBV)-related and hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) tissues and cell lines. It is known to play a fundamental role in signaling cancer progression, whereas its prognostic role in HCC remains unexplored. METHODS: As a prognostic biomarker, this study analyzed Wnt-1 protein expression in 63 histology-verified HCC patients receiving curative resection. In each paired tumor and nontumor specimen, Wnt-1 levels were semiquantitatively measured by Western blotting and expressed by tumor/nontumor ratio. The data were further correlated with quantitative real-time PCR as well as with beta-catenin and E-cadherin expression by immunohistochemistry. Cumulative tumor recurrence-free survival curves were constructed using the Kaplan-Meier method and compared by the log-rank test. RESULTS: The results showed that 26 (group I) and 37 (group II) HCC patients had an expression ratio of Wnt-1 > or =1.5 and <1.5, respectively. The amount of Wnt-1 estimated by tumor/nontumor ratio correlated with the results by quantitative real-time PCR. High tumor Wnt-1 expression correlated with enhanced nuclear beta-catenin accumulation, diminished membranous E-cadherin expression, and increased tumor recurrence after curative tumor resection. CONCLUSIONS: These results suggest that Wnt-1 may be used as a predisposing risk factor for HCC recurrence. The use of tumor Wnt-1 as prognostic biomarker may identify patients with HBV- and/or HCV-related HCC patients with a high risk of tumor recurrence who may then benefit from further intensive therapy after surgery.

Lamivudine monotherapy for chronic hepatitis B infection with acute exacerbation revisited.

BACKGROUND: Acute exacerbation (AE) of chronic hepatitis B virus (HBV) infection in cancer chemotherapy patients and in organ transplant recipients receiving immunosuppressants may cause catastrophe and high mortality. Hence, immediate treatment with nucleoside analogues for such patients has become a consensus. Anti-HBV therapeutic trials in Asia have shown that AE of chronic hepatitis B (CH-B) may result in increased sustained remission (SR) rate with lamivudine monotherapy. Nonetheless, AE episodes in CH-B patients may evolve uneventfully and lead to spontaneous remission. Thus, the policy of immediate anti-HBV therapy for AE patients reaches an impasse. Once treatment is initiated, life long HBV suppression may be necessary. OBJECTIVE: To determine whether lamivudine monotherapy during an AE of CH-B results in an increase in SR compared with no therapy. METHODS: A cohort of 154 CH-B patients seropositive for hepatitis B e antigen with AE formed the study group. This included 102 cases receiving a nationwide therapeutic trial of 18-month lamivudine monotherapy that were compared with 52 cases with no therapy. All were observed for at least 30 months, which encompassed the 18-month on treatment period and a 12-month posttreatment follow-up. RESULTS: No significant increase was observed in the SR rate in the lamivudine treatment group compared with the spontaneous remission rate in the untreated patients (P=0.782, Fisher's exact test). CONCLUSION: AE does not increase the SR rate during 18-month lamivudine monotherapy. Immediate lamivudine therapy for AE patients is not justified as mandatory. The policy should be only applied to AE patients with impending liver failure.

Chronic autoimmune hepatitis with Epstein-Barr virus superinfection: a case report and review of literature.

A 66-year-old female presented with acute illness of severe hepatic dysfunction. She had a past history of chronic hepatitis of low disease activity. After admission and clinical investigation including liver biopsy, it showed an underlying chronic liver disease suggestive of autoimmune hepatitis (AIH) with early liver cirrhosis. Together with other clinical features, this patient was diagnosed as definite AIH type 1 by using the IAIHG (International Autoimmune Hepatitis Group) criteria. During this episode, superinfection by Epstein-Barr virus (EBV) was evidenced by positive PCR (polymerase chain reaction) test, and serial changes of EBV VCA IgM and IgG tests. Severe hepatic impairment was evidenced by markedly elevated AST level 3090 IU/L, high bilirubin level 26.4 mg/dL, and presence of ascites. The patient gradually recovered and liver function improved in agreement with the decline of EBV VCA titers. Immunosuppressive therapy resulted in further improvement of the aminotransferases levels. This is an unusual case of EBV superinfection on pre-existing AIH with early cirrhosis, which caused enhancement of the autoimmune disease process and resulted in severe hepatic decompensation and jaundice. We herein describe the case and briefly review the literature.

Anti-sense morpholino oligonucleotide assay shows critical involvement for NF-kappaB activation in the production of Wnt-1 protein by HepG2 cells: oncology implications.

The link of proto-oncogenic protein Wnt-1 production with NF-kappaB activation has been functionally demonstrated in PC12 cells, a rat pheochromocytoma cell line of neural crest lineage, while it is not yet verified in human cells. The link can be indirectly supported in our previous report that functional proteomics identifies enhanced expression of NF-kappaB-associated Wnt-1 production in human hepatocellular carcinoma tissues. This study aimed to further validate this link in human cells using anti-sense strategy. The effects of sequence-specific anti-sense morpholino oligonucleotides (ONs) targeting against pre-mRNA sequences of human p50 and p65 subunits of NF-kappaB as well as Wnt-1 genes were investigated. It revealed that all the three morpholino ONs inhibited NF-kappaB activation in human hepatoblastoma cell line HepG2 cells along with decreased Wnt-1 production. Chromatin immunoprecipitation assay ascertained the direct binding of NF-kappaB-p50 to the Wnt-1 promoter. Additionally, anti-P50 and anti-P65 morpholino ONs also repressed the phosphorylation of Ikappa Balpha which temporarily correlated with the inhibition of NF-kappaB activation accompanied by decreased Wnt-1 production by HepG2 cells. In summary, NF-kappaB activation is critically involved in the production of Wnt-1 by HepG2 cells. These results may have important oncology implications in treating patients with NF-kappaB-associated Wnt-1-producing cancers.

Anti-tumor potential of 15,16-dihydrotanshinone I against breast adenocarcinoma through inducing G1 arrest and apoptosis.

Chemotherapeutic drugs are usually designed to induce cancer cell death via cell cycle arrest and/or apoptosis pathways. In this study, we used the chemical drug 15,16-dihydrotanshinone I (DHTS) to inhibit breast cancer cell proliferation and tumor growth, and investigate the underlying molecular mechanisms. Human breast cancer cell lines MCF-7 and MDA-MB-231 were both used in this study, and DHTS was found to significantly decrease cell proliferation by a dose-dependent manner in both cells. Flow cytometry indicated that DHTS induced G1 phase arrest in synchronous MCF-7 and MDA-MB-231 cells. When analyzing the expression of cell cycle-related proteins, we found that DHTS reduced cyclin D1, cyclin D3, cyclin E, and CDK4 expression, and increased CDK inhibitor p27 expression in a dose-dependent manner. In addition, DHTS inhibited the kinase activities of CDK2 and CDK4 by an immunocomplex kinase assay. In addition, DHTS also induced apoptosis in both cells through mainly mitochondrial apoptosis pathways. We found that DHTS decreased the anti-apoptotic protein Bcl-xL level and increased the loss of mitochondria membrane potential and the amount of cytochrome c released. Moreover, DHTS activated caspase-9, caspase-3, and caspase-7 and caused cell apoptosis. The fact that DHTS-induced apoptosis could be blocked by pretreating cells with pan-caspase inhibitor confirmed that it is mediated through activation of the caspase-3-dependent pathway. In a nude mice xenograft experiment, DHTS significantly inhibited the tumor growth of MDA-MB-231 cells. Taken together, these results suggest that DHTS can inhibit human breast cancer cell proliferation and tumor growth, and might have potential chemotherapeutic applications.

HBcAg-specific CD4+CD25+ regulatory T cells modulate immune tolerance and acute exacerbation on the natural history of chronic hepatitis B virus infection.

Acute exacerbations (AEs) of chronic hepatitis B (CH-B) are accompanied by increased T cell responses to hepatitis B core and e antigens (HBcAg/HBeAg). Why patients are immunotolerant (IT) to the virus and why AEs occur spontaneously on the immunoactive phase remain unclear. The role of HBcAg-specific CD4(+)CD25(+) regulatory T (T(reg)) cells in AE and IT phases was investigated in this study. The SYFPEITHI scoring system was employed to predict MHC class II-restricted epitope peptides on HBcAg overlapping with HBeAg that were used for T(reg)-cell cloning and for the construction of MHC class II tetramers to measure T(reg) cell frequencies (T(reg) f). The results showed that HBcAg-specific T(reg) f declined during AE accompanied by increased HBcAg peptide-specific cytotoxic T lymphocyte frequencies. Predominant Foxp3-expressing T(reg) cell clones were generated from patients on the immune tolerance phase, while the majority of Th1 clones were obtained from patients on the immunoactive phase. T(reg) cells from liver and peripheral blood of CH-B patients express CD152 and PD1 antigens that exhibit suppression on PBMCs proliferation to HBcAg. These data suggest that HBcAg peptide-specific T(reg) cells modulate the IT phase, and that their decline may account for the spontaneous AEs on the natural history of chronic hepatitis B virus infection.

Significant association of HLA-DQ5 with autoimmune hepatitis in Taiwan.

Genetic predisposition is known to be an important etiopathogenic factor of autoimmune hepatitis (AIH). HLA antigens associated with AIH have been well studied in Western countries and Japan, but there is no HLA typing data of AIH patients in Taiwan. We therefore investigated HLA phenotypes and their association with AIH patients and compared the results with those of normal subjects and patients with chronic liver disease. Group 1 consisted of 22 AIH patients. All were born in Taiwan with no history of blood transfusion. Group 2 consisted of 19 chronic liver disease patients. Group 3 consisted of 81 unrelated healthy subjects who were normal blood donors. All three groups were tested for HLA phenotypes (HLAA, B, C, DR, DQ) using the polymerase chain reaction-sequence specific probe method. The statistical method used was Fisher's exact test. We found that HLA-DQ5 was significantly more frequent in the AIH group compared to the control group (RR, 2.03; p = 0.034). Low frequency of A1 (n = 2/22), B8 (n = 1/22) and DR3 (n = 0/22) were noted compared to results from the West; only HLA-DR4 showed a higher rate in our AIH patients (n = 8/22). This is a preliminary report of our study of HLA antigens in AIH patients. Further investigation to characterize AIH patients into HLA allelic subgroups is being done.

Type 1 autoimmune hepatitis in Taiwan: diagnosis using the revised criteria of the International Autoimmune Hepatitis Group.

Autoimmune hepatitis (AIH) is rare in Asian countries compared to the West, and an exceptionally low prevalence was noted previously in Taiwan. Using the revised criteria of the IAIHG, 48 cases of AIH patients were diagnosed. All patients were consecutively diagnosed over a period of 5 years. Detailed medical histories including disease onset, hepatitis B and C, alcohol, drugs, blood transfusion, and family history of autoimmune disease were recorded. Clinical manifestations, result of steroid therapy, outcome, and survival rate were investigated and analyzed. Clinical data on AIH patients with cirrhosis and without cirrhosis were compared and analyzed for their outcome. The statistical methods used were Fisher's exact test, Wilcoxon rank sum test, and Kaplan-Meier curve. Forty-eight patients were diagnosed as AIH type 1, with a median age of 58 years and a female:male ratio of 37:11. The most common clinical features at presentation were fatigue, jaundice, and anorexia. Ninety-eight percent of patients were ANA positive, and most of the patients showed elevated values of AST, ALT, serum globulin, and bilirubin. A substantial proportion of patients presented with poor liver function at entry and 35% of patients had liver cirrhosis, with relatively prolonged PT (P=0.001) and poorer outcome (P=0.005) compared to the noncirrhotics. As a whole there was a favorable treatment response and the overall survival rate was 85%. We conclude that the incidence of AIH in Taiwan is much higher than previously presumed and AIH type 1 is the predominant type of the disease. Although a substantial proportion of AIH patients presented with poor hepatic function at entry, as a whole there was a favorable clinical outcome.

Nonresponse to 18-month lamivudine monotherapy in chronic hepatitis B patients with dual genotype B and C infection and acute exacerbation.

Molecular epidemiologic studies have indicated the possible existence of mixed infection of different hepatitis B virus (HBV) genotypes in chronic hepatitis B (CH-B) carriers, but the effect of dual HBV genotype B and C infection on the efficacy of lamivudine therapy remains unclear. We report four CH-B patients with dual HBV genotype B and C infection and acute exacerbation who received lamivudine monotherapy for about 18 months. None of them had achieved a sustained response at the end of the 18-month trial of treatment.

Different viral kinetics between hepatitis C virus genotype 1 and 2 as on-treatment predictors of response to a 24-week course of high-dose interferon-alpha plus ribavirin combination therapy.

To elucidate the genotype-specific virus-host-drug interaction and the on-treatment viral kinetics in predicting sustained virologic response (SVR), serial serum hepatitis C virus (HCV) ribonucleic acid (RNA) levels at baseline, treatment week 2 (W2), treatment week 4 (W4), and treatment week 12 (W12) were measured in 199 chronic HCV-infected Taiwanese patients receiving interferon-alpha (INF-alpha) 6 million units (MU) three times weekly plus 1000 to 1200 mg/day of ribavirin for 24 weeks. The SVR rate was 90.5% (95/105) for HCV genotype 2 (HCV-2) patients and 47.9% (45/94) for HCV-1 patients (P < 0.0001). HCV-2 patients had a significantly higher rate of rapid virologic response (RVR) at W2 than HCV-1 patients. HCV RNA negativity at W4 had the highest accuracy of prediction (80%) of SVR with sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 81%, 79%, 78%, and 82%, respectively, for HCV-1 patients. HCV RNA negativity or 2 logs drop at W4 had the highest accuracy of prediction (92%) with sensitivity, specificity, PPV, and NPV of 100%, 20%, 92%, and 100%, respectively, for HCV-2 patients. In multivariate analysis, the significant factors associated with SVR in HCV-1 patients were HCV RNA negativity at W12 and W4. HCV RNA negativity or 2 logs drop was the only significant factor associated with SVR in HCV-2 patients. In conclusion, a RVR at W4 could predict an SVR with a high degree of accuracy to a 24-week course of high-dose IFN/ribavirin for both HCV-1 patients and HCV-2 patients. With respect to each HCV genotype, the on-treatment virologic responses are the most important factors associated with SVR.

Enlarged lymph nodes in porta hepatis: sonographic sign of chronic hepatitis B and C infections.

PURPOSE: Enlarged lymph nodes in the hepatoduodenal ligament are prevalent in chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV); however, the clinical significance of this sonographic finding in an endemic area is unknown. METHODS: Six hundred outpatients were categorized into 4 groups (nonviral, HBV, HCV, and HBV and HCV) using viral markers. The prevalence and size of enlarged lymph nodes were compared. Correlation between clinical parameters and nodal size was evaluated. RESULTS: The incidence of detectable nodes in both the HBV group and the HCV group was significantly increased (56.9% and 69.4%, respectively; both p < 0.001) compared with the nonviral group; this rate was independent of aminotransferase levels. Nodal width was the only significant parameter when viral and nonviral groups were compared (p < 0.05). If a width of more than 5 mm was used to predict HBV or HCV infection, the positive predictive rate was 88% and the specificity was 89%. CONCLUSIONS: Lymph nodes in the hepatoduodenal ligament, especially those wider than 5 mm, suggest chronic HBV or HCV infection instead of only chronic hepatitis, especially in an endemic area such as Taiwan.

Enhanced nuclear factor-kappa B-associated Wnt-1 expression in hepatitis B- and C-related hepatocarcinogenesis: identification by functional proteomics.

Chronic infections with hepatitis B and C viruses (HBV and HCV) are etiologically linked to hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Both viruses may induce activation of nuclear factor-kappa B (NF-kappaB) in hepatocytes that plays a crucial role in the regulation of cell growth and apoptosis. Functional proteomics analysis of proteins associated with NF-kappaB signaling complexes in both viruses-related HCC tumor and non-tumor tissues may disclose possible common mechanisms in hepatocarcinogenesis. By functional proteomics, we analyzed proteins associated with NF-kappaB-signaling complexes in four-paired human HCC tumor and non-tumor tissues from HBV- and HCV-infected patients, respectively, and in one-paired tissue with dual viral infection. The quantity of NF-kappaB-associated proteins was semi-quantitatively measured by protein spot intensity on the gels of two-dimensional polyacrylamide gel electrophoresis. The results showed that overexpression of NF-kappaB-associated Wnt-1 protein in tumor part was detected in the majority of HBV- and HCV-infected HCC samples. These data suggest that enhanced expression of NF-kappaB-associated Wnt-1 protein might be a mechanism of hepatocarcinogenesis common to HBV- and HCV-infected patients. NF-kappaB signaling pathway and Wnt-1 protein could be potential targets for designing highly effective therapeutic agents in treating HCC and for chemoprevention of hepatocarcinogenesis.

Isolated gastric varices due to focal splenic vein stenosis.

Left-sided portal hypertension due to splenic vein stenosis is a very rare disease. We report a case of this condition in a 21-year-old woman who suffered from a first episode of tarry stool passage with fresh blood vomiting. Panendoscopy showed isolated gastric varices while sonography showed a normal liver but the presence of splenomegaly with prominent collateral circulations. Further imaging studies, including abdominal computed tomography, splenoportography and percutaneous transhepatic portography, revealed a focal stenotic proximal splenic vein resulting in left-sided portal hypertension. The collateral circulation ran from the short gastric veins via the left gastric veins into the main portal vein. The intraportal venous pressure was within normal limits. Splenectomy was performed and near normal wedge liver biopsy pathology confirmed non-cirrhotic extrahepatic portal hypertension. The patient had no further variceal bleeding after surgery.

A method to increase tetramer staining efficiency of CD8+ T cells with MHC-peptide complexes: therapeutic applications in monitoring cytotoxic T lymphocyte activity during hepatitis B and C treatment.

The development of peptide-MHC tetrameric complexes heralds a new era in the study of antigen-specific T cells and their role in viral infections. However, the frequencies of tetramer-staining CD8+ T cells in fresh peripheral blood mononuclear cells (PBMCs) are usually below 1% in patients with chronic hepatitis B and C viruses (HBV and HCV) as well as human immunodeficiency virus (HIV) infections, which makes difficult the comparison and sequential evaluation of different individuals. Thus, the development of a method to enumerate efficiently antigen-specific CD8+ T cells will be clinically beneficial in monitoring the antiviral cellular immunity during therapy. We report here a modified CRI-p culture method (cytotoxic T lymphocyte response index of the epitope-peptide method), using a panel of peptides to stimulate PBMCs in bulk culture. The modified CRI-p cultured cells were, in turn, subjected to fluorescence-activated cell sorter (FACS) analysis, tetramer staining or T-cell functional assays to quantify the antiviral immunity of HLA-A2 (+) HBV and HCV patients receiving antiviral therapies. The results obtained showed that patients with a sustained response had a significantly higher increase in the frequencies of tetramer staining of virus-specific CD8+ T cells than did nonresponders. This method permits semi-quantitative determination of the relative strength of CTL activity against a panel of peptides and provides a large number of cells for FACS analysis from a single blood sampling. Significantly, it achieves high frequencies of tetramer staining of CD8+ T cells allowing the data of different individuals to be easily compared and sequentially evaluated. The mechanisms involved in this method are discussed.

Adenovirus type 5 E1A sensitizes hepatocellular carcinoma cells to gemcitabine.

Hepatocellular carcinoma (HCC) is resistant to conventional chemotherapy. A few clinical trials have shown that the cytidine analogue gemcitabine appears to have antitumor activity for HCC, but the overall survival times remain to be improved. In this study, we examined the synergistic effect of adenovirus type 5 E1A (E1A) and gemcitabine on HCC and found that E1A sensitized J5, J7, Huh7, and HepG2 HCC cells to gemcitabine. To further study the E1A-mediated chemosensitization, we established stable cell lines that expressed the E1A gene and then examined whether E1A could have proapoptotic activity while expressed in HCC cells. Our results clearly showed that E1A sensitized HCC cells to gemcitabine through induction of apoptosis. To study the underlying mechanism, we tested nuclear factor (NF)-kappaB activity and found that NF-kappaB was activated in HCC cells treated with gemcitabine but not in HCC cells that expressed E1A. Occurrence of apoptosis entails cleavage of poly (ADP-ribose) polymerase (PARP), a nuclear protein involved in DNA repair, genome stability, and maintenance of telomere length. Our study showed that gemcitabine enhanced PARP expression. However, E1A did not induce PARP cleavage but rather suppressed PARP expression at the transcriptional level. Further study showed that both NF-kappaB and PARP played protective roles in the prevention of E1A+gemcitabine-induced apoptosis.

Determinants for sustained HBeAg response to lamivudine therapy.

There are inconsistent data on the durability of hepatitis B e antigen (HBeAg) seroconversion after lamivudine is discontinued. The aim of this study was to examine the determinants for sustained HBeAg response to lamivudine therapy. Both host and viral factors as well as the drug factor were compared between 43 patients with sustained HBeAg response and 39 patients whose response was not sustained. All of them received a mean period of 16 months (range, 3-55 months) lamivudine therapy and had achieved complete response (HBeAg seroconversion plus HBV DNA seroclearance by hybrid capture assay and normal alanine aminotransferase [ALT]) and were followed-up for a mean period of 44 months (range, 12-88 months). Stepwise logistic regression model was used to estimate the sustained response on the presence of the following variables: age; gender; pretherapy ALT; total bilirubin and HBV DNA levels; time to HBeAg seroconversion; additional lamivudine treatment after HBeAg seroconversion; total duration of treatment; hepatitis activity index scores; periportal, intralobular, and portal inflammation and fibrosis scores; scores excluding fibrosis; status of precore mutation; basal core promoter mutation; and genotype. The results showed that genotype (OR, 5.922; 95% CI, 1.611-21.768; P =.007), age (OR, 0.943; 95% CI, 0.891-0.997; P =.040), and additional treatment (OR, 1.097; 95% CI, 1.028-1.171; P =.005) were independent factors to sustained HBeAg response. Further categorical analysis disclosed that patients with genotype B, age < or =36 years, and additional lamivudine treatment over 8 months have higher sustained response. In conclusion, HBV genotype, age, and additional treatment are the major determinants for the sustained HBeAg response to lamivudine therapy.

Activation of Th1 immunity is a common immune mechanism for the successful treatment of hepatitis B and C: tetramer assay and therapeutic implications.

Both chronic hepatitis B and C virus (HBV and HCV) infections respond ineffectively to current antiviral therapies. Recent studies have suggested that treatment outcomes may depend on the development of type 1 T helper (Th1) and Th2 cell responses. Specifically, activation of Th1 immunity may play a major role in successfully treating hepatitis B and C. This model was revisited herein by evaluating immune responses in 36 HBV and 40 HCV patients with or without treatment, in an attempt to find a common immune mechanism for successful treatment. The immune responses in all examined cases were studied by peripheral blood mononuclear cell (PBMC) proliferation and cytokine responses to viral antigens, cytotoxic T lymphocyte (CTL) responses, enzyme-linked immunospot (ELISPOT) assay, and tetramer staining of virus-specific CD8+ T cells. The overall results revealed that all responders among both HBV- and HCV-infected cases displayed significantly higher PBMC proliferation to viral antigens with a predominant Th1 cytokine profile. Furthermore, the Th1-dominant responses were associated with significant enhancement of CTL activities and were correlated with ELISPOT data, while non-responders responded more weakly. During therapy, the numbers of tetramer-staining, virus-specific CD8+ T cells showed greater increases in responders than in non-responders (p = 0.001). The frequencies determined by the tetramer assay were approximately 200-fold higher than data estimated by limiting-dilution analysis. In conclusion, activation of Th1 immunity accompanied by enhancement of CTL activity during therapy is a common immune mechanism for successfully treating hepatitis B and C, and therefore may have important therapeutic implications.