Hepatitis: Chang TT

Cheng PN, Chang TT. · National Cheng Kung University, Medical College and Hospital, Tainan, Taiwan, ROC. · Expert Rev Anti Infect Ther. · Pubmed #18847396 No free full text.

Abstract: Entecavir has demonstrated safety and efficacy in the treatment of chronic hepatitis B infection. It is the prototype for the cyclopentane class of nucleoside/nucleotide chronic hepatitis B antiviral agents. It has a high potency and, due to its structural formula and mechanism of action, entecavir is associated with emergence of minimal resistance in the long-term treatment of nucleoside-naive patients. Research suggests that long-term treatment may be required for chronic hepatitis B patients, especially those who acquire HBV early in life, to achieve maximum viral suppression and improve outcomes. Several recent studies have evaluated the long-term safety, efficacy and development of resistance in nucleoside-naive patients treated with entecavir. Results indicate that the long-term use of entecavir is well tolerated and associated with continuous clinical improvement -- with an increasing number of patients achieving undetectable levels of HBV DNA, HBeAg seroconversion and minimal resistance. These data underscore the position of entecavir for first-line therapy and highlight its role in the long-term treatment of chronic hepatits B.

Fan YF, Lu CC, Chang YC, Chang TT, Lin PW, Lei HY, Su IJ. · Institute of Basic Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan. · J Gastroenterol Hepatol. · Pubmed #10847439 No free full text.

Abstract: BACKGROUND AND AIMS: The expression of hepatitis B viral (HBV) antigens in liver tissue reflects the replicative status of chronic HBV infection. We have previously recognized a novel marginal pattern of hepatitis B surface antigen (HBsAg) in hepatocytes, which usually clusters in groups and emerges at the late non-replicative phase. This study was designed to investigate whether the marginal-type HBsAg represented the gene product of a specific HBV-surface mutant. METHODS: Microdissection of cirrhotic nodules homogeneously expressing marginal HBsAg was performed on two of 12 resected livers from HBsAg-seropositive patients with hepatocellular carcinoma. The gene presumably encoding marginal HBsAg was polymerase chain reaction (PCR)-cloned, sequenced and analysed. In vitro transfection and expression of the cloned surface mutant plasmids were performed on the Huh7 cell line to illustrate intrahepatic HBsAg expression. RESULTS: Immunohistochemical staining revealed that the marginal HBsAg was positive for pre-S1 and thus contained large surface proteins. The PCR cloning and sequencing of the genes presumably encoding marginal-type HBsAg in both cases revealed the same deletion at the 5' terminus (nt 2-55) of pre-S2. A point mutation on the small-surface (S) antigen was also found in one case. The pre-S2 deletion sequence and the mutation sites of the S gene coincide with human lymphocyte antigen-restricted T- and/or B-cell epitopes. In vitro transfection of the mutant plasmid revealed a blot-like retention or accumulation of HBsAg in the cytoplasm or at the periphery of hepatocytes, accompanied by a decreased secretion of HBsAg in the culture supernatant, mimicking intrahepatic expression. CONCLUSION: A natural pre-S2 deletion mutant was identified in hepatocytes expressing a novel marginal pattern of HBsAg, which probably contains mutant, large, surface proteins. The biological significance of the pre-S2 deletion mutant should be interesting in view of the clustering proliferation of hepatocytes expressing marginal HBsAg.

Shouval D, Lai CL, Chang TT, Cheinquer H, Martin P, Carosi G, Han S, Kaymakoglu S, Tamez R, Yang J, Tenney D, Brett-Smith H. · Liver Unit, Hadassah - Hebrew University Hospital, Ein-Kerem, Jerusalem 91120, Israel. · J Hepatol. · Pubmed #19070393 No free full text.

Abstract: BACKGROUND/AIMS: To evaluate the off-treatment durability of response in HBeAg-negative chronic hepatitis B patients who achieved a protocol-defined 'Response' (HBV-DNA<0.7MEq/mL and ALT<1.25xULN) with entecavir at 48 weeks and the efficacy of entecavir in patients treated beyond one year. METHODS: Entecavir-treated and lamivudine-treated patients who achieved a protocol-defined 'Response' were evaluated off-treatment for HBV-DNA<300copies/mL and ALT normalisation. Entecavir- and lamivudine-treated patients who achieved a protocol-defined 'Virological Response' (HBV-DNA<0.7MEq/mL but ALT1.25xULN) at 48 weeks, continued blinded treatment until they achieved Response or 96 weeks, whichever came first. RESULTS: Among 'Responders' who discontinued treatment after 48 weeks, 7/257 (3%) entecavir-treated and 10/201 (5%) lamivudine-treated patients sustained HBV-DNA below 300copies/mL at 24-weeks off-treatment. Among the 54 patients who continued blinded treatment in the second year, 7/26 (27%) entecavir-treated and 6/28 (21%) lamivudine-treated patients normalised ALT and 22/26 (85%) entecavir-treated and 16/28 (57%) lamivudine-treated patients maintained HBV-DNA<300copies/mL at end-of-dosing. The safety profiles of both drugs remained comparable through a second year of treatment. CONCLUSIONS: The majority of protocol-defined Responders relapsed after 1 year when treatment was discontinued. Treatment with entecavir beyond 1 year provided continued virological and biochemical benefit.

Cheng PN, Wei YL, Chang TT, Chen JS, Young KC. · Department of Internal Medicine, Medical College, National Cheng Kung University, Tainan, Taiwan. · J Med Virol. · Pubmed #18428145 No free full text.

Abstract: Multiple interferon-stimulated genes (ISGs) involving T-cell activation are upregulated during initial interferon-alpha-based therapy for chronic hepatitis C virus (HCV) infection. However, the long-term impact on therapeutic outcome in patients remains unknown. In this study, the effects of anti-HCV therapy on the surface expression of HLA-ABC, CD86, and CD28 were longitudinally assessed. These proteins are integral membrane receptors of antigen presentation and triggering of costimulatory signals for activating CD8+ T cells. Peripheral blood mononuclear cells were collected at baseline and post-treatment for 1 day, and 2, 4, 12, and 24 weeks, respectively. This treatment led to a time-related elevation of membrane levels of HLA-ABC and CD86 on B-cells and monocytes in patients with a sustained response (n = 23), but not in those without (n = 8). Meanwhile, upregulation of CD28 on CD4+ and CD8+ T cells was comparable in both groups of sustained responders and non-responders. Steady increases in the B cells' surface and intracellular HLA-ABC were observed, thus, the surface-to-intracellular ratios did not alter over the period of treatment. Furthermore, multivariate analysis shows that increased HLA-ABC on monocytes by week 12 correlates significantly with sustained response (P = 0.033). In conclusion, differential modulation of T-cell activation ISGs, such as HLA-ABC and CD86 might correlate with the outcome of interferon-alpha-based therapy in chronic hepatitis C patients.

Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, DeHertogh D, Wilber R, Zink RC, Cross A, Colonno R, Fernandes L, Anonymous00171. · Queen Mary Hospital, Hong Kong, China. · N Engl J Med. · Pubmed #16525138 links to  free full text

Abstract: BACKGROUND: Entecavir is a potent and selective antiviral agent that has demonstrated efficacy in phase 2 studies in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. METHODS: In this phase 3, double-blind trial, we randomly assigned 648 patients with HBeAg-negative chronic hepatitis B who had not previously been treated with a nucleoside analogue to receive 0.5 mg of entecavir or 100 mg of lamivudine once daily for a minimum of 52 weeks. The primary efficacy end point was histologic improvement (a decrease by at least two points in the Knodell necroinflammatory score, without worsening of fibrosis). RESULTS: Histologic improvement after 48 weeks of treatment occurred in 208 of 296 patients in the entecavir group who had adequate baseline liver-biopsy specimens that could be evaluated (70 percent), as compared with 174 of 287 such patients in the lamivudine group (61 percent, P=0.01). More patients in the entecavir group than in the lamivudine group had undetectable serum hepatitis B virus (HBV) DNA levels according to a polymerase-chain-reaction assay (90 percent vs. 72 percent, P<0.001) and normalization of alanine aminotransferase levels (78 percent vs. 71 percent, P=0.045). The mean reduction in serum HBV DNA levels from baseline to week 48 was greater with entecavir than with lamivudine (5.0 vs. 4.5 log [on a base-10 scale] copies per milliliter, P<0.001). There was no evidence of resistance to entecavir. Safety and adverse-event profiles were similar in the two groups. CONCLUSIONS: Among patients with HBeAg-negative chronic hepatitis B who had not previously been treated with a nucleoside analogue, the rates of histologic improvement, virologic response, and normalization of alanine aminotransferase levels were significantly higher at 48 weeks with entecavir than with lamivudine. The safety profile of the two agents was similar, and there was no evidence of viral resistance to entecavir. (ClinicalTrials.gov number, NCT00035789.).

Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, Lok AS, Han KH, Goodman Z, Zhu J, Cross A, DeHertogh D, Wilber R, Colonno R, Apelian D, Anonymous00170. · National Cheng Kung University Medical College, Tainan, Taiwan. · N Engl J Med. · Pubmed #16525137 links to  free full text

Abstract: BACKGROUND: Entecavir is a potent and selective guanosine analogue with significant activity against hepatitis B virus (HBV). METHODS: In this phase 3, double-blind trial, we randomly assigned 715 patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B who had not previously received a nucleoside analogue to receive either 0.5 mg of entecavir or 100 mg of lamivudine once daily for a minimum of 52 weeks. The primary efficacy end point was histologic improvement (a decrease by at least two points in the Knodell necroinflammatory score, without worsening of fibrosis) at week 48. Secondary end points included a reduction in the serum HBV DNA level, HBeAg loss and seroconversion, and normalization of the alanine aminotransferase level. RESULTS: Histologic improvement after 48 weeks occurred in 226 of 314 patients in the entecavir group (72 percent) and 195 of 314 patients in the lamivudine group (62 percent, P=0.009). More patients in the entecavir group than in the lamivudine group had undetectable serum HBV DNA levels according to a polymerase-chain-reaction assay (67 percent vs. 36 percent, P<0.001) and normalization of alanine aminotransferase levels (68 percent vs. 60 percent, P=0.02). The mean reduction in serum HBV DNA from baseline to week 48 was greater with entecavir than with lamivudine (6.9 vs. 5.4 log [on a base-10 scale] copies per milliliter, P<0.001). HBeAg seroconversion occurred in 21 percent of entecavir-treated patients and 18 percent of those treated with lamivudine (P=0.33). No viral resistance to entecavir was detected. Safety was similar in the two groups. CONCLUSIONS: Among patients with HBeAg-positive chronic hepatitis B, the rates of histologic, virologic, and biochemical improvement are significantly higher with entecavir than with lamivudine. The safety profile of the two agents is similar, and there is no evidence of viral resistance to entecavir. (ClinicalTrials.gov number, NCT00035633.).

Chang TT, Gish RG, Hadziyannis SJ, Cianciara J, Rizzetto M, Schiff ER, Pastore G, Bacon BR, Poynard T, Joshi S, Klesczewski KS, Thiry A, Rose RE, Colonno RJ, Hindes RG, Anonymous00131. · National Cheng Kung University Medical College, Tainan, Taiwan. · Gastroenterology. · Pubmed #16230074 No free full text.

Abstract: BACKGROUND & AIMS: Entecavir is a nucleoside analogue with potent in vitro activity against lamivudine-resistant hepatitis B virus (HBV). This randomized, dose-ranging, phase 2 study compared the efficacy and safety of entecavir with lamivudine in lamivudine-refractory patients. METHODS: Hepatitis B e antigen (HBeAg)-positive and -negative patients (n = 182), viremic despite lamivudine treatment for > or =24 weeks or having documented lamivudine resistance substitutions, were switched directly to entecavir (1.0, 0.5, or 0.1 mg daily) or continued on lamivudine (100 mg daily) for up to 76 weeks. RESULTS: At week 24, significantly more patients receiving entecavir 1.0 mg (79%) or 0.5 mg (51%) had undetectable HBV DNA levels by branched chain DNA assay compared with lamivudine (13%; P < .0001). Entecavir 1.0 mg was superior to entecavir 0.5 mg for this end point (P < .01). After 48 weeks, mean reductions in HBV DNA levels were 5.06, 4.46, and 2.85 log(10) copies/mL on entecavir 1.0, 0.5, and 0.1 mg, respectively, significantly higher than 1.37 log(10) copies/mL on lamivudine. Significantly higher proportions of patients achieved normalization of alanine aminotransferase levels on entecavir 1.0, 0.5, and 0.1 mg (68%, 59%, and 47%, respectively) than on lamivudine (6%). One virologic rebound due to resistance occurred (in the 0.5-mg group). CONCLUSIONS: In HBeAg-positive and HBeAg-negative lamivudine-refractory patients, treatment with entecavir 1.0 and 0.5 mg daily was well tolerated and resulted in significant reductions in HBV DNA levels and normalization of alanine aminotransferase levels. One milligram of entecavir was more effective than 0.5 mg in this population.

Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, Marcellin P, Lim SG, Goodman Z, Ma J, Arterburn S, Xiong S, Currie G, Brosgart CL, Anonymous00056. · Department of Medicine and Hepatology, Henry Dunant Hospital, Athens, Greece. · N Engl J Med. · Pubmed #15987916 links to  free full text

Abstract: BACKGROUND: Treatment with adefovir dipivoxil for 48 weeks resulted in histologic, virologic, and biochemical improvement in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. We evaluated the effect of continued therapy as compared with cessation of therapy. METHODS: One hundred eighty-five HBeAg-negative patients with chronic hepatitis B were assigned to receive 10 mg of adefovir dipivoxil or placebo once daily for 48 weeks (ratio, 2:1). After week 48, patients receiving adefovir dipivoxil were again randomly assigned either to receive an additional 48 weeks of the drug or to switch to placebo. Patients originally assigned to placebo were switched to adefovir dipivoxil. Patients treated with adefovir dipivoxil during weeks 49 through 96 were subsequently offered continued therapy. The primary end points were changes in hepatitis B virus (HBV) DNA and alanine aminotransferase levels. RESULTS: Treatment with adefovir dipivoxil resulted in a median decrease in serum HBV DNA of 3.47 log copies per milliliter (on a base-10 scale) at 96 weeks and 3.63 log copies per milliliter at 144 weeks. HBV DNA levels were less than 1000 copies per milliliter in 71 percent of patients at week 96 and 79 percent at week 144. In the majority of patients who were switched from adefovir dipivoxil to placebo, the benefit of treatment was lost (median change in HBV DNA levels from baseline, -1.09 log copies per milliliter; only 8 percent of patients had levels below 1000 copies per milliliter at week 96). Side effects during weeks 49 through 144 were similar to those during the initial 48 weeks. Resistance mutations rtN236T and rtA181V were identified in 5.9 percent of patients after 144 weeks. CONCLUSIONS: In patients with HBeAg-negative chronic hepatitis B, the benefits achieved from 48 weeks of adefovir dipivoxil were lost when treatment was discontinued. In patients treated for 144 weeks, benefits were maintained, with infrequent emergence of viral resistance.

Lee SD, Yu ML, Cheng PN, Lai MY, Chao YC, Hwang SJ, Chang WY, Chang TT, Hsieh TY, Liu CJ, Chen DS. · Department of Medicine, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taipei 100, Taiwan. · J Viral Hepat. · Pubmed #15850469 No free full text.

Abstract: Previous studies in Caucasian patients showed treatment of chronic hepatitis C with pegylated interferon/ribavirin was well tolerated, and produced a higher response rate especially in genotype 1 infections. However, it is unknown whether this conclusion can be extrapolated to patients with Chinese ethnic origin. A total of 153 patients with biopsy-proven chronic hepatitis C were randomly assigned to receive either weekly injection of peginterferon alpha-2b 1.5 mcg/kg plus oral ribavirin (1000 or 1200 mg/day, depending on body weight) (PEG group, n = 76) or 3 MU of interferon alpha-2b t.i.w. plus ribavirin (IFN group, n = 77) for 24 weeks. Sustained virological response (SVR) was defined as the sustained disappearance of serum hepatitis C virus (HCV) RNA at 24 weeks after the end of treatment by polymerase chain reaction assay. Baseline demographic, viral and histological characteristics were comparable between the two groups. Using an intent-to-treat analysis, HCV genotype 1 patients showed a significantly higher SVR in patients receiving PEG-IFN rather than IFN (65.8%vs 41.0%, P = 0.019), but no difference was found in genotype non-1 patients (PEG vs IFN: 68.4%vs 86.8%, P = 0.060). Genotype 1 patients (28.6%) in the PEG-IFN group relapsed, as compared with 52.9% in the IFN group (P = 0.040). Multivariate analyses showed early virological response at week 12 of therapy and genotype non-1 were significant predictors to SVR. As compared with the IFN group, patients receiving PEG-IFN had a significantly higher rate of discontinuation, dose reduction, fever, headache, insomnia, leucopenia and thrombocytopenia. In genotype 1 chronic hepatitis C Chinese patient, PEG-IFNalpha2b ribavirin had significantly better SVR and lower relapse rate when compared to IFN/ribavirin. Both regimens can be recommended for genotype non-1 chronic hepatitis C Chinese patients. However, a higher rate of adverse events and discontinuance of therapy were noted in patients treated with PEG-IFNalpha2b ribavirin.

Chang TT, Lai CL, Chien RN, Guan R, Lim SG, Lee CM, Ng KY, Nicholls GJ, Dent JC, Leung NW. · Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan. · J Gastroenterol Hepatol. · Pubmed #15482535 No free full text.

Abstract: BACKGROUND AND AIMS: This study assessed the efficacy and safety of up to 4 years of lamivudine treatment and the clinical relevance of the emergence of YMDD-variant hepatitis B virus (HBV). METHODS: Fifty-eight Chinese adult patients with chronic hepatitis B (CHB) were randomized to lamivudine 100 mg/day for up to 5 years and were monitored for YMDD-variant HBV, hepatitis B e antigen (HBeAg) seroconversion (loss of HBeAg and detectable antibody to HBeAg) and serum alanine aminotransferase (ALT) concentrations. Four-year data are reported here. RESULTS: The rate of HBeAg seroconversion increased with extended therapy and also with higher baseline ALT concentrations. YMDD-variant HBV was detected in 67% (39/58) of patients at some point during treatment. After 4 years, a total of 47% (27/58) of patients achieved HBeAg seroconversion. Thirty-three per cent (13/39) of patients with YMDD-variant HBV achieved HBeAg seroconversion; this increased to 57% (8/14) in patients with moderately elevated (>2-5 x upper limit of normal) pre-treatment ALT concentrations. The proportion of patients that achieved normal serum ALT increased from 29% (17/58) at baseline to 69% (31/45) following 4 years of treatment. That included 68% (23/34) of patients with YMDD-variant HBV and 73% (8/11) of those without the variant. All patients receiving lamivudine had reduced serum concentrations of HBV-DNA compared with baseline, despite the emergence of YMDD-variant HBV in 39 patients. Lamivudine was generally well tolerated; there was little change in the number or type of drug-related adverse events in the fourth year of the study. CONCLUSIONS: Despite the emergence of YMDD-variant HBV, Chinese patients showed increased HBeAg seroconversion and improvement in ALT levels with an increased duration of treatment with lamivudine.

Cheng PN, Marcellin P, Bacon B, Farrell G, Parsons I, Wee T, Chang TT. · Division of Gastroenterology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan. · J Viral Hepat. · Pubmed #15357646 No free full text.

Abstract: Re-treatment with interferon-alpha alone for chronic hepatitis C nonresponders to interferon-alpha monotherapy is almost ineffective. This multicentre, randomized, parallel-group, dose-finding study evaluated the efficacy of interferon-beta-1a in the treatment of chronic hepatitis C patients unresponsive to interferon-alpha. A total of 267 patients were randomized to one of four groups: subcutaneous interferon-beta-1a 12 MIU (44 microg) or 24 MIU (88 microg) administered three times weekly or daily. Patients were treated for 48 weeks and then followed up for an additional 24 weeks. There was a trend towards a dose-response relationship regarding virological [loss of detectable serum hepatitis C virus (HCV) RNA] and biochemical response (normalization of serum alanine aminotransferase). Overall, 22 patients (8.3%) had a virological response at the end of treatment; nine patients (3.4%) had a sustained virological response (SVR). Strikingly, 21.7% (5/23) of Chinese patients achieved SVR. Univariate analysis revealed that race was the only variable related to SVR [odds ratio (OR) 16.6; 95% CI 4.1-67.3; P < 0.0001]. Multiple logistic regression analysis also confirmed that more Chinese patients achieved SVR than non-Chinese patients (OR 12.3; 95% CI 2.6-59.3; P = 0.0017). In addition, complete clearance of HCV-RNA occurred earlier in Chinese than in non-Chinese responders (median 2 vs 30 weeks; P = 0.020). Thirty-six patients were withdrawn from treatment because of adverse events. Most adverse events were mild or moderate in severity. In conclusion, interferon-beta-1a provided considerable clinical benefit in Chinese patients with chronic hepatitis C unresponsive to interferon-alpha. The evaluation of interferon-beta-1a in this setting is progressing.

Cheng PN, Chow NH, Hu SC, Young KC, Chen CY, Jen CM, Chang TT. · Division of Gastroenterology, Department of Internal Medicine, National Chen-Kung University Hospital, Tainan, Taiwan, ROC. · Dig Liver Dis. · Pubmed #12643293 No free full text.

Abstract: BACKGROUND: Interferon a with ribavirin combination therapy is effective but still unsatisfactory in the treatment of patients with interferon-relapsed chronic hepatitis C. AIMS: To compare, in a randomized, double blind, placebo-controlled study, high-dose interferon-alpha2b with or without ribavirin in the treatment for interferon-relapsers. PATIENTS: A total of 52 patients with interferon-relapsed chronic hepatitis C were randomly assigned to receive 24-week treatment with interferon-alpha2b (6 MU three times per week) combined with either ribavirin (1,000 to 1,200 mg per day) or a matched placebo and then followed for an additional 24 weeks. METHODS: Hepatitis C virus RNA was detected by reverse-transcription polymerase chain reaction. For determining viral concentration, the commercial bDNA Quantiplex hepatitis C virus-RNA 2.0 assay was used. Genotyping was performed by reverse hybridization assay RESULTS: At the end of treatment, no detectable hepatitis C virus RNA levels were observed in 92% (24/26) of patients on interferon alpha2b/ribavirin and 81% (21/26) of patients on interferon alpha2b/placebo. At the end of the follow-up, a higher sustained virological response rate was seen in patients treated with interferon alpha2b/ribavirin than those treated with interferon alpha2b/placebo (69% vs 23%, p < 0.001). Patients with either initially high levels of viral concentration or with genotype 1 responded poorly. Patients who received interferon-alpha2b/ribavirin treatment and in whom no hepatitis C virus RNA was detected at 4th week after treatment had 90% chance to achieve sustained virological response. CONCLUSIONS: High-dose interferon-alpha2b plus ribavirin treatment is highly effective in interferon-relapsed patients.

Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W, Shiffman ML, Jeffers L, Goodman Z, Wulfsohn MS, Xiong S, Fry J, Brosgart CL, Anonymous00292. · Service d'Hépatologie, INSERM Unité 481, and Centre de Recherches Claude Bernard sur les Hépatites Virales, Hôpital Beaujon, Clichy, France. · N Engl J Med. · Pubmed #12606735 links to  free full text

Abstract: BACKGROUND: In preclinical and phase 2 studies, adefovir dipivoxil demonstrated potent activity against hepatitis B virus (HBV), including lamivudine-resistant strains. METHODS: We randomly assigned 515 patients with chronic hepatitis B who were positive for hepatitis B e antigen (HBeAg) to receive 10 mg of adefovir dipivoxil (172 patients), 30 mg of adefovir dipivoxil (173), or placebo (170) daily for 48 weeks. The primary end point was histologic improvement in the 10-mg group as compared with the placebo group. RESULTS: After 48 weeks of treatment, significantly more patients who received 10 mg or 30 mg of adefovir dipivoxil per day than who received placebo had histologic improvement (53 percent [P<0.001], 59 percent [P<0.001], and 25 percent, respectively), a reduction in serum HBV DNA levels (by a median of 3.52 [P<0.001], 4.76 [P<0.001], and 0.55 log copies per milliliter, respectively), undetectable levels (fewer than 400 copies per milliliter) of serum HBV DNA (21 percent [P<0.001], 39 percent [P<0.001], and 0 percent, respectively), normalization of alanine aminotransferase levels (48 percent [P<0.001], 55 percent [P<0.001], and 16 percent, respectively), and HBeAg seroconversion (12 percent [P=0.049], 14 percent [P=0.01], and 6 percent, respectively). No adefovir-associated resistance mutations were identified in the HBV DNA polymerase gene. The safety profile of the 10-mg dose of adefovir dipivoxil was similar to that of placebo; however, there was a higher frequency of adverse events and renal laboratory abnormalities in the group given 30 mg of adefovir dipivoxil per day. CONCLUSIONS: In patients with HBeAg-positive chronic hepatitis B, 48 weeks of 10 mg or 30 mg of adefovir dipivoxil per day resulted in histologic liver improvement, reduced serum HBV DNA and alanine aminotransferase levels, and increased the rates of HBeAg seroconversion. The 10-mg dose has a favorable risk-benefit profile for long-term treatment. No adefovir-associated resistance mutations were identified in the HBV DNA polymerase gene.

Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, Marcellin P, Lim SG, Goodman Z, Wulfsohn MS, Xiong S, Fry J, Brosgart CL, Anonymous00291. · Department of Medicine and Hepatology, Henry Dunant Hospital, Athens, Greece. · N Engl J Med. · Pubmed #12606734 links to  free full text

Abstract: BACKGROUND: Adefovir dipivoxil, a nucleotide analogue, demonstrated clinically significant antiviral activity in patients with chronic hepatitis B in phase 1 and 2 clinical trials. METHODS: We randomly assigned 185 patients with chronic hepatitis B who were negative for hepatitis B e antigen (HBeAg) to receive either 10 mg of adefovir dipivoxil or placebo once daily for 48 weeks in a 2:1 ratio and a double-blind manner. The primary end point was histologic improvement. RESULTS: At week 48, 64 percent of patients who had base-line liver-biopsy specimens available in the adefovir dipivoxil group had improvement in histologic liver abnormalities (77 of 121), as compared with 33 percent of patients in the placebo group (19 of 57, P<0.001). Serum hepatitis B virus (HBV) DNA levels were reduced to fewer than 400 copies per milliliter in 51 percent of patients in the adefovir dipivoxil group (63 of 123) and in 0 percent of those in the placebo group (0 of 61, P<0.001). The median decrease in log-transformed HBV DNA levels was greater with adefovir dipivoxil treatment than with placebo (3.91 vs. 1.35 log copies per milliliter, P<0.001). Alanine aminotransferase levels had normalized at week 48 in 72 percent of patients receiving adefovir dipivoxil (84 of 116), as compared with 29 percent of those receiving placebo (17 of 59, P<0.001). No HBV polymerase mutations associated with resistance to adefovir were identified. The safety profile of adefovir dipivoxil was similar to that of placebo. CONCLUSIONS: In patients with HBeAg-negative chronic hepatitis B, 48 weeks of adefovir dipivoxil treatment resulted in significant histologic, virologic, and biochemical improvement, with an adverse-event profile similar to that of placebo. There was no evidence of the emergence of adefovir-resistant HBV polymerase mutations.

Lin CC, Wu JC, Chang TT, Huang YH, Wang YJ, Tsay SH, Chow NH, Chang FY, Lee SD. · Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC. · J Viral Hepat. · Pubmed #11703575 No free full text.

Abstract: The effect of interferon (IFN) on hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) has not been fully investigated in Chinese patients. We enrolled 58 HBeAg-negative CHB Chinese patients with hepatitis B viremia in Taiwan to evaluate the response to IFN. 30 patients received recombinant IFN 5 million units 3 times weekly for 6-10 months, and 28 patients who refused IFN treatment served as controls. Rates of virological response and biochemical response were higher in the treated group at the end of treatment (57% vs 18%, P = 0.006, and 73% vs 29%, P = 0.002, respectively). Both effects were superior in the treated group at 6 months after IFN withdrawal (virological: 30% vs 7%, P = 0.06; biochemical: 47% vs 7%, P = 0.002). Improvement of liver histological activities with persistently biochemical response was found in 65% of the treated patients. After a mean of 32 months' follow-up, virological response was rarely maintained (17% vs 4%, P = 0.228) but biochemical response was better in the treated group (27% vs 4%, P = 0.039). None of the treated patients but five controls developed severe complications of CHB during the follow-up period. A larger total IFN dosage or a younger age (< or = 40 years) were associated with 'sustained' virological response. Younger age and higher baseline alanine transaminase values (> or = 120 Ul(-1)) were related to 'sustained' biochemical response.

Leung NW, Lai CL, Chang TT, Guan R, Lee CM, Ng KY, Lim SG, Wu PC, Dent JC, Edmundson S, Condreay LD, Chien RN, Anonymous00252. · Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong. · Hepatology. · Pubmed #11391543 No free full text.

Abstract: A study in Chinese patients with chronic hepatitis B showed that treatment with lamivudine for 1 year significantly improves liver histology and enhances hepatitis B e antigen (HBeAg) seroconversion compared with placebo. Fifty-eight patients from this 1-year study have received long-term treatment with lamivudine 100 mg; the outcome of 3 years of lamivudine is reported here. Before treatment, all patients had detectable HBeAg. HBeAg seroconversion (HBeAg-negative, anti-HBe-positive), hepatitis B virus (HBV)-DNA suppression, alanine transaminase (ALT) normalization, emergence of YMDD variant HBV, liver histology, and long-term safety were assessed. After 3 years of continuous treatment with lamivudine 100 mg daily, 40% (23 of 58) of patients achieved HBeAg seroconversion. In patients with baseline serum ALT >2 x upper limit of normal (ULN), the rate of HBeAg seroconversion was 65% (17 of 26). Median serum HBV-DNA concentrations were below the level of detection, and median ALT concentrations were within the normal range throughout 3 years of treatment. YMDD variant HBV emerged in 33 of 58 (57%) patients during the 3 years, of whom 9 (27%) achieved HBeAg seroconversion (6 after emergence of YMDD variant HBV). ALT levels and histologic scores after emergence of YMDD variant HBV did not show major deterioration. Lamivudine was well tolerated during 3 years of therapy. In conclusion, these data in Chinese patients with chronic hepatitis B show enhanced seroconversion rates with extended lamivudine treatment. Up to two thirds of patients with moderately elevated pretreatment ALT achieved HBeAg seroconversion after 3 years of therapy.

Liaw YF, Leung NW, Chang TT, Guan R, Tai DI, Ng KY, Chien RN, Dent J, Roman L, Edmundson S, Lai CL. · Liver Research Unit, Chang Gung Memorial Hospital and University, Taipei, Taiwan. · Gastroenterology. · Pubmed #10889166 No free full text.

Abstract: BACKGROUND & AIMS: One-year lamivudine therapy significantly suppressed hepatitis B virus (HBV) replication, improved hepatic necroinflammatory activity, and prevented progression of fibrosis. However, the effects of prolonged therapy are unknown. METHODS: A total of 334 Asian patients with chronic hepatitis B from a previously reported 1-year study were randomized to receive either lamivudine (100 or 25 mg) or placebo for another year. The effects of treatment on serum HBV-DNA suppression, alanine transaminase (ALT) normalization, and hepatitis B e antigen (HBeAg) seroconversion were measured. The presence of YMDD variant HBV and its effect were also determined. RESULTS: A significantly greater proportion of patients achieved sustained HBV-DNA suppression and ALT normalization with 100 mg lamivudine daily for 2 years compared with lamivudine for 1 year followed by placebo for the second year (P<0.001). Daily lamivudine therapy for 2 years was safe and resulted in incremental HBeAg seroconversion from 17% at week 52 to 27% at week 104. HBeAg seroconversion during continued lamivudine therapy increased linearly with increasing pretherapy ALT levels (P< 0.001). Despite the emergence of YMDD mutant in 38% of the patients, they continued to clear serum HBeAg and maintain lower median serum HBV-DNA and ALT levels than baseline values. In contrast, ALT levels increased 8-12 weeks after switching from lamivudine to placebo, but returned to normal once lamivudine treatment was resumed. CONCLUSIONS: Treatment with lamivudine for 2 years is both well tolerated and efficacious in patients with chronic hepatitis B.

Tseng KC, Cheng PN, Wu IC, Chang CK, Chou AL, Liu WC, Chang TT. · Department of Internal Medicine, Buddhist Dalin Tzu Chi General Hospital, Chiayi, Taiwan. · Hepatogastroenterology. · Pubmed #19621708 No free full text.

Abstract: BACKGROUND/AIMS: Adefovir dipivoxil treatment leads to higher HBeAg seroconversion rates than placebo. The study was to evaluate which clinical or virological variables correlate with endpoints (e.g. HBeAg seroconversion and HBV DNA <10(5) copies/mL) during Adefovir dipivoxil or placebo therapy. METHODOLOGY: Fifty-two patients were enrolled with 33 in the ADV group and 19 in the placebo group. The correlation between clinical/virological variables and endpoints was evaluated by logistic regression as well as stratified analyses using Fisher's exact test. RESULTS: After one year of treatment, HBeAg seroconversion was associated with low pre-treatment HBV DNA levels. HBeAg seroconversion rates categorized by pre-treatment HBV DNA levels were distinct in the placebo group (<10(7) vs. >10(7) copies/mL, P=0.037) and in the ADV group (<10(8) vs. >10(8) copies/mL, P=0.039). In addition, HBV DNA levels reductions at week 4, week 8 and week 12 were associated with higher rates of HBeAg seroconversion. CONCLUSIONS: Low pre-treatment HBV DNA level is predictive of HBeAg seroconversion in patients treated with Adefovir dipivoxil or placebo. Adefovir dipivoxil may provide additional benefits for HBeAg seroconversion in patients with pre-treatment HBV DNA levels between 10(7) and 10(8) copies/mL. Profound early HBV DNA reduction may contribute to HBeAg seroconversion.

Wang CS, Yao WJ, Chang TT, Wang ST, Chou P. · Community Medicine Research Center and Institute of Public Health, National Yang Ming University, Shih-Pai, Taipei, Taiwan. · Cancer Epidemiol Biomarkers Prev. · Pubmed #19549812 No free full text.

Abstract: BACKGROUND: The risk of type 2 diabetes on the development of hepatocellular carcinoma remains inconclusive in different hepatitis statuses. METHODS: We prospectively followed a community-based cohort with 5,929 persons in southern Taiwan from January 1997 through December 2004, made up of 4,117 seronegative, 982 anti-hepatitis C virus-positive [HCV(+)], 696 hepatitis B surface antigen-positive [HBsAg(+)], and 134 coinfected persons. Before the study, 546 participants had developed diabetes. Hepatocellular carcinoma diagnoses were from the National Cancer Registry. RESULTS: After 50,899 person-years of follow-up, 111 individuals had developed hepatocellular carcinoma. The highest risk of hepatocellular carcinoma, compared with seronegative individuals without diabetes, was in anti-HCV(+) individuals with diabetes [incidence rate ratio (IRR), 76.0], then coinfected (IRR, 46.0), anti-HCV(+) without diabetes (IRR, 26.1), HBsAg(+) with diabetes (IRR, 21.4), and seronegative with diabetes (IRR, 7.2; P < 0.001). Anti-HCV(+) (n = 132) and seronegative individuals (n = 352) with diabetes had a higher cumulative incidence rate of hepatocellular carcinoma than those without diabetes (log-rank test, P < 0.001). Multivariate Cox proportional hazards analysis showed that gender, age, body mass index > or =30, HBsAg(+) [hazards ratio (HR), 12.6], anti-HCV(+) (HR, 18.8), coinfection (HR, 25.9), and diabetes [HR, 2.7; 95% confidence interval (95% CI), 1.7-4.3] were independent predictors of hepatocellular carcinoma (P < 0.05). After stratifying hepatitis status in multivariate Cox analysis, diabetes was significant for seronegative (HR, 5.4; 95% CI, 1.7-17.1) and anti-HCV(+) individuals (HR, 3.1; 95% CI, 1.7-5.4). Body mass index > or =30 was significant for HBsAg(+) individuals (HR, 3.3; 95% CI, 1.3-8.1). CONCLUSION: Type 2 diabetes is a strong independent predictor of hepatocellular carcinoma in anti-HCV(+) and seronegative individuals but not in HBsAg(+) individuals.

Tseng KC, Chen LH, Chen CY, Chang TT, Chou AL, Wu IC, Cheng PN. · Department of Internal Medicine, Buddhist Dalin Tzu Chi General Hospital. · Hepatol Res. · Pubmed #19254345 No free full text.

Abstract: Aim: Anemia during combination therapy with pegylated interferon alfa-2b plus ribavirin (RBV) for chronic hepatitis C virus (HCV) patients usually leads to RBV dose reduction or discontinuation. This study evaluated the effect of erythropoietin-beta (EPO-beta) to maintain RBV dose and hemoglobin (Hb) level in chronic HCV patients treated with antiviral combination therapy. Methods: Eighty-eight chronic HCV patients who developed anemia during therapy were enrolled into this retrospective study: 55 in the EPO-beta group and 33 in the untreated group. The study endpoints were to assess the RBV maintenance and the changes in Hb. Results: A higher percentage of patients with RBV maintenance was observed in the EPO-beta group compared with the untreated group (nadir Hb level <10.5 g/dL; 70% vs. 38%, P = 0.020; nadir Hb < 10 g/dL; 62% vs. 27%, P = 0.046). The mean Hb change from week 12 to week 20 was higher in the EPO-beta group when compared with the untreated group, especially for patients receiving a total EPO-beta dose of more than 16 000 U (+0.70 g/dL vs. -0.32 g/dL, P = 0.023) and of 10 000 U-14 000 U (+0.60 g/dL vs. -0.32 g/dL, P = 0.023). Conclusions: Low-dose EPO-beta can maintain RBV dose and increase Hb levels in anemic chronic HCV patients receiving combination therapy.

Young KC, Lien HM, Lin CC, Chang TT, Lee GB, Chen SH. · Department of Medical Technology, National Cheng Kung University Hospital, Tainan, Taiwan, ROC. · Talanta. · Pubmed #18968504 No free full text.

Abstract: A method to quantitatively perform reverse transcription-competitive PCR (RT-cPCR) of hepatitis C virus followed by both microchip and capillary electrophoretic separation and detection was described. In this method, HCV wild-type (WT) RNA extracted from serum was coretrotranscribed and coamplified with a constant amount of recombinant internal standard (IS) RNA which had the same primer binding region as the target RNA and was constructed by removing a centrally located 25-bp segment from the target template. A linear calibration curve was constructed by adding IS RNA at a constant concentration of 8000 copies mul(-1) into a series of RNA target standards ranging from 400 to 10(6) copies mul(-1). The amplified IS and target DNA were detected by both capillary and microchip electrophoresis via laser-induced fluorescence (LIF) using Cy5-labelled primer as the fluorescence probe. The method was further demonstrated for the quantitation of clinical patients with low, medium, and high viral titer and the results were found to be comparable to those determined by the commercial bDNA assay.

Wu IC, Shiffman ML, Tong MJ, Marcellin P, Mondou E, Frederick D, Snow-Lampart A, Sorbel J, Rousseau F, Chang TT. · Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China. · Clin Infect Dis. · Pubmed #18840078 No free full text.

Abstract: BACKGROUND: This study evaluated the persistence of hepatitis B e antigen (HBeAg) seroconversion (which is considered to be an important therapeutic end point) after adefovir dipivoxil treatment. METHODS: Forty-five patients who experienced confirmed HBeAg seroconversion and had a serum hepatitis B virus DNA level < 10(5) copies/mL while receiving 10 mg of adefovir dipivoxil in a prior study were enrolled in the present study. At the time of the last dose of adefovir dipivoxil (baseline), the median age of the patients was 35 years, 64% were male, 73% were Asian, 27% were white, the median alanine aminotransferase level was 25 IU/L, and the median serum hepatitis B virus DNA level was 3.0 log copies/mL. The median follow-up time was 150 weeks (range, 13-252 weeks). RESULTS: Forty-one patients maintained sustained seroconversion at the last 2 assessments, and 4 experienced seroreversion at weeks 12 (3 patients) and 16 (1 patient) of follow-up. Approximately 50% of patients had a hepatitis B virus DNA level < 1000 copies/mL at the last visit of the study period. Of 13 patients who were viremic and had available samples at the last visit, 11 had basal core promoter and/or precore mutations. Notably, 8 of these 11 patients had basal core promoter and/or precore mutations before adefovir dipivoxil therapy despite being HBeAg positive. The median duration of adefovir dipivoxil treatment was shorter before seroconversion (48 vs. 108 weeks; P = .03) and longer after seroconversion (41 vs. 22 weeks; P = .02) for patients who experienced sustained seroconversion, compared with the patients who experienced seroreversion. CONCLUSIONS: Prolonged adefovir dipivoxil therapy after HBeAg seroconversion appeared to increase the likelihood of sustained HBeAg seroconversion. Most patients who experienced HBeAg seroconversion and had viremia had precore and/or basal core promoter mutants, which usually existed before initiation of adefovir dipivoxil therapy.

Liu WC, Lindh M, Buti M, Phiet PH, Mizokami M, Li HH, Sun KT, Young KC, Cheng PN, Wu IC, Chang TT. · Department of Life Sciences, Mingdao University, Changhua, Taiwan. · Intervirology. · Pubmed #18812698 No free full text.

Abstract: OBJECTIVES: Eight genotypes (A-H) of hepatitis B virus (HBV) are known with variations in nucleotide sequences greater than 8%. Several recent publications found that the clinical course and outcome of antiviral therapy depended on the genotype of the infecting HBV strain. Large epidemiological studies will require the availability of a system which is rapid, reliable and can be performed on a large number of samples. METHODS: To establish a simple and accurate genotyping method, the study collected 369 HBV complete genomic sequences from the GenBank database. Type-specific primers were also designed that separated HBV genotypes A to G by multiplex polymerase chain reaction. RESULTS: By comparison with the traditional restriction fragment length polymorphism method, over 93% of 441 samples were accurately genotyped by current assay, with a higher detection rate and sensitivity to detect mixed HBV infections. CONCLUSIONS: This methodology can be applied only to areas prevalent with HBV genotypes A to G. However, it provides an efficient alternative for clinical diagnosis and large-scale studies.

Marcellin P, Chang TT, Lim SG, Sievert W, Tong M, Arterburn S, Borroto-Esoda K, Frederick D, Rousseau F. · Hopital Beaujon, Paris, France. · Hepatology. · Pubmed #18752330 No free full text.

Abstract: Treatment of 171 patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) with adefovir dipivoxil (ADV) 10 mg over 48 weeks resulted in significant histological, virological, serological, and biochemical improvement compared with placebo. The long-term efficacy and safety of ADV in a subset of these patients was investigated for up to 5 years. Sixty-five patients given ADV 10 mg in year 1 elected to continue in a long-term safety and efficacy study (LTSES). At enrollment, the 65 LTSES patients were a median 34 years old, 83% male, 74% Asian, 23% Caucasian, median baseline serum hepatitis B virus (HBV) DNA 8.45 log(10) copies/mL, and median baseline alanine aminotransferase (ALT) 2.0 x upper limit of normal. At 5 years on study, the median changes from baseline in serum HBV DNA and ALT for the 41 patients still on ADV were 4.05 log(10) copies/mL and -50 U/L, respectively. HBeAg loss and seroconversion were observed in 58% and 48% of patients by end of study, respectively. Fifteen patients had baseline and end of follow-up liver biopsies; improvements in necroinflammation and fibrosis were seen in 67% and 60% of these patients, respectively. Adefovir resistance mutations A181V or N236T developed in 13 LTSES patients; the first observation was at study week 195. There were no serious adverse events related to ADV. CONCLUSION: Treatment with ADV beyond 48 weeks was well tolerated and produced long-term virological, biochemical, serological, and histological improvement.

Gish RG, Lok AS, Chang TT, de Man RA, Gadano A, Sollano J, Han KH, Chao YC, Lee SD, Harris M, Yang J, Colonno R, Brett-Smith H. · Division of Hepatology and Complex GI, California Pacific Medical Center, San Francisco, California, USA. · Gastroenterology. · Pubmed #17983800 No free full text.

Abstract: BACKGROUND & AIMS: Entecavir demonstrated superior benefit to lamivudine at 48 weeks in nucleoside-naive patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB). We evaluated continued entecavir and lamivudine treatment through 96 weeks. METHODS: 709 HBeAg-positive CHB patients were randomized to entecavir 0.5 mg (n = 354) or lamivudine 100 mg (n = 355) once daily. At week 52, protocol-defined virologic responders could continue blinded treatment for up to 96 weeks. Patients continuing in year 2 (entecavir, n = 243; lamivudine, n = 164) were assessed for serum hepatitis B virus (HBV) DNA, alanine aminotransferase (ALT) normalization, HBeAg seroconversion, and safety. Cumulative confirmed proportions of all treated patients who achieved these responses were also analyzed. RESULTS: Among patients treated in year 2, 74% of entecavir-treated versus 37% of lamivudine-treated patients achieved HBV DNA <300 copies/mL by polymerase chain reaction (PCR), and 79% of entecavir-treated versus 68% of lamivudine-treated patients normalized ALT levels. Similar proportions of entecavir-treated and lamivudine-treated patients achieved HBeAg seroconversion (11% vs 12%, respectively). Higher proportions of entecavir-treated than lamivudine-treated patients achieved cumulative confirmed HBV DNA <300 copies/mL by PCR (80% vs 39%; P < .0001) and ALT normalization (87% vs 79%; P = .0056) through 96 weeks. Cumulative confirmed HBeAg seroconversion occurred in 31% of entecavir-treated versus 25% of lamivudine-treated patients (P = NS). Through 96 weeks, no patient experienced virologic breakthrough due to entecavir resistance. The safety profile was comparable in both groups. CONCLUSIONS: Entecavir treatment through 96 weeks results in continued benefit for patients with HBeAg-positive CHB.