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Biomedical subjects

C M Chu

Publications and source records attributed to C M Chu.

At least 55 records · Page 3Linked to original sources
PubMed2000

Clearance of the original hepatitis B virus YMDD-motif mutants with emergence of distinct lamivudine-resistant mutants during prolonged lamivudine therapy.

Tyrosine-methionine-aspartate-aspartate (YMDD)-motif mutants may emerge and elicit immune clearance during prolonged lamivudine treatment. The aim of this study was to investigate the virological events following development of the original mutants. Twenty-three patients who developed YMDD-motif mutants during the Asian lamivudine trial were included. Serial serum samples from these patients were subjected to sequence analysis to identify new mutants. Site-directed mutagenesis experiments were performed to investigate whether the new mutations were responsible for lamivudine resistance. Of the 23 patients included, 13 harbored either one or a mixture of the two common YMDD-motif mutants (methionine 552-to-isoleucine [M552I] and leucine 528-to-methionine/methionine 552-to-valine [L528M/M552V]) throughout the course, whereas in the remaining 10 patients, distinct mutants became dominant over the original mutants to cause continuing chronic hepatitis. Of them, 3 developed an alanine 529-to-threonine (A529T) mutant, 6 developed a leucine 528-to-methionine/methionine 552-to-isoleucine (L528M/M552I) mutant, and 1 developed these two mutants sequentially. Site-directed mutagenesis experiments confirmed that the aforementioned mutations were responsible for the resistance to lamivudine in vitro. The nucleotide substitution in the A529T mutant concomitantly generated a stop codon at the surface gene, leading to impaired secretion of HBsAg. Strikingly, the replication of this mutant was lamivudine dependent. These results suggested that distinct lamivudine-resistant mutants could emerge and replace the original YMDD-motif mutants as the cause of continuing chronic hepatitis during prolonged lamivudine therapy.

Adult↗
PubMed2000

Prednisolone priming enhances Th1 response and efficacy of subsequent lamivudine therapy in patients with chronic hepatitis B.

Asian lamivudine trial has shown that hepatitis B e antigen (HBeAg) seroconversion rate during 1 year of lamivudine therapy was only 16% but was 64% in the subgroup of patients with a pretherapy serum alanine transaminase (ALT) level over 5 times the upper limit of normal (ULN). To test whether ALT rebound following corticosteroid priming enhances response to lamivudine therapy, a pilot study was conducted in 30 patients with ALT levels less than 5x ULN (43-169; N < 36 U/L). They received 30 mg of prednisolone daily for 3 weeks, 15 mg daily for 1 week, no treatment for 2 weeks, and then 150 mg of lamivudine daily for 9 months. Complete response (CR) was defined as ALT normalization with HBV-DNA seroclearance and HBeAg seroconversion. Peripheral blood mononuclear cell proliferation and cytokine secretion in response to recombinant HBV core antigen were serially assayed in 7 patients during priming and after withdrawal of prednisolone. Clinical rebound with an ALT over 5x ULN was observed in 20 patients (67%). Of these 20, 12 (60%) showed CR as compared with 1 (10%) of the 10 patients without significant ALT rebound (P <.002). The HBeAg seroconversion sustained in 70% of the patients 3 to 6 months after the end of lamivudine therapy. Immunological assays revealed that the responders showed Th1 dominant response and higher stimulation index to prednisolone priming. No serious side effect was encountered. These results suggest that corticosteroid priming induced immune/ALT rebound greatly enhances response to lamivudine therapy in chronic hepatitis B. Confirmation by randomized controlled trial is needed.

Adolescent↗
PubMed1999

Etiology of sporadic acute viral hepatitis in Taiwan: the role of hepatitis C virus, hepatitis E virus and GB virus-C/hepatitis G virus in an endemic area of hepatitis A and B.

The etiology of sporadic acute hepatitis was studied in 334 consecutive patients from Taiwan (237 men and 97 women, aged 16-81 years), with emphasis on the role of hepatitis C virus (HCV), hepatitis E virus (HEV), and GB virus-C/hepatitis G virus (GBV-C/HGV) in acute non-A, non-B (NANB) hepatitis and in HBsAg carriers with superimposed acute hepatitis. According to the conventional diagnostic criteria, there were 12 cases (3.6%) of acute hepatitis A, 17 cases (5.1%) of acute hepatitis B, 128 cases (38.3%) of acute NANB hepatitis, and 177 cases (53.0%) of acute hepatitis in HBsAg carriers (those who were HBsAg positive but IgM anti-HBc negative). Among 128 cases of acute NANB hepatitis, 70 (54.7%) had acute hepatitis C (HCV RNA positive), 5 (3.9%) had acute hepatitis E (IgM anti-HEV positive), and the other 53 (41.4%) were presumably acute hepatitis non-A-E. The prevalence of acute hepatitis A, B, E, and non-A-E showed no significant sex difference, whereas acute hepatitis C was significantly more prevalent in females. The prevalence of acute hepatitis A and B decreased and that of acute hepatitis C increased significantly with increasing age. In contrast, acute hepatitis E and non-A-E showed no significant age predominance. Of 177 HBsAg carriers with acute hepatitis, 64 (36.1%) demonstrated non-B hepatotropic virus superinfection, with HCV being the most common (60.9%), followed by hepatitis D, E, and A viruses, and the other 55 (31.1%) and 58 (32.8%) were presumed to have acute exacerbation of chronic hepatitis B or superimposed acute hepatitis non-A-E, respectively. Serum GBV-C/HGV RNA was detected in 3-4% of acute hepatitis non-A-E cases, suggesting its limited role in these cases.

Acute Disease↗
PubMed1999

Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection.

To examine the long-term effect of interferon (IFN) therapy in patients with chronic hepatitis B virus (HBV) infection, particularly on survival and hepatocellular carcinoma (HCC) prevention, 101 male patients with chronic hepatitis B in a randomized controlled trial were followed up for 1.1 to 11.5 years after the end of therapy. Of the 101 patients, 34 patients received a placebo (control), and 67 patients were treated with IFN (31 patients were treated with IFN alone and 36 patients were treated with IFN after prednisolone priming). Follow-up studies included clinical, biochemical, and virological aspects and HCC screening every 3 to 6 months. Twenty-eight (42%) of the 67 IFN-treated patients and 8 (24%) of the 34 untreated patients seroconverted by the end of the trial. During follow-up, 22 (56%) of the 39 patients who did not seroconvert in the treated group and 5 (19%) of the 26 patients who did not seroconvert in the control group showed a delayed sustained response (P <.005). The cumulative incidence of sustained response was highest in the steroid priming group (P =.049 vs. the IFN-alone group; P =.028 vs. the control group). HCC was detected in 1 (1.5%) of the 67 treated patients and 4 (12%) of the 34 untreated patients (P =.043). The interval between entry and HCC detection was 3.5 to 8.2 years. The cumulative incidence of HCC development was significantly higher in the control group than in the treated group (P =.013). In contrast, the cumulative survival rate was higher in the treated group than the control group (P =. 018). Multivariate analysis showed that IFN therapy, preexisting cirrhosis, and the patient's age at entry are significant independent factors for both survival and HCC development. The results suggest that IFN has long-term beneficial effects in terms of HBV clearance, reduction of HCC, and prolonging survival.

Adolescent↗
PubMed1999

Acute exacerbation and hepatitis B virus clearance after emergence of YMDD motif mutation during lamivudine therapy.

Lamivudine is a potent inhibitor of hepatitis B virus (HBV) replication, but its long-term use may be associated with HBV tyrosine-methionine-aspartate-aspartate (YMDD) motif mutation. To examine the clinical features and course after emergence of YMDD mutants, 55 patients who received lamivudine therapy over 104 weeks at our unit were assayed for YMDD mutation(s). Thirty-two of them were found to have the YMDD mutation. They continued lamivudine therapy and were followed up weekly or biweekly if clinically indicated. Thirty (93.7%) of them showed elevation of alanine transaminase (ALT), and 13 (40.6%) experienced acute exacerbation at 4 to 94 weeks (median, 24 weeks) after emergence of the YMDD mutant. The incidence of exacerbation is much higher than 4.3% in patients without the YMDD mutation (P =.003). Compared with patients without exacerbation, patients with exacerbation had a significantly higher serum HBV-DNA level after emergence of the YMDD mutant (P <.005). Before exacerbation, serum HBV-DNA level was rising to its peak, followed by the peaking of ALT (247-2,010 U/L) 1 to 4 weeks later. Three patients developed hepatic decompensation, but then in association with hepatitis B e antigen (HBeAg) seroconversion, recovered. Of the 12 evaluable patients, 8 (75%) showed HBeAg seroconversion, and 3 showed mutant clearance within 1 to 5 months after exacerbation. In contrast, none of the patients without exacerbation showed HBeAg seroconversion (P <.001). These results indicate that acute exacerbations may occur after emergence of the YMDD mutation. The incidence, clinicopathological features, and subsequent course, and possibly the underlying immune mechanisms, are similar to those of wild-type HBV chronic infection. Because severe hepatitis may occur, patients should be followed carefully once the YMDD mutant emerges.

Adolescent↗
PubMed1999

Effects of overlapping parametric resonances on the particle diffusion process.

The evolution of the beam distribution in a double-rf system with a phase modulation on either the primary or secondary rf cavity was measured. We find that the particle diffusion process obeys the Einstein relation if the phase space becomes globally chaotic. When dominant parametric resonances still exist in the phase space, particles stream along the separatrices of the dominant resonance, and the beam width exhibits characteristic oscillatory structure. The particle-tracking simulations for the double-rf system are employed to reveal the essential diffusion mechanism. Coherent octupolar motion has been observed in the bunch beam excitation. The evolution of the longitudinal phase space in the octupole mode is displayed.

Journal Article↗
PubMed1999

Viral superinfection in previously unrecognized chronic carriers of hepatitis B virus with superimposed acute fulminant versus nonfulminant hepatitis.

The role of viral superinfection in hepatitis B surface antigen carriers with superimposed fulminant (n = 60) versus nonfulminant (n = 90) acute hepatitis was studied. The frequency of hepatitis A virus (HAV) (0 versus 2.2%), HCV (18.3 versus 21.1%), HDV (15.0 versus 7.8%), and HEV (1.7 versus 4.4%) infection showed no significant difference, while simultaneous HCV and HDV infection was significantly more prevalent in the former (8.3 versus 0%). Only 3. 6% of fulminant cases and 3.3% of nonfulminant controls were HGV RNA positive.

Acute Disease↗
PubMed1999

Fulminant hepatic failure in acute hepatitis C: increased risk in chronic carriers of hepatitis B virus.

BACKGROUND/AIMS: The role of hepatitis C virus (HCV) in fulminant hepatitis remains controversial. This study was conducted to investigate the risk of fulminant hepatitis C in relation to HCV genotypes and concurrent infection of other viruses. PATIENTS: 109 HCV RNA positive patients from 334 consecutive cases hospitalised to a medical centre in northern Taiwan for overt acute viral hepatitis were prospectively evaluated. METHODS: HCV RNA was detected by a combined reverse transcription-polymerase chain reaction assay. HCV genotypes were analysed using a genotype specific probe based assay in the 5' untranslated region. RESULTS: 39 patients tested positive for hepatitis B surface antigen but negative for IgM antibody to hepatitis B core antigen, indicating concurrent chronic hepatitis B virus (HBV) infection. Twelve patients were hepatitis G virus (HGV) RNA positive. Genotyping of HCV disclosed 1b in 93, 1b mixed with 2a/2c or 1b mixed with 2b in 11, and not classified in five. Serum titres of HCV RNA were <10(5) copies/ml in 77, 10(5)-10(7) copies/ml in 25, and >10(7) copies/ml in seven. Eleven patients (10.1%) had fulminant hepatitis as a complication. Development of fulminant hepatitis did not correlate with age and gender of the patients, concurrent HGV infection, HCV genotypes, or serum titre of HCV RNA. However, the incidence (95% confidence interval) of fulminant hepatitis in patients with underlying chronic HBV infection was 23. 1% (9.9 to 36.3%), which is significantly higher than in those without (2.9% (-1.0 to 6.8%)). In 39 patients with concurrent chronic HBV infection, the clinical and virological characteristics showed no significant difference between those with fulminant hepatitis and those without. CONCLUSIONS: Acute hepatitis C in patients with concurrent chronic HBV infection is associated with a substantial risk of fulminant hepatitis.

Acute Disease↗
PubMed1999

Indocyanine green clearance test in non-cirrhotic hepatitis patients: a comparison and analysis between conventional blood sampling method and Finger Piece Monitoring method.

BACKGROUND: The indocyanine green (ICG) Finger Piece Monitor system is a non-invasive method for measuring blood ICG concentrations for the evaluation of hepatic function. This study was conducted to determine its clinical usefulness in non-cirrhotic patients. METHODS: Traditional liver function tests, alpha-fetoprotein, prothrombin time, and ICG clearance tests, by both blood sampling method and Finger Piece Monitoring method were performed simultaneously on 56 non-cirrhotic hepatitis patients. The plasma clearance rate (K) and 15-minute retention ratio (R15) of ICG were analyzed and compared with traditional liver function test results. RESULTS: The clearance rate using the Finger Piece Monitoring method was slightly lower than that of the blood sampling method (9.16 +/- 5.00%/min vs. 11.24 +/- 3.56%/min) with good correlation (r = 0.721, p = 0.0003). The 15-minute retention ratio using the Finger Piece Monitoring method showed better correlation with blood sampling method (32.83 +/- 23.99% vs. 28.49 +/- 23.74%, r = 0.944, p = 0.0002). Analysis between traditional laboratory tests and fR15 revealed a higher fR15 value in patients with bilirubin-total-T > or = 3 mg/dl (49.71 +/- 26.22% vs. 22.23 +/- 13.48%), alpha-fetoprotein > or = 100 ng/ml (61.96 +/- 15.84% vs. 28.52 +/- 21.74%), and PT prolongation > or = 3 sec (71.46 +/- 16.80% vs. 29.03 +/- 21.06%). CONCLUSION: There is a good correlation between the conventional blood sampling method and the ICG Finger Piece Monitoring system method. The ICG Finger Monitoring system provides an alternative for traditional laboratory tests for the evaluation of hepatic dysfunction in hepatitis patients.

Adult↗
PubMed1998

G1 phase dependent nuclear localization of relaxed-circular hepatitis B virus DNA and aphidicolin-induced accumulation of covalently closed circular DNA.

During chronic hepatitis B virus (HBV) infection, virus persistence relies on the maintenance of a pool of covalently closed circular DNA (cccDNA) in the nuclei of infected hepatocytes. To achieve this, HBV DNA has to be transported from the cytoplasm to the nucleus. By carrying out subcellular fractionation experiment, both of the relaxed-circular (RC) and single-stranded (SS) HBV DNA were found in the cytoplasm whereas only RC form could be detected in the nucleus of a hepatoblastoma cell line (HepG2) stably producing HBV. This fraction of nuclear RC viral DNA was clearly demonstrated in the G1 but not S phase of synchronized HepG2 cells. Conversely, the relative amount of cytoplasmic RC viral DNA in the S phase was larger than that in the G1 phase. Although no cccDNA could be detected in HepG2 cells without synchronization, an increasing amount of cccDNA in the nucleus was demonstrated after prolonged incubation of the cells in aphidicolin. Finally, by undertaking in situ hybridization using a probe specific to plus-strand HBV DNA, nuclear viral DNA was detected predominantly in the G1 phase of HepG2 cells. In summary, the results indicated that only RC but not SS form of HBV DNA was localized to the nuclei of HepG2 cells. The nuclear localization occurred preferentially in the G1 but not S phase and prolonged treatment with aphidicolin resulted in accumulation of nuclear cccDNA.

Aphidicolin↗
PubMed1998

Identification of a novel strain of hepatitis E virus responsible for sporadic acute hepatitis in Taiwan.

Hepatitis caused by the hepatitis E virus (HEV) is a self-limited disease and occurs most frequently as epidemic or sporadic hepatitis in developing countries. The role of HEV in sporadic acute hepatitis in areas without a history of hepatitis E epidemics is obscure. Recently, it was found that more than 10% of the patients with acute non-A, non-B, non-C hepatitis in Taiwan were associated with an acute HEV infection. Nucleotide sequences of the regions within the first open reading frame of HEV were determined in four cases and were 96.7-100% identical to each other. As compared to the isolates from China, Pakistan, Burma, India, Africa, and Mexico, the similarities were, however, only 71.7-79.3%. Phylogenetic analysis revealed that the four Taiwan isolates were categorized as a novel HEV group (the Taiwan strain), which was distinct from all of the strains isolated from other parts of the world. In addition, the isolates from China, Burma, India, and Pakistan were catalogued as the second genotype of HEV (the Asian strain), and the Mexican isolate as the third (the Mexican strain). The African isolate was more related to the Asian type and might be a subtype of the Asian strain. A simple genotyping method by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) is described. The findings also support the hypothesis that HEV may be responsible for some sporadic acute non-A, non-B, non-C hepatitis in other developed countries.

Base Sequence↗
PubMed1998

Emergence of an S gene mutant during thymosin alpha1 therapy in a patient with chronic hepatitis B.

The presence of a hepatitis B virus S gene mutant was investigated in a patient being treated with thymosin alpha1. He was seropositive for hepatitis B e antigen throughout therapy but was intermittently seronegative for hepatitis B surface antigen (HBsAg) by an RIA. Sequence analysis revealed an S gene mutant in HBsAg-seronegative serum with two consecutive amino acid substitutions: threonine115-to-isoleucine and threonine116-to-asparagine, whereas no amino acid substitution or deletion was found in the pre-S region. A site-directed mutagenesis experiment confirmed that these mutations were responsible for the failure to detect HBsAg. In summary, an S gene mutant was identified in an HBsAg-seronegative patient. The mutations were located outside the putative "a" determinant. The emergence of an S gene mutant during thymosin alpha1 treatment suggests that enhanced host immunity against HBsAg may play a role in its antiviral activity.

Adult↗
PubMed1998

Progression of the proportion of hepatitis B virus precore stop mutant following acute superinfection of hepatitis C.

To examine the progression of the proportion of hepatitis B virus (HBV) precore stop mutant (codon 28 of precore sequence; TGG to TAG) in the viral population of patients with dual hepatitis virus (B and C) infection, a series of serum samples obtained from six cases with chronic hepatitis B with acute hepatitis C superinfection were analysed by the method of amplification-created restriction site. At the time of superinfection, all patients included in the study were negative for hepatitis B e antigen and positive for its antibody. During the follow up of 30-90 months, in five of the six patients, three different patterns were observed: (i) the proportion of precore stop mutant increased in the first 20 months after acute hepatitis C virus superinfection and then decreased progressively thereafter (two cases); (ii) the proportion of precore stop mutant decreased progressively after superinfection (two cases); and (iii) no precore stop mutant was found during the course (one case). The remaining patient showed a progressive increase in the proportion of precore stop mutant over a period of 9 months after superinfection. Rather than the progressive increase in the proportion of precore stop mutants during the natural course of chronic HBV infection alone, the results of the present study showed a reverse course of progression following acute hepatitis C virus superinfection. This observation raised the possibility of a preferential or accumulative suppression on precore stop mutant by hepatitis C virus in the later stage of dual infection.

Adult↗
PubMed1998

Clinical and virological course of chronic hepatitis B virus infection with hepatitis C and D virus markers.

OBJECTIVE: Hepatitis B, C, and delta virus (HBV, HCV, HDV) share similar transmission routes; thus, dual or triple infections may occur and even persist in the same patient. However, little is known about the presentations and course of chronic HBV infection with HCV and HDV markers, which this study examined. METHODS: Antibodies against HCV (anti-HCV) and HDV (anti-HDV) were assayed as appropriate in patients with HBV infection. The clinical, pathological, and virological presentations as well as the course of the disease in patients with HBV/HDV/HCV triple infection markers were then reviewed. RESULTS: A total of 60 patients, 51 men and nine women, age 19-67 yr (mean 45.9+/-1.6 yr) were identified. Of these 60 patients, five (8.3%) were HBeAg positive and 10 (16.7%) cirrhotic at entry, 30 (50%) presented with acute superinfection (HCV or HDV, or both) and the remaining 30 presented with chronic liver disease. On presentation, 16 (53.3%) of the 30 patients with acute superinfection showed hepatic decompensation and eight (26.7%) died. In contrast, only one of the patients with "chronic liver disease" presented with hepatic decompensation. Of the 42 patients followed up for 1-15 (mean, 4.7+/-0.6) yr, 45.2% showed remission and 19% showed HBsAg seroclearance, whereas 12.5% of the 32 noncirrhotics developed cirrhosis and three of the nine cirrhotics became decompensated. At the end of follow-up, 29 patients (69.9%) were still seropositive for HCV-RNA but only nine (22.5%) were seropositive for HDV-RNA and five (12.5%) were seropositive for HBV-DNA. CONCLUSIONS: These results suggest that infection with HBV, HCV, and HDV triple markers is a severe disease in acute superinfection stage but that the course is relatively benign, slowly progressive, and usually dominated by HCV.

Adult↗
PubMed1998

Low-level viremia and intracellular expression of hepatitis B surface antigen (HBsAg) in HBsAg carriers with concurrent hepatitis C virus infection.

Assays of hepatitis B virus (HBV) replication and antigen expression in HBV surface antigen (HBsAg) carriers with concurrent hepatitis C or D virus (HCV or HDV) infection revealed that HCV and HDV can suppress HBV replication but that HCV also substantially suppresses HBV surface protein expression. HBsAg carriers with concurrent HCV infection thus have low-level viremia and intracellular HBsAg.

Carrier State↗