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Biomedical subjects

A S Lok

Publications and source records attributed to A S Lok.

At least 37 records · Page 2Linked to original sources
PubMed1999

Mutations in the hepatitis B virus polymerase gene associated with antiviral treatment for hepatitis B.

Significant advances have been made, during the last 5 years, in the treatment of chronic hepatitis B. Several new antiviral agents: lamivudine, famciclovir, lobucavir and adefovir, have been shown to be safe and effective in inhibiting hepatitis B virus (HBV) replication. These compounds can be administered orally and are well tolerated. However, virus clearance is uncommon after short courses (<6 months) of therapy. Lamivudine and famciclovir have been evaluated in Phase III clinical trials in patients with chronic hepatitis B as well as in liver transplant recipients. Unfortunately, drug-resistant mutants involving the HBV polymerase gene, leading to breakthrough infection, have been reported in some patients who have received long courses (>/= 12 months) of treatment. The incidence, clinical outcome and biological significance of these mutants will be reviewed.

Amino Acid Sequence↗
PubMed1998

Hepatitis B virus S mutants in liver transplant recipients who were reinfected despite hepatitis B immune globulin prophylaxis.

Long-term hepatitis B immune globulin (HBIG) has been shown to reduce hepatitis B virus (HBV) reinfection in patients transplanted for hepatitis B. The aim of this study was to determine the prevalence of HBV S gene mutations in liver transplant recipients who developed recurrent hepatitis B despite HBIG prophylaxis, and to determine if these mutations can revert after withdrawal of HBIG. The entire S gene sequences in pre- and posttransplant sera from 20 patients who developed recurrent hepatitis B despite HBIG prophylaxis were compared. Ten (50%) patients had 18 amino acid substitutions involving the 'a' determinant in the posttransplant samples. These mutations were absent in 93% of the pretransplantation clones analyzed. There was a significant correlation between the development of mutations in the 'a' determinant region and the duration of HBIG therapy. Most of the mutations result in changes in predicted antigenicity of the S protein. During follow-up, mutations in 14 (78%) of 18 affected codons in the 'a' determinant region reverted back to the pretransplantation sequences; only 1 codon had a de novo change after the withdrawal of HBIG. Two control patients who did not receive HBIG had no change in the 'a' determinant in their posttransplantation samples. These data support the hypothesis that mutations in the S gene were induced or selected by immune pressure exerted by HBIG. HBV S mutants may play a role in HBV reinfection in liver transplant recipients who received HBIG prophylaxis.

Adult↗
PubMed1998

Predictive value of aminotransferase and hepatitis B virus DNA levels on response to interferon therapy for chronic hepatitis B.

In a previously reported randomized controlled trial of interferon-alpha (IFN-alpha) for chronic hepatitis B, we found a significant difference in response between Chinese adults with elevated vs normal pretreatment aminotransferase (ALT) levels. The aim of this study was to determine the correlation between serum hepatitis B virus (HBV) DNA levels and response to IFN therapy. HBV DNA levels in residual stored sera from patients who participated in the above trial were quantified by a branched DNA (bDNA) assay. Nominal logistic regression was used to estimate the probability of response to IFN treatment as a function of pretreatment ALT and/or HBV DNA levels. We found a significant (P < 0.01) correlation between the HBV DNA levels at midtreatment and response to IFN therapy. Response was achieved in 53% of patients who had undetectable HBV DNA levels at midtreatment but in only 17% of those who remained HBV DNA positive (P < 0.01). In contrast, the probabilities of response for patients with baseline HBV DNA levels over the range 10 to 10000 million equivalents (MEq) ml-1 were almost identical. We also found a significant correlation between the pretreatment ALT levels and response to IFN therapy. The probabilities of response for patients with pretreatment ALT levels of 500 and 100 IU l-1 were higher than for patients with normal ALT levels by two and onefold, respectively. Our findings may help to improve the cost-effectiveness of IFN therapy for chronic hepatitis B by guiding the selection of patients for therapy and in optimizing the duration of treatment for the individual patient.

Adult↗
PubMed1998

Hepatitis C virus genotypes in patients on renal replacement therapy.

BACKGROUND: Chronic hepatitis C virus (HCV) infection is prevalent among patients on renal replacement therapy. Viral genomic differences can contribute to diversities in clinical manifestation. The distribution of HCV genotypes depends on the geographical region and risk factors unique to the patient population. We determined the HCV genotypes in patients on renal replacement therapy in order to define the genotypic profile and examine the relationship between genotype, mode of renal replacement therapy, and the prevalence as well as severity of liver disease. METHODS: HCV genotypes were determined by restriction fragment length polymorphism and sequencing of the 5'-untranslated region in 21 renal allograft recipients, 29 patients on dialysis, and 26 non-renal failure controls. RESULTS: The most prevalent genotype among patients with renal failure was 1b (78%), followed by 1a (10%) and 6a (8%). 2 renal allograft recipients with 6a infection probably acquired HCV from the same donor. The relative prevalence of HCV genotypes was similar to that of controls. While renal allograft recipients demonstrated more severe liver disease than dialysis patients, the prevalence and severity of chronic hepatitis were similar between patients with 1b and non-1b infection. CONCLUSIONS: Resemblance of genotype distribution in Hong Kong to that of southern China and east Asia suggests common epidemiological evolution of HCV infection in these regions. Our results imply that in addition to viral characteristics, host factors such as the immunosuppressed state play an important role in the pathogenesis of liver disease in these patients.

Adult↗
PubMed1997

Clearance of hepatitis B surface antigen after bone marrow transplantation: role of adoptive immunity transfer.

Adoptive immunity transfer has been reported to be effective in clearing chronic hepatitis B virus (HBV) infection. Two hundred twenty-six patients who received allogeneic bone marrow transplantation (BMT) between May 1990 and September 1995 were screened for hepatitis B markers. Twenty-one patients were hepatitis B surface antigen (HBsAg) positive before BMT. The median follow-up period was 20 months (range, 2-59 months). Two of these patients had sustained clearance of HBV infection after transplantation. Both patients were hepatitis B e antigen (HBeAg)-negative, hepatitis B e antibody (anti-HBe)-positive, and serum HBV DNA-negative (by dot-blot hybridization) before BMT. Both had a flare in the serum alanine transaminase (ALT) level around the time of HBsAg clearance. Sustained clearance of HBsAg was observed in 2 of the 5 patients who received hepatitis B surface antibody (anti-HBs)-positive marrow but in none of the 16 patients who received anti-HBs-negative marrow (P < .05). One additional patient who received anti-HBs-positive marrow had transient HBsAg seroconversion. Among the 18 patients who remained persistently HBsAg-positive after BMT, 3 had HBeAg seroconversion and 3 had reversion to HBeAg positivity. In this study, we found a significant association between clearance of HBV infection and anti-HBs-positive bone marrow donors. Adoptive immunity transfer is effective in clearing HBV from patients with chronic HBV infection.

Adolescent↗
PubMed1997

Diagnosis of hepatitis C.

Currently, the second- and third-generation enzyme immunoassays (EIA-2 and EIA-3) for hepatitis C virus antibody (anti-HCV) are the most practical screening tests for the diagnosis of HCV infection. The need for and the choice of supplementary or confirmatory tests depend on the clinical setting and the likelihood of a true-positive EIA result. Detection of HCV RNA in serum by polymerase chain reaction (PCR) assay is the gold standard for the diagnosis of HCV infection. However, the lack of uniformity in current PCR assays has tarnished this standard. Confirmatory tests for the diagnosis of HCV infection are in general unnecessary in anti-HCV-positive patients who present with chronic liver disease. When indicated, the most appropriate test in this setting is a qualitative PCR assay for HCV RNA. Confirmatory tests should always be performed in anti-HCV-positive blood donors and individuals with normal aminotransferase levels. The most appropriate approach is to retest for anti-HCV using recombinant immunoblot assay (RIBA) and then test for HCV RNA using PCR assay in those who are RIBA positive or indeterminate. Liver histology is the gold standard in assessing severity of liver disease. Quantitative tests for serum HCV RNA levels do not help to determine the severity of liver disease. At the moment, HCV genotyping should be considered a research tool and not a part of the diagnostic work-up in clinical practice. The goals of treatment for chronic hepatitis C are sustained biochemical and virological response. Viral clearance should be determined by qualitative PCR assay. Quantifying serum HCV RNA level can help in predicting response to interferon treatment, but further studies using more standardized assays are needed to determine if these values can be used to select patients for treatment.

Algorithms↗
PubMed1997

High degree of conservation in the hepatitis B virus core gene during the immune tolerant phase in perinatally acquired chronic hepatitis B virus infection.

BACKGROUND: Mutations in the hepatitis B virus genome have been implicated in the persistence of hepatitis B virus infection and the pathogenesis of hepatitis B virus related liver disease. In view of the heterogeneity in published sequences, data from cross-sectional studies of unrelated subjects cannot differentiate true mutations from infections with variant sequences. AIMS/METHODS: We compared the hepatitis B virus core gene sequences of 42 HBsAg positive subjects from 11 Chinese families with those of the index patients (maternal carriers) to determine the frequency and rate of true hepatitis B virus core gene mutations in patients with chronic hepatitis B virus infection. RESULTS: Completely identical nucleotide sequences were present in all the family members and index patients in two families, suggesting that the hepatitis B virus core gene can be conserved for more than 20 years. The high degree of sequence conservation in these families is related to the young age of the subjects (mean 19.2+/-8.9 years), the fact that they were all HBeAg positive and that 75% of them had persistently normal aminotransferase levels. Longitudinal studies confirmed that mutations were rare in those who remained HBeAg positive with normal aminotransferase levels (immune tolerant phase), but significantly more common in HBeAg positive subjects who had elevated aminotransferase levels and in those who cleared HBeAg (immune clearance phase), the rates of nucleotide and amino acid changes were respectively: 0.28+/-0.12 vs 1.30+/-0.26/10(3) nt position/yr and 0.04+/-0.01 vs 0.18+/-0.5/10(2) codon/yr. CONCLUSIONS: Identical nucleotide differences could be found in the sequences of all the subjects in some families. These differences were more likely to be due to intra-familial transmission of stable variants. Sequence analysis based on comparisons with published sequences would have led to over-reporting of mutations. The hepatitis B virus core gene can remain highly conserved for more than two decades during the immune tolerant phase of perinatally acquired chronic hepatitis B virus infection. However, significant changes can occur within 2-3 years during the immune clearance phase.

Adolescent↗
PubMed1997

Acute liver failure due to hepatic involvement by hematologic malignancy.

Infiltration of the liver by secondary malignancies is a rare cause of acute liver failure. Acute liver failure caused by malignant infiltration is associated with almost 100% mortality and is typically diagnosed postmortem. Richter's transformation is a well-recognized complication of chronic lymphocytic leukemia. This transformation is the progression of chronic lymphocytic leukemia to a high-grade lymphoma. We describe the case of a 64-year-old man with a history of chronic lymphocytic leukemia who presented with acute liver failure. Liver biopsy revealed hepatic infiltration by a high-grade lymphoma. The patient responded to chemotherapy with normalization of hepatic function and remained disease-free after eight months. This case represents the first report of Richter's transformation presenting as acute liver failure. It also represents the fourth reported case of a patient with acute liver failure secondary to involvement by a hematopoietic malignancy that was successfully recognized and treated.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Interferon treatment for hepatitis C virus infection in patients on haemodialysis.

BACKGROUND: This study examined the efficacy and tolerability of interferon alpha-2b (IFN) in the treatment of chronic hepatitis C virus (HCV) infection in patients on maintenance haemodialysis. METHODS: A 24-month prospective cohort study was performed in 11 HCV RNA-positive haemodialysis patients, who were treated with IFN at 3 MU thrice weekly for 6 months. Serial biochemical and virological monitors included serum alanine aminotransferase levels, and HCV RNA by both qualitative PCR assay and quantitative bDNA assay. HCV genotypes were determined by PCR and nucleotide sequencing. Ten patients had baseline liver biopsy. RESULTS: HCV genotypes 1b and 2b were identified in 10 and one patients respectively. Six (55%) patients had biochemical and/or histological features of chronic active hepatitis before treatment. All 11 patients became HCV RNA-negative by PCR, with normalization of deranged aminotransferase levels, within 2-8 weeks of IFN therapy. HCV RNA reappeared in eight (73%) patients 2-8 weeks after the cessation of IFN, while biochemical relapse occurred in six (55%) patients. Sustained eradication of HCV was achieved in three (27%) patients. Sustained responders were characterized by pretreatment HCV RNA level < 3.5 x 10(5) Eq/ml as determined by the bDNA assay, and less severe histological abnormalities ('Total score' 1.7 +/- 1.2 compared to 5.4 +/- 2.2 in relapsers, P < 0.05). HCV RNA levels were similar before and after IFN treatment in non-responders and relapsers. Persistent malaise and poor appetite were noted in eight (73%) patients during IFN therapy. Other side-effects of IFN included the exacerbation of anaemia, induction of resistance to erythropoietin, weight loss, and reduced serum albumin level. CONCLUSIONS: Eradication of chronic HCV infection with IFN can be achieved in 27% of haemodialysis patients. Predictors of sustained response include low baseline HCV RNA level and mild liver pathology. Virological relapse can occur despite normal liver biochemistry. Exacerbation of anaemia, erythropoietin resistance, and malnutrition constitute the side-effects of IFN that deserve special attention in uraemic subjects.

Adult↗
PubMed1996

High rate of mutations in the hepatitis B core gene during the immune clearance phase of chronic hepatitis B virus infection.

Cross-sectional studies reported that hepatitis B core gene mutations are associated with active liver disease and responsiveness to interferon therapy. In view of the heterogeneity in published sequences, it is not possible to tell whether the differences in sequences observed were true mutations that developed during the course of infection. We conducted a longitudinal study to determine the rate of hepatitis B core gene mutations and the timing of these mutations in relation to hepatitis B virus replication, activity of liver disease, hepatitis B virus replication, activity of liver disease, hepatitis B e antigen (HBeAg) seroconversion, and interferon therapy. Serial sera from 55 patients with chronic hepatitis B infection were analyzed by direct sequencing of the hepatitis B precore/core gene to identify the nucleotide and amino acid changes that emerged during during follow-up. Patients who remained HBeAg positive and had normal amino transferase levels (Group I) maintained higher serum hepatitis B virus (HBV) DNA levels but significantly lower rates of both nucleotide and amino acid changes during follow-up compared with patients who remained HBeAg positive but had elevated aminotransferase levels (Groups II) and patients who cleard HBeAg (Group III). The rates of nucleotide and amino acid changes in Groups I, II, III patients were: 0.4 +/- 0.1, 1.9 +/- 0.3, and 2.4 +/- 0.4/nucleotide position/year; and 0.04 +/- 0.02, 0.21 +/- 0.05, and 0.38 +/- 0.07/codon/year, respectively. Most of the amino acid changes in Groups II and III patients occured during or shortly after flares in amino transferase levels, before HBeAg seroconversion. Similar rates of nucleotide and amino acid changes were found in interferon treated versus untreated patients, and in responders versus nonresponders. There was no difference in the location or nature of the hepatitis B core gene mutations between patients with and without HBeAg seroconversion, interferon treated versus untreated patients, and interferon responders versus nonresponders. In summary, changes in the hepatitis B core gene sequence was rarely detected in patients who were still in the immune tolerant phase but very high rates of changes were found during the immune clearance of chronic hepatitis B infection. Interferon therapy did not induce a higher rate or specific pattern of mutations in the hepatitis B core gene. Response to interferon therapy in HBeAg positive patients was unrelated to the number or location of hepatitis B core gene mutations.

Adult↗
PubMed1996

Correlation between serum HCV RNA and aminotransferase levels in patients with chronic HCV infection.

Cross-sectional studies on the correlation between serum hepatitis C virus (HCV) RNA and alanine aminotransferase (ALT) levels in patients with chronic hepatitis C have yielded conflicting results. We conducted a longitudinal study to examine the correlation between HCV viremia and serum ALT levels in individual patients over time. Serial samples (mean 9) from 25 patients with chronic HCV infection, including interferon-treated and untreated immunocompetent and immunosuppressed patients, collected over a period of 1-4.8 years (mean 2.6 years) were tested for HCV RNA and ALT levels using a highly reproducible quantitative (bDNA) assay. A significant correlation was found between serum HCV RNA and ALT levels in the patients who received IFN therapy, but no correlation was observed in the untreated patients. Among the untreated patients, the immunosuppressed patients had significantly higher HCV RNA levels (39 +/- 4 vs 3.6 +/- 8 Meq/ml, P < 0.0001) but significantly lower ALT (56 +/- 11 vs 97 +/- 12 units/liter, P = 0.03) levels when compared to the immunocompetent ones. In summary, we found no correlation between serum HCV RNA and ALT levels in chronic hepatitis C patients who are not receiving interferon therapy. Immunosuppression results in higher HCV RNA but lower ALT levels.

Adult↗
PubMed1996

Effect of human immunodeficiency virus infection on hepatitis C virus infection in hemophiliacs.

Chronic liver disease due to hepatitis C virus (HCV) infection is a major problem in hemophiliacs. Recent reports suggested that hemophiliacs coinfected with hepatitis C virus and human immunodeficiency virus (HIV) have an increased incidence of liver failure but the mechanism of accelerated liver injury is not clear. We tested plasma from 100 hemophiliacs for anti-HCV by second generation ELISA, anti-HIV by EIA, and HCV RNA and HIV RNA by branched DNA and polymerase chain reaction assays to determine if hemophiliacs coinfected with HCV and HIV have higher HCV RNA levels and more active liver disease. Seventy-nine (79%) patients were anti-HCV positive, of whom 85% were HCV RNA positive. None of the anti-HCV-negative patients had detectable HCV RNA in plasma. Forty-two (42%) patients were anti-HIV positive, of whom 47% had detectable HIV RNA. All the anti-HIV-positive patients were also anti-HCV positive. The prevalence of both anti-HCV and anti-HIV increased significantly with age. There was no difference in HCV RNA levels between anti-HIV-positive and anti-HIV-negative patients (mean: 21 +/- 4 vs 18 +/- 5 Meq/ml), although HCV RNA levels were significantly higher in anti-HIV-positive patients with CD4 counts < 200/mm3 (P = 0.008). There was an inverse correlation between HCV RNA levels and CD4 counts but no correlation was found between HCV RNA and serum aminotransferase levels. We found a high prevalence of HCV and HIV coinfection in our hemophiliacs. Hepatitis C virus replication appears to be increased in patients with severe immunodeficiency secondary to progressive HIV infection. However, there was no correlation between HCV RNA and serum ALT level, suggesting that HCV is not directly cytopathic.

Adolescent↗
PubMed1996

Iron overload in patients with chronic hepatitis C: a clinicopathologic study.

Recent studies suggest that increased hepatic iron may impair the response to interferon therapy in patients with chronic hepatitis C. We reviewed the records and liver biopsies of 72 patients with chronic hepatitis C to determine the prevalence of iron overload and to evaluate whether there is a correlation between serum and hepatic iron concentrations and activity of liver disease. Patients with other causes of liver disease or iron overload were excluded. Necroinflammatory activity and fibrosis were evaluated using modified Knodell score. Hepatic iron was assessed using Brissot's grading system. Increased serum iron and ferritin levels were found in 29% and 43% patients, respectively. Hepatic iron grades 0, I, II, III, and IV were present in 37%, 35%, 25%, 3%, and 0% of patients, respectively. A significant correlation was found between hepatic iron grade and serum ferritin (P = .0001). There was no correlation between hepatic iron grade and histological activity index or fibrosis score. In summary, we found a high proportion of patients with chronic hepatitis C had mild to moderate increase in hepatic iron content even when patients with alcoholism and recurrent transfusions were excluded. However, very few patients had severely increased iron load.

Adolescent↗
PubMed1996

Update of the Adult and Pediatric Liver Transplant Program at the University of Michigan.

Significant technical innovations and improvements in immunosuppression have been introduced into our liver transplant program since its inception in 1985. The indications for transplantation have been extended to younger and older patients, and simultaneously more patients with comorbidities have been accepted for transplant. The net impact of these changes has been a continuing trend toward improved survival. Overall, patients with hepatitis B or malignancy have had poor survival rates. The introduction of prophylactic anti-hepatitis B immunoglobulin and lamivudine, and better selection of patients with malignancy may improve results for these patients in the future. As in other programs, our most vexing problem is the continuing scarcity of donor organs which has led to an ever-expanding waiting list, more deaths while awaiting transplant, and more suffering before transplantation. The introduction of living donor hepatic transplantation will be of some help in alleviating this shortage. We are confident that the evolution of our program into a joint multidisciplinary structure will provide more efficient, convenient and cost-effective care to our patients.

Adolescent↗
PubMed1995

Naturally occurring core-gene-defective hepatitis B viruses.

This study was undertaken to determine the prevalence of core-gene-defective hepatitis B virus (HBV) in patients with chronic HBV infection, and the nature and significance of the deletions. PCR was performed on sera from 263 patients with chronic HBV infection. Seventeen (6.5%) patients had smaller band(s) in addition to a band of the expected size. Additional bands were also detected in the follow-up samples from 80% and 3% patients who had respectively, multiple and single bands initially. Six patients were further studied by direct sequencing. Four patients had in-frame deletions leading to loss of codons 79-122 of the core gene. Two patients had identical frameshift deletions of nucleotides 2204-2333 resulting in the loss of the first nine codons of the overlapping P gene. Follow-up samples from three of four patients studied showed deletions identical to those in the initial samples. The persistence of these deletions suggests that they were stable and that they may contribute to the chronicity of infection.

Adult↗
PubMed1995

Greater diversity of hepatitis C virus genotypes found in Hong Kong than in mainland China.

A hepatitis C virus (HCV) genotyping PCR assay based on type-specific primers was expanded to include genotype 6a as well as genotypes 1a, 1b, 2a, and 3a. The nucleotide sequences of a 194-bp fragment in the center of the HCV core gene showed that the homologies between genotype 6a and genotypes 1a, 1b, 2a, 2b, 3a, and 5 were 81.2, 82.1, 73.8, 77.3, 81.4, and 78.9%, respectively. A high degree of homology (99.6%) was seen in the amplified core region among eight clinically unrelated genotype 6a isolates. Although the Hong Kong Chinese patients had predominantly genotype 1b (70%), it was noteworthy that genotype 6a was the second most common genotype (14%). Four other HCV genotypes--1a, 1b, 2a, and 2b--were also present. In contrast, HCV infection by mainland China was confined to genotypes 1b and 2a. Thus, we found a greater diversity of HCV genotypes in Hong Kong than in mainland China.

Base Sequence↗