Management of hepatitis B: 2000--summary of a workshop.
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Animals↗
Biomedical subjects
E J Heathcote
Publications and source records attributed to E J Heathcote.
Transcription-mediated amplification is more sensitive than conventional PCR-based assays for detecting residual serum HCV RNA at end of treatment.
OBJECTIVE: In patients chronically infected with hepatitis C virus (HCV) undergoing antiviral therapy, sustained virologic response is suggested by viral clearance by end of treatment (EOT). Viral clearance is defined by nondetection of serum HCV RNA, usually by qualitative PCR-based assays with limits of detection ranging from 100 to 1000 copies/ml. However, some individuals relapse after achieving apparent viral clearance by EOT. These individuals may have low levels of viremia not detected by current PCR methods. The aim of this retrospective study was to determine whether the Bayer HCV RNA Qualitative Assay, which employs Transcription Mediated Amplification (TMA) and detects 50 HCV RNA copies/ml, could detect residual serum HCV RNA in patients who achieved apparent viral clearance by EOT and subsequently relapsed. METHODS: Samples were obtained at EOT (wk 24 or 48) and follow-up (wk 24-26 posttreatment) from 97 patients treated for HCV (78 relapsing patients, 19 sustained responders). All samples in which HCV RNA was not detected by PCR were tested in a blinded manner for HCV RNA by the TMA-based assay. RESULTS: HCV RNA was detected by the TMA-based assay in 27 (34.6%) EOT and 76 (97.4%) follow-up samples from relapsing patients, but not in any of the EOT or follow-up samples from sustained responders. CONCLUSION: Residual serum HCV RNA was detected by the TMA-based assay in EOT samples from 34.6% of patients that had achieved apparent viral clearance by PCR. The detection of HCV RNA by the TMA-based assay could help redefine EOT response and assist in the antiviral management of HCV infection.
Antiviral Agents↗
Peginterferon alfa-2a in patients with chronic hepatitis C.
BACKGROUND: Covalent attachment of a 40-kd branched-chain polyethylene glycol moiety to interferon alfa-2a results in a compound (peginterferon alfa-2a) that has sustained absorption, a slower rate of clearance, and a longer half-life than unmodified interferon alfa-2a. We compared the clinical effects of a regimen of peginterferon alfa-2a with those of a regimen of interferon alfa-2a in the initial treatment of patients with chronic hepatitis C. METHODS: We randomly assigned 531 patients with chronic hepatitis C to receive either 180 microg of peginterferon alfa-2a subcutaneously once per week for 48 weeks (267 patients) or 6 million units of interferon alfa-2a subcutaneously three times per week for 12 weeks, followed by 3 million units three times per week for 36 weeks (264 patients). All the patients were assessed at week 72 for a sustained virologic response, defined as an undetectable level of hepatitis C virus RNA (<100 copies per milliliter). RESULTS: In the peginterferon group, 223 of the 267 patients completed treatment and 206 completed follow-up. In the interferon group, 161 of the 264 patients completed treatment and 154 completed follow-up. In an intention-to-treat analysis in which patients who missed the examination at the end of treatment or follow-up were considered not to have had a response at that point, peginterferon alfa-2a was associated with a higher rate of virologic response than was interferon alfa-2a at week 48 (69 percent vs. 28 percent, P=0.001) and at week 72 (39 percent vs. 19 percent, P=0.001). Sustained normalization of serum alanine aminotransferase concentrations at week 72 was also more common in the peginterferon group than in the interferon group (45 percent vs. 25 percent, P=0.001). The two groups were similar with respect to the frequency and severity of adverse events, which were typical of those associated with interferon alfa. CONCLUSIONS: In patients with chronic hepatitis C, a regimen of peginterferon alfa-2a given once weekly is more effective than a regimen of interferon alfa-2a given three times weekly.
Adult↗
Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis.
BACKGROUND: Chronic hepatitis C virus (HCV) infection in patients with cirrhosis is difficult to treat. In patients with chronic hepatitis C but without cirrhosis, once-weekly administration of interferon modified by the attachment of a 40-kd branched-chain polyethylene glycol moiety (peginterferon alfa-2a) is more efficacious than a regimen of unmodified interferon. We examined the efficacy and safety of peginterferon alfa-2a in patients with HCV-related cirrhosis or bridging fibrosis. METHODS: We randomly assigned 271 patients with cirrhosis or bridging fibrosis to receive subcutaneous treatment with 3 million units of interferon alfa-2a three times weekly (88 patients), 90 microg of peginterferon alfa-2a once weekly (96), or 180 microg of peginterferon alfa-2a once weekly (87). Treatment lasted 48 weeks and was followed by a 24-week follow-up period. We assessed efficacy by measuring HCV RNA and alanine aminotransferase and by evaluating liver-biopsy specimens. A histologic response was defined as a decrease of at least 2 points on the 22-point Histological Activity Index. RESULTS: In an intention-to-treat analysis, HCV RNA was undetectable at week 72 in 8 percent, 15 percent, and 30 percent of the patients treated with interferon alfa-2a and with 90 microg and 180 microg of peginterferon alfa-2a, respectively (P=0.001 for the comparison between 180 microg of peginterferon alfa-2a and interferon alfa-2a). At week 72, alanine aminotransferase concentrations had normalized in 15 percent, 20 percent, and 34 percent of patients, respectively (P=0.004 for the comparison between 180 microg of peginterferon alfa-2a and interferon alfa-2a). In the subgroup of 184 patients with paired liver-biopsy specimens, the rates of histologic response at week 72 were 31 percent, 44 percent, and 54 percent, respectively (P=0.02 for the comparison between 180 microg of peginterferon alfa-2a and interferon alfa-2a). All three treatments were similarly tolerated. CONCLUSIONS: In patients with chronic hepatitis C and cirrhosis or bridging fibrosis, 180 microg of peginterferon alfa-2a administered once weekly is significantly more effective than 3 million units of standard interferon alfa-2a administered three times weekly.
Antiviral Agents↗
Ursodeoxycholic acid for primary biliary cirrhosis.
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Cholagogues and Choleretics↗
Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B.
The prognosis of decompensated cirrhosis resulting from chronic hepatitis B is poor, and the benefits of treatment with interferon are outweighed by serious side effects and by the risk of fatal exacerbation of disease activity. Lamivudine rapidly reduces hepatitis B virus (HBV)-DNA in serum to undetectable levels. We have treated 35 patients with chronic hepatitis B and decompensated cirrhosis with lamivudine 100 mg or 150 mg orally once daily. Pretreatment, all were positive for HBV-DNA in serum. Ten had Child-Pugh class B and 25 had Child-Pugh class C liver disease. Seven patients underwent liver transplantation within 6 months of treatment initiation, 5 patients died within 6 months, and 23 patients were treated for at least 6 months (mean = 19 months). In a majority of these 23 cases, there was a slow but marked improvement in liver function, which was most apparent after 9 months of treatment, with a decrease in serum bilirubin from 67 +/- 13 to 30 +/- 4 micromol/L (P <.05, baseline vs. 9 months), an increase in serum albumin from 27 +/- 1 to 34 +/- 1g/L (P <.05), and a decrease in Child-Pugh score from 10.3 +/- 0.4 to 7.5 +/- 0.5 (P <.05). Three patients developed resistance to lamivudine because of a mutation in the YMDD motif, but liver function did not deteriorate. We conclude that inhibition of viral replication with lamivudine results in a significant improvement of liver function in patients with decompensated HBV cirrhosis, but the long-term benefits remain uncertain.
Bilirubin↗
Vitamin D-receptor genotypes as independent genetic predictors of decreased bone mineral density in primary biliary cirrhosis.
BACKGROUND & AIMS: Hepatic osteodystrophy is a complication of primary biliary cirrhosis (PBC). Allelic polymorphisms of the vitamin D receptor (VDR) gene are related to bone mineral density (BMD) in normal cohorts and those with primary osteoporosis. We sought to establish the prevalence of reduced bone mass in PBC, correlate BMD with VDR gene polymorphisms, and identify risk factors for the development of hepatic osteodystrophy. METHODS: Seventy-two female patients with PBC were evaluated prospectively. Clinical information, BMD assessment, disease severity, and osteoporosis risk factors were documented, and multivariate regression modeling was performed. RESULTS: Twenty-four percent of the patients were osteoporotic at the lumbar spine and 32% at the femur. Severe bone loss (z score <-2.0) occurs 4 times more frequently in patients with PBC compared with controls. Body weight (P = 0.003) and postmenopausal status (P = 0.012) correlated independently with BMD. VDR genotype (P = 0.01) correlated with lower BMD at the spine only. CONCLUSIONS: Osteoporosis is a common complication of PBC. VDR genotype predicts lower BMD in patients with PBC. Studies are warranted to investigate the mechanism(s) by which VDR as well as other candidate genes may contribute to the development of hepatic osteodystrophy in PBC.
Adult↗
Are antibodies to carbonic anhydrase II specific for anti-mitochondrial antibody-negative primary biliary cirrhosis?
Antibodies to carbonic anhydrase II (CAII) have been reported to be specific to anti-mitochondrial antibody (AMA)-negative primary biliary cirrhosis (PBC). We examined whether antibodies to CAII are specific for AMA-negative PBC or a nonspecific response in autoimmune liver disease. Antibody assays to CAII, by western immunoblot (dilution 1:200), were performed on sera from 16 AMA-negative PBC patients, 21 AMA-positive PBC patients, 21 autoimmune hepatitis type 1 (AIH) patients, and 18 alcoholic liver disease (ALD) patients. CAII antibody activity was found in 8 of 16 (50%) of the AMA-negative PBC patients, 9 of 21 (43%) of the AMA-positive PBC group, 10 of 21 (48%) of the AIH group, and in 3 of 18 (17%) of the ALD control group. There was no difference in the prevalence of CAII antibody reactivity between the AMA-negative PBC, AMA-positive PBC, and AIH groups. In conclusion, we determined that CAII antibodies are detected with equal frequency in AMA-positive PBC and AIH. Given that CAII antibodies have been reported in other nonhepatic autoimmune diseases, we conclude that CAII antibodies are likely a nonspecific marker of autoimmunity rather than specific for AMA-negative PBC.
Adult↗
Serum cytokine values and fatigue in chronic hepatitis C infection.
Patients with chronic hepatitis C infection often experience fatigue. In many clinical situations, an association between fatigue and altered serum cytokine levels has been found. Altered cytokine levels in patients with hepatitis C have not shown a correlation with the degree of serum transaminase elevation or pathological change on liver biopsy. The aim of our study was to examine whether there was an association between abnormal serum cytokine levels and fatigue in patients with compensated chronic hepatitis C. Patients referred to a tertiary care hepatology clinic who were hepatitis C antibody positive and who had elevated alanine aminotransferase (ALT) levels were eligible for entry into the study. A control group was also included. Subjects in both groups who had characteristics other than hepatitis C that were known to alter cytokine values and/or cause fatigue were excluded. Patients completed a validated questionnaire to determine their fatigue severity score (FSS). Bioassays were used to measure interleukin (IL)-1, IL-6 and tumour necrosis factor-alpha (TNF-alpha) levels in early morning serum samples taken from patients and controls. Altered cytokine values were defined as those more than two standard deviations above the mean control value. Data was analysed using SPSS, version 8.01. Of the 78 patients with chronic hepatitis C who participated in the study, 19 (24%), 24 (30%) and 45 (56%) had elevated levels of IL-1, IL-6 and TNF-alpha, respectively, compared with only two (6%) of the control group who had elevation of any of the three cytokines. No correlation was found between the FSS and serum cytokine levels, when analysed singly or in combination, in patients with chronic hepatitis C. Hence, alteration in early morning serum levels of IL-1, IL-6 and TNF-alpha in patients with chronic hepatitis C infection and elevated ALT levels bear no correlation with the symptom of fatigue.
Alanine Transaminase↗
Management of primary biliary cirrhosis. The American Association for the Study of Liver Diseases practice guidelines.
Primary biliary cirrhosis (PBC) is a presumed autoimmune disease of the liver, which predominantly affects women once over the age of 20 years. Most cases are diagnosed when asymptomatic (60%). The antimitochondrial antibody is present in serum in most, but not in all, patients with PBC. The disease generally progresses slowly but survival is less than an age- and gender-matched general population. The symptomatic patient may have fatigue, generalized pruritus, portal hypertension, osteoporosis, skin xanthomata, fat soluble vitamin deficiencies, and/or recurrent asymptomatic urinary tract infections. Many nonhepatic autoimmune diseases are found in association with PBC and may prompt initial presentation. To date, immunosuppressive therapy has not been shown to prolong survival in PBC. The hydrophilic bile acid, ursodeoxycholic acid (UDCA), has been shown when given in a dose of 13 to 15 mg/kg daily for up to 4 years to delay the time to liver transplantation or death. This therapy also causes a significant improvement of all the biochemical markers of cholestasis but has no beneficial effects on any of the symptoms or associated disorders. Treatment with UDCA does not obviate the need for liver transplantation. Therapies to prevent complications arising from malabsorption, portal hypertension, and/or osteoporosis are required as well. Good control of pruritus can be achieved in most patients. PBC is diagnosed with increasing frequency, but the agent(s) responsible for this slowly progressive destruction of the interlobular bile ducts remains elusive and hence a specific therapy remains unavailable.
Autoantibodies↗
Prevalence of IgA antibodies to endomysium and tissue transglutaminase in primary biliary cirrhosis.
The association between celiac disease and primary biliary cirrhosis has been described in several case reports and small screening studies, with varying prevalence rates. Stored sera from 378 patients with primary biliary cirrhosis were tested for immunoglobulin (Ig) A endomysium and tissue transglutaminase antibodies. Ten patients were positive for both antibodies (2.6%); five of these patients had had small bowel biopsies confirming celiac disease. A further 44 patients (11.6%) had raised titres of IgA tissue transglutaminase antibody but were negative for IgA endomysium antibody. The increased prevalence of celiac-related antibodies in patients with primary biliary cirrhosis suggests that the two conditions are associated, although the reason for the association remains unclear. Patients with primary biliary cirrhosis should be considered to be at high risk for celiac disease. Although liver biochemistry does not improve when these patients are fed a gluten-free diet, the complications of untreated celiac disease warrant the identification and treatment of the condition in this population.
Celiac Disease↗
Clinical significance of serum bilirubin levels under ursodeoxycholic acid therapy in patients with primary biliary cirrhosis.
We determined whether the normalization of serum bilirubin level (SBL) induced by ursodeoxycholic acid (UDCA) therapy was associated with an improved clinical outcome in patients with primary biliary cirrhosis (PBC). We estimated the prognostic values of SBL measured after 6 months of UDCA treatment for survival free of orthotopic liver transplantation (OLT). We used a database of 548 patients with PBC followed in three trials of UDCA. Among UDCA-treated patients, we compared survival free of OLT in patients with normalized SBL (</=17 micromol/L) with those who had persistently elevated SBL. Difference in survival was tested between UDCA-treated patients whose SBL normalized with treatment and placebo patients who had normal baseline SBL. We evaluated, in each treatment group, the prognostic value of 6-month SBL. Survival was estimated using the Kaplan-Meier method and compared by the Cox model. Survival free of OLT was significantly longer in patients who had normalized SBL (P <. 0001; relative risk [RR]: 3.7, UDCA group). Survival free of OLT was not significantly different between UDCA patients with normalized SBL and placebo patients with a normal baseline SBL (P =.69). For several cutoffs of 6-month SBL, RRs of OLT or death were similar in UDCA-treated and placebo patients: the RR of OLT or death associated with a 6-month SBL more than 30 micromol/L was 6.0 for UDCA and 5.7 for placebo groups. In conclusion, normalization of SBL during therapy is associated with improved clinical outcome. SBL under UDCA therapy is a prognostic factor in PBC. SBL under UDCA therapy should be interpreted as in untreated patients.
Bilirubin↗
Detection of occult low-grade b-cell non-Hodgkin's lymphoma in patients with chronic hepatitis C infection and mixed cryoglobulinemia.
Hepatitis C virus (HCV) is both hepatotropic and lymphotropic and has been shown to be associated with the benign lymphoproliferative disorder, mixed cryoglobulinemia (MC). Preliminary studies suggest that there may be an association between chronic hepatitis C, MC, and non-Hodgkin's lymphoma (NHL). The aim of this study was to determine whether patients with chronic HCV and MC have occult bone marrow NHL. Sixteen patients with chronic HCV and clinically active MC underwent bone marrow biopsy and aspiration. Flow cytometry was performed looking for abnormal B-cell lineage. Molecular genetic studies were performed to identify B-cell monoclonality. Nine of 16 patients (56%) had abnormal marrow morphology, 7 (44%) were interpreted as suspicious for lymphoma, and 2 (13%) as consistent with lymphoma. Flow cytometry on 13 patients identified 5 (39%) with increased B-cell populations. Molecular analysis on 13 patients identified 3 (23%) with monoclonal proliferation of the B-cell lineage. All 13 patients tested for Epstein-Barr virus were negative by polymerase chain reaction (PCR). Four of 16 patients (25%) had marrow morphology and evidence of a monoclonal B-cell population by flow cytometry and/or molecular studies, consistent with B-cell NHL. These findings confirm the presence of lymphoproliferative disorders in patients with chronic HCV and MC. Some of these disorders meet the morphological and molecular criteria for the diagnosis of malignant lymphoma.
Adult↗
Chronic hepatitis C virus patients with breakthroughs during interferon treatment can successfully be retreated with consensus interferon. The Consensus Interferon Study Group.
Patients with chronic hepatitis C who have not had a sustained hepatitis C virus (HCV)-RNA response or serum alanine transaminase (ALT) response to a 6-month course of interferon (IFN) may respond to higher dose retreatment with consensus interferon (CIFN). Some nonresponders to initial IFN treatment have a transient response defined as undetectable HCV RNA or normalization of ALT during treatment, but subsequently have a "breakthrough" while still on treatment. The aim of this study was to determine if nonresponders who had breakthroughs responded differently to CIFN retreatment than nonresponders without breakthroughs using data from a large, multicenter trial. ALT and HCV RNA were monitored frequently during initial IFN therapy (either 9 mcg CIFN or 3 MU IFN-alpha2b 3 times per week). HCV-RNA breakthroughs were observed in 86 of 467 (18%) of all treated patients, and ALT breakthroughs were observed in 90 of 467 (19%) of all treated patients. There was no association between breakthroughs and the presence of either binding or neutralizing anti-IFN antibodies. When the patients who were nonresponders to initial IFN treatment were retreated with CIFN (15 mcg) for 12 months, 27% of those with viral breakthroughs had a sustained viral response compared with 8% in prior nonresponders without breakthroughs (P =.102). Sustained ALT responses were observed in 39% with breakthroughs compared with 10% in those without breakthroughs (P =.014). The data suggest that prior nonresponders with breakthroughs have a greater chance of responding to retreatment than do nonresponders without breakthroughs. However, most breakthrough patients would be missed unless repeated HCV-RNA testing were conducted during therapy.
Alanine Transaminase↗
Racial differences in responses to therapy with interferon in chronic hepatitis C. Consensus Interferon Study Group.
The likelihood of a sustained response to a course of interferon in patients with chronic hepatitis C correlates with several clinical and viral factors, including age, viral genotype and initial levels of hepatitis C virus (HCV) RNA in serum. The role of race and ethnicity has not been assessed. We evaluated the association of race with response to interferon in a large randomized, controlled trial using either consensus interferon (9 microg) or interferon alfa-2b (3 million units) given three times weekly for 24 weeks. African-American patients participating in the study were similar to white patients in mean age (43 vs. 42 years) and baseline levels of HCV RNA (3.6 vs. 3.0 million copies/mL) but had lower rates of cirrhosis (5% vs. 12%) and more frequently had viral genotype 1 (88% vs. 66%: P =.004). Most strikingly, the rates of end-of-treatment and sustained virological responses were lower among the 40 African-American patients (5% and 2%) than among the 380 white patients (33% and 12%) (P =.04 and.07). Rates of response among Hispanic and Asian-American patients were not statistically different than non-Hispanic white patients. Median viral levels decreased by week 24 of therapy by 2.5 logs in white patients (from 3.0 to 0.012 million copies/mL) but by only 0.5 logs among African- American patients (from 3.6 to 1.8 million copies/mL). Thus, there are marked racial differences in virological responses to interferon in hepatitis C that must be considered in assessing trials of interferon therapy and in counseling patients regarding treatment. The differences in response rates are as yet unexplained.
Adolescent↗
Effect of pretransplantation ursodeoxycholic acid therapy on the outcome of liver transplantation in patients with primary biliary cirrhosis.
As ursodeoxycholic acid (UDCA) delays the need for transplantation, this could result in patients with more comorbid disease, therefore more likely to have a worse outcome posttransplantation. The aim of this study is to compare posttransplantation outcome in patients who received UDCA versus placebo who subsequently required a liver transplant. Data on all trial patients referred for transplantation were retrospectively collected from three randomized controlled trials of UDCA in patients with primary biliary cirrhosis (PBC). An intent-to-treat analysis was conducted with patients assigned to their original treatment allocation. UDCA and placebo groups were compared at trial entry, transplant referral, just before transplantation, and 1 month and 1 year posttransplantation. From 1987 to 1996, 37 UDCA-treated and 53 placebo patients were referred for transplantation; their age, sex, and serum bilirubin levels were similar at study entry. Immediately before transplantation, these two groups were again similar with respect to age, bilirubin level, Mayo risk score, and serum creatinine level. Posttransplantation survival rates at 1 month were 93.9% in the UDCA group and 88.4% in the placebo group, and 1 year survival rates were 90.3% and 78.4%, respectively (not significant). Posttransplantation, the two groups had similar rates of infection (53.9% v 58%); however, rejection occurred significantly less often in the UDCA group; 42.9% versus 68. 8% in the placebo group (P =.04). The posttransplantation outcome of UDCA-treated patients with PBC is no different from those who were administered placebo. There is no evidence to suggest the beneficial effect of UDCA in delaying the need for transplantation is associated with a worse outcome once liver transplantation becomes necessary.
Age Factors↗
Long-term follow-up of a randomized trial of interferon therapy for chronic hepatitis B in a predominantly homosexual male population.
BACKGROUND/AIMS: Extended follow-up of a previously published therapeutic trial with interferon alfa is now available to further clarify the long-term outcome of HIV-negative and HIV-positive subjects with chronic hepatitis B virus infection after interferon alfa therapy. METHODS: Forty-five subjects with compensated liver disease and chronic hepatitis B infection with evidence of active hepatitis B replication were studied. These subjects were enrolled between 1986 and 1991 and had been randomized, stratified by HIV status, to either receive interferon therapy (10 MU/m2 of lymphoblastoid interferon alfa 3 times per week for 12 weeks) or no treatment. Hepatitis B serology, serum hepatitis B viral DNA and alanine aminotransferase were measured on an annual to biannual basis. CD4-positive T lymphocyte counts and HIV RNA concentration were also obtained. RESULTS: From 9 months post-interferon alfa treatment to the end of the extended follow-up (4 to 9 years), the relative risk of seroconverting to anti-HBe positive for subjects who had received interferon alfa therapy compared to those who did not was not significant in either HIV-negative (p = 0.80) or HIV-positive (p = 0.62) subjects. CONCLUSIONS: Unlike the first 9 months following interferon alfa therapy, the rate of elimination of markers of hepatitis B virus replication, regardless of HIV status, was not increased above the natural rate beyond 9 months following interferon alfa therapy.
Adult↗
Evidence-based therapy of primary biliary cirrhosis.
Primary biliary cirrhosis (PBC) is a disease which predominantly affects middle-aged women and is characterized by destruction of the interlobular bile ducts by chronic, often granulomatous, inflammation. This causes ductopenia and consequent cholestasis. Progressive fibrosis leads to cirrhosis and eventual liver failure. The frequent association of other autoimmune diseases and direct laboratory evidence of disturbed immune function suggest that PBC is an immune-mediated liver disease. Hence many clinical trials of therapy have employed immunosuppressive drugs. Another approach to therapy has been to reduce the degree of liver damage secondary to the cholestasis by altering the intra-hepatic bile acid milieu. These very different approaches to treatment of PBC are reviewed.
Azathioprine↗