Decline in pulmonary function during chronic hepatitis C virus therapy with modified interferon alfa and ribavirin.

Rare interstitial lung disease cases have been reported with albinterferon alfa-2b (albIFN) and pegylated interferon alfa-2a (Peg-IFNα-2a) in chronic hepatitis C virus (HCV) patients. Systematic pulmonary function evaluation was conducted in a study of albIFN q4wk vs Peg-IFNα-2a qwk in patients with chronic HCV genotypes 2/3. Three hundred and ninety-one patients were randomly assigned 4:4:4:3 to one of four, open-label, 24-week treatment groups including oral ribavirin 800 mg/d: albIFN 900/1200/1500 µg q4wk or Peg-IFNα-2a 180 µg qwk. Standardized spirometry and diffusing capacity of the lung for carbon monoxide (DLCO) were recorded at baseline, weeks 12 and 24, and 6 months posttreatment, and chest X-rays (CXRs) at baseline and week 24. Baseline spirometry and DLCO were abnormal in 35 (13%) and 98 (26%) patients, respectively. Baseline interstitial CXR findings were rare (4 [1%]). During the study, clinically relevant DLCO declines (≥15%) were observed in 173 patients (48%), and were more frequent with Peg-IFNα-2a and albIFN 1500 µg; 24 weeks posttreatment, 57 patients (18%) still had significantly decreased DLCO, with a pattern for greater rates with albIFN vs Peg-IFNα-2a. One patient developed new interstitial CXR abnormalities, but there were no clinically relevant interstitial lung disease cases. The risk of persistent posttreatment DLCO decrease was not related to smoking, alcohol, HCV genotype, sustained virologic response, or baseline viral load or spirometry. Clinically relevant DLCO declines occurred frequently in chronic HCV patients receiving IFNα/ribavirin therapy and commonly persisted for ≥6 months posttherapy. The underlying mechanism and clinical implications for long-term pulmonary function impairment warrant further research.

Randomized trial of albinterferon alfa-2b every 4 weeks for chronic hepatitis C virus genotype 2/3.

Albinterferon alfa-2b (albIFN) is a fusion protein of recombinant human albumin/recombinant interferon (IFN)-α-2b, with ∼200-h half-life. Safety/efficacy of albIFN q4wk was evaluated in 391 treatment-naive patients with chronic hepatitis C virus (HCV) genotype 2/3. Patients were randomized 3:4:4:4 to one of four open-label treatment groups: pegylated IFN (Peg-IFN)-α-2a 180 µg qwk or albIFN 900, 1200 or 1500 µg q4wk, plus oral ribavirin 800 mg/day, for 24 weeks. Primary efficacy endpoint was sustained virologic response (SVR; HCV RNA <20 IU/mL 24 weeks post-treatment). SVR rates were as follows: 85%, 76%, 76% and 78% with Peg-IFNα-2a and albIFN 900, 1200 and 1500 µg, respectively (P = NS); corresponding rapid virologic response rates (HCV RNA <43 IU/mL at week 4) were as follows: 78%, 49% (P < 0.001), 60% (P = 0.01) and 71%. SVR rates were not influenced by interleukin 28B genotype, although rapid virologic response rates were greater with interleukin 28B CC (P = NS). Serious adverse event rates were as follows: 4%, 11%, 3% and 3% with Peg-IFNα-2a and albIFN 900, 1200 and 1500 µg, respectively. No increase in serious/severe respiratory events was noted with albIFN. Fewer absolute neutrophil count reductions <750/mm(3) occurred with albIFN (P = 0.03), leading to fewer IFN dose reductions. Haemoglobin reductions <10 g/dL were less frequent with albIFN 900 and 1200 µg vs 1500 µg and Peg-IFNα-2a (P = 0.02), leading to fewer ribavirin dose reductions. albIFN administered q4wk produced fewer haematologic reductions than Peg-IFNα-2a, but had numerically lower SVR rates (P = NS) in patients with chronic HCV genotype 2/3.

Response-guided therapy for patients with hepatitis C virus genotype 6 infection: a pilot study.

The optimal duration of treatment with pegylated interferon (PEG-IFN) plus ribavirin (RBV) in patients with hepatitis C virus (HCV) genotype 6 is unknown. This study was aimed at determining treatment response on the basis of rapid virological response (RVR) of HCV genotype 6 in comparison with genotypes 1 and 3. Sixty-six treatment naïve patients were treated with PEG-IFN-α2a (180 µg/week) plus weight-based RBV (1000-1200 mg/day). Patients with genotype 1 n = 16) and genotype 3 (n = 16) were treated for a fixed duration of 48 and 24 weeks, respectively. Patients with genotype 6 (n = 34) who achieved RVR were treated for 24 weeks (response-guided therapy) and the remaining patients were treated for 48 weeks (standard therapy). The mean baseline HCV RNA levels were not statistically different between groups (6.4 ± 0.8, 6.0 ± 1.0 and 6.5 ± 0.8 Log(10) IU/mL for genotypes 1, 3 and 6, respectively). Patients with genotypes 1, 3 and 6 achieved RVR in 43.8%, 87.5% and 73.5% of cases, respectively. One patient with genotype 1 and 3 with genotype 6 were considered nonresponders and discontinued therapy. Sustained virological response (SVR) was achieved in 62.5%, 81.3% and 76.5% of patients with genotypes 1, 3 and 6, respectively. The SVR rate in patients with genotype 6 who underwent response-guided therapy was 88%. This pilot study suggested that the SVR rate of HCV genotype 6 was at an intermediate level between those of genotypes 3 and 1. Treatment with PEG-IFN plus RBV for 24 weeks may be sufficient for patients with genotype 6 who achieve RVR. Prospective randomized trials are required to evaluate this response-guided strategy in a larger number of patients with genotype 6.

Favorable outcome of orthotopic liver transplantation in very high-risk situations.

BACKGROUND: Favorable outcomes of marginal liver grafts depends on optimal perioperative control and good recipient parameters. The aim of this study was to assess the results of marginal liver grafts associated with prolonged ischemic times and high-risk recipients. METHODS: We retrospectively reviewed data from patients who underwent orthotopic liver transplantation between 2001 and 2005. The patients were divided into two groups: group 1 received marginal liver grafts with ischemia times >or= 12 hours and recipient United Network for Organ Sharing (UNOS) status 1, 2A, and 2B. Patients who had marginal liver grafts with ischemic times less than 12 hours and/or better UNOS status were classified as group 2. We compared initial graft function as well as patient and graft survivals at 1 year between the two groups. RESULTS: Among 31 patients who were reviewed, four were excluded because of incomplete data and 24/27 received marginal liver grafts. Seven patients were classified into group 1, and 17 into group 2. The initial poor function rate was 85.7% (6/7 patients) and 76.47% (13/17 patients) in groups 1 and 2, respectively. The 1-year survival rate in group 1 was 85.7% (6/7 patients) and 94.12% (16/17 patients) in group 2. CONCLUSION: Marginal liver grafts can be used with favorable outcomes even in high-risk situations, such as prolonged ischemia times and high-risk recipients.

Pretransplant prediction of prognosis after liver transplantation in primary sclerosing cholangitis using a Cox regression model.

Liver transplantation remains the only treatment for patients with end-stage primary sclerosing cholangitis (PSC); however, selection criteria for the procedure and its timing remains uncertain. The aim of this study was to identify pretransplant variables associated with survival after transplantation and to devise a Cox regression model for prediction of post-transplant survival. We studied 118 patients transplanted for PSC at the Queen Elizabeth Hospital, Birmingham, UK, being followed for up to 91/4 years after the procedure. The association between pretransplant data and the post-transplant survival up to 1 year was studied using the logrank test (univariate analyses) and Cox multiple regression analysis. Univariate analyses showed the following variables to be associated with a decreased post-transplant survival: high serum creatinine, high serum bilirubin, biliary tree malignancy, previous upper abdominal surgery, hepatic encephalopathy, ascites, and Crohn's disease, whereas ulcerative colitis was associated with increased post-transplant survival (all P

Tacrolimus in liver transplantation.

Tacrolimus has been in clinical use for ten years. It was launched in a hail of publicity following the successful treatment of cases with apparently irreversible rejection using conventional immunosuppressive therapies. Since that time, the overall experience with the drug has increased considerably. The purpose of this article is to review tacrolimus comprehensively, including evidence derived from major clinical trials, to enable the reader to become familiar with its clinical role, including a comparison with its main competitor, cyclosporin. Tacrolimus was discovered in 1984, it predominantly acts via inhibition of T-cell mediated immunity, and to a lesser extent B-cell humoral immunity. The agent was introduced into clinical medicine in 1989 and was soon shown to be a highly effective immunosuppressive agent, receiving approval in 1994 by the Food and Drug Administration (FDA) for primary immunosuppression in adult and paediatric liver transplantation. Tacrolimus has proved to be a major development in transplantation. Whilst the available data have been hindered to some extent by deficiencies of trial design in the major studies, there is still more comparative clinical data available for tacrolimus than for any of its predecessors. The overall balance of risk benefit is considered by many to be tipped in favour of tacrolimus; it is likely that with more long-term follow-up results becoming available in liver and other solid organ transplants, the benefits will appear clearer.

Caffeine clearance by two point analysis: a measure of liver function in chronic liver disease.

This study attempted to compare the pharmacokinetic parameters of caffeine in patients with chronic liver disease and in normal subjects and to define the two sampling times which are suitable for determining caffeine clearance in these patients. Ten decompensated and eight compensated cirrhotic patients, and nine patients with chronic hepatitis were given a 3.5 mg/kg single oral dose of caffeine, followed by measurement of serum caffeine concentrations at 0, 30, 60, 90 minutes and 3, 5, 10, 24 and 36 hours using the HPLC technique. Caffeine clearance and its elimination rate constant in the decompensated cirrhotic patients were significantly lower than those in the compensated cirrhotic patients and much lower than in normal subjects (p > 0.01). Caffeine clearance in chronic hepatitis patients was also significantly lower than in normal subjects. The volumes of distribution of caffeine in compensated and decompensated cirrhotic patients and normal subjects were significantly different. There was also a significant difference between normal subjects and the chronic hepatitis group. Serum caffeine clearance showed a good correlation with Child Pugh's score at r = -0.788. Two sampling times within 10 to 24 hours after oral dose of caffeine served as the best sampling points for determination of caffeine clearance by the simple equation; Cl = kel approximately Vd (Vd is a fixed value in each group). It was clearly shown that caffeine clearance, calculated by two point analysis, would be a simple and useful method for measuring liver function in chronic liver disease.

Prevalence of hepatitis E virus infection in Thailand.

Hepatitis E, also known as epidemic, non-A, non-B hepatitis, is an acute, enteric, infectious disease. The disease is usually mild, except in pregnant women, who suffer a high fatality rate from fulminant hepatic failure. Information on the disease in Thailand is limited. The prevalence of antibodies to the aetiological agent, hepatitis E virus (HEV), was therefore studied, in various groups of subjects from several regions of this country, using commercial ELISA for anti-HEV IgG and IgM. The prevalence of anti-HEV IgG, which was 9%-22% in the adult subjects (blood donors, pregnant women, patients with acute hepatitis and cases seen during an outbreak of hepatitis), increased with age. It was relatively low in children and adolescents from Bangkok (3.6%) and in children from the north-east (1.8%-6.2%) and south (2.3%) of the country. Five (7%) of the 68 patients with acute viral hepatitis who were tested for anti-HEV IgM were found positive. Although these five cases had jaundice (four cases), diarrhoea (three) and/or dark urine (at least four cases), all of these clinical signs were self-limiting and had no sequelae. Given the apparently high prevalence of HEV infection in young adults in Thailand, control measures, including provision of clean water supplies and better personal sanitation and food hygiene, should be implemented to prevent an epidemic of the disease.