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Recurrent hepatitis C genotype 1b following liver transplantation: treatment with combination interferon-ribavirin therapy.

BACKGROUND: Recurrent hepatitis C is very common leading to graft cirrhosis in a significant proportion of patients. Preliminary reports of combination therapy with interferon-ribavirin have been promising but generally applied to selected patients with chronic mild disease. Little is known, however, about the efficacy and risk of adverse effects when it is used in general clinical practice. AIMS: To analyse the efficacy (biochemical, virological and histological response) and tolerance of combination therapy in patients with recurrent hepatitis C genotype 1b. METHODS: Twenty-four patients (mean age 54 years; range 37-67 years; 75% male) with recurrent hepatitis C virus (histology at baseline: acute hepatitis (n = 3); chronic hepatitis (n = 21) with F3 or 4 in 77%) were treated with 12 months interferon (1.5-3 MU thrice weekly) + ribavirin (600-1200 mg daily) followed by 6 months ribavirin (58%), at a median of 427 days (56-2812) after transplantation. RESULTS: Seven patients (29%) discontinued therapy due to side effects, mainly anaemia, at a median of 3 months since initiation. Dose modifications were required in 88% of those completing the whole course of therapy. Overall, the sustained virological and biochemical response was 12.5%. This rate was slightly higher (18%) if only the 17 patients who finished the whole course of therapy were analysed. Histological improvement was achieved in 31.5% of treated patients. CONCLUSIONS: Combination therapy has a very limited efficacy in the liver transplant setting, although some benefit may be achieved, even in those with advanced graft fibrosis. Tolerance, however, remains a matter of concern.

Delayed onset of severe hepatitis C-related liver damage following liver transplantation: a matter of concern?

Although histological hepatitis occurs in the majority of hepatitis C virus (HCV)-infected liver transplant recipients, the natural history is highly variable. Whereas progression to cirrhosis occurs in up to 30% after 3 to 7 years, the disease remains stable in another third of patients, in whom protocol liver biopsies might be avoided. However, there is recent concern that with prolonged follow-up, some patients with initial benign recurrence may develop a late-onset aggressive course. Aims of the study are to determine the incidence and factors associated with this event. Based on yearly protocol biopsies (median, five biopsies; range, three to seven biopsies), we evaluated the histological outcome of 57 HCV type 1b-infected transplant recipients with initial benign recurrence, defined as stable histological state (fibrosis stage F0 or F1) during the first 3 years posttransplantation. Severe late-onset liver damage is defined as progression to F3 or F4 in patients with previous benign recurrence. Potential predictors of this event include demographics, donor-related factors, liver enzyme levels at 1 and 3 (or baseline) years posttransplantation, activity grade and fibrosis stage at 1 and 3 years posttransplantation, nonalcoholic steatohepatitis-related variables occurring within the first 3 years posttransplantation (diabetes, hyperlipidemia, obesity), use of some drugs (renin-angiotensin inhibitors, ursodeoxycholic acid), and the advent of any unusual event. The incidence of severe late-onset liver damage was 35% (n = 20). Twelve transplant recipients progressed to F3, whereas 8 transplant recipients progressed to F4. Sudden histological deterioration was observed on postoperative biopsy 5 in 12 patients; biopsy 6 or 7, in 7 patients; and biopsy 4, in 1 patient. Variables associated with this event in univariate analysis were fibrosis stage and activity grade (and its components) at baseline (P <.0001), recipient female gender (P =.04), alanine aminotransferase (ALT) level at 1 year posttransplantation (P =.02), and aspartate aminotransferase (AST) and ALT levels at baseline (P =.008 and P =.005, respectively). By multivariate analysis, only one variable was retained in the model: fibrosis stage at baseline (relative risk, 11; 95% confidence interval, 3 to 41; P =.0007), whereas AST level almost reached statistical significance (P =.07). In conclusion, delayed HCV-related severe liver damage is not infrequent in transplant recipients with initial benign recurrence, occurring in approximately one third of them. The presence of some degree of fibrosis at baseline appears to predict this sudden change in the natural history of recurrent hepatitis C. Based on these findings, we recommend continuing protocol biopsies and evaluating potential antiviral therapy in transplant recipients with evidence of some fibrosis (even if it is only portal).

Severe recurrent hepatitis C after liver retransplantation for hepatitis C virus-related graft cirrhosis.

An increase in the number of hepatitis C virus (HCV)-infected transplant recipients at need for repeated liver transplantation is anticipated. To date, there is a certain reluctance to accept these patients because of an increased organ shortage, early reports suggesting a poor outcome, and uncertainty regarding the natural history of recurrent hepatitis C in the second graft. The aim of this study is to determine the outcome of patients undergoing retransplantation for HCV-related graft cirrhosis. Of 49 transplant recipients with HCV-related allograft cirrhosis, 31 patients developed decompensation with criteria for retransplantation. Thirteen patients were denied this option. Of the 18 patients accepted, 6 patients died while on the waiting list (5 patients died of graft cirrhosis at a median of 3.2 months of listing), and 12 patients have undergone retransplantation (median, 10 months since HCV cirrhosis). After retransplantation, 8 patients (67%) died at a median of 8 months, and 4 patients (33%) remain alive after 1.9 years of follow-up. Causes and times of death from retransplantation were: surgical complications, n = 3 (perioperative period); HCV cirrhosis of the second graft, n = 2 (at 9 and 54 months); fibrosing cholestatic hepatitis, n = 1 (at 2 years); lymphoproliferative disorder, n = 1 (at 7 months); and endocarditis, n = 1 (at 3.5 years, with underlying cirrhosis). Of the 4 patients alive, fibrosis stages in the last biopsy specimens are stage 1 (n = 1), stage 3 (n = 1), and stage 4 or cirrhosis (n = 1; one patient has not undergone biopsy), despite antiviral therapy. The outcome of retransplantation for HCV cirrhosis of the first graft is very poor because of multiple complications. The severity of recurrent HCV disease in the second graft seems to be related to that observed in the first graft.

Hepatocellular carcinoma: Can it be considered a controversial indication for liver transplantation in centers with high rates of hepatitis C?

Hepatocellular carcinoma (HCC) is still considered a controversial indication for liver transplantation (LT), mainly because of long waiting times and underlying viral cirrhosis. The goal was to evaluate the outcome of LT in 104 patients with HCC and cirrhosis, mainly hepatitis C virus (HCV)-related, in a center with a short waiting time (median, 105 days). Four groups were formed according to the HCC and HCV status: HCV positive with HCC (group 1, n = 81), HCV negative with HCC (group 2, n = 23), HCV positive without HCC (group 3, n = 200), and HCV negative without HCC (group 4, n = 207). Predictive factors of tumor recurrence were demographics, tumor related (size or number of nodules, capsule, bilobar involvement, vascular or lymphatic invasion, clinical and pathologic TNM staging, pre-LT percutaneous ultrasound-guided ethanol injection or transarterial chemoembolization, alpha-fetoprotein levels), donor and surgery related, and year of transplantation. The same variables and "tumor recurrence (yes/no)" were applied to evaluate the effect on survival. The median follow up was 29 months (range, 0 to 104 months). Patient survival was 70% at 1 year and 59% at 5 years for group 1, 87% at 1 year and 77% at 5 years for group 2, 81% at 1 year and 64% at 5 years for group 3, and 88% at 1 year and 77% at 5 years for group 4 (P =.013). Survival was significantly lower in patients with HCC than in those without (74% and 63% versus 85% and 70%, at 1 and 5 years, respectively; P =.05). The causes of death in those with and without HCC were tumor recurrence (24%) and recurrent HCV (8%) versus sepsis (34%) and recurrent HCV (14%). HCC recurrence occurred in 12 patients (11.5%) at a median of 14 months (range, 3 to 60 months) with a probability increasing from 8% at 1 year to 16% at 5 years. In patients with HCC, tumor recurrence was associated with vascular invasion (P =.0004) by multivariate analysis; variables predictive of survival were donor old age (P =.01), viral-related etiology (P =.02), and tumor recurrence (P =.001). Although LT still remains an adequate indication for HCC in centers with high prevalence of HCV infection and short waiting times, both tumor and HCV-related recurrent diseases hamper significantly the outcomes of these patients.

Contribution of obesity to hepatitis C-related fibrosis progression.

OBJECTIVE: Hepatitis C virus (HCV) disease progression is variable. Identification of factors predictive of rapid progression is an important goal for improving patient management. The aim of this study was to evaluate the predictive role of several variables, including some that are etiologically related to the nonalcoholic steatohepatitis (NASH) syndrome such us obesity, in fibrosis progression in both patients with elevated and normal transaminase levels. METHODS: A total of 114 chronic HCV-infected (HCV-RNA positive) patients were recruited prospectively between 2000 and 2001. All patients had at least one liver biopsy. The annual change in fibrosis stage (fibrosis progression rate) was assessed from the time of presumed infection (fibrosis = 0) among those who had only one biopsy (n = 97) or between two biopsies if these were available (n = 17). Based on published data, we arbitrarily defined a patient as a rapid progressor when the fibrosis progression rate was > 0.2 U/yr. Potential predictors of rapid progression were: age at infection and biopsy, sex, significant alcohol intake (> 50 g/day), risk factor of HCV acquisition (based on answers to a questionnaire), obesity (based on body mass index [BMI]), autoantibodies, iron overload (ferritin, transferrin saturation), diabetes, hyperlipidemia, anti-HBcore IgG, genotype, and viral load. RESULTS: The median fibrosis progression rate was 0.05 U/yr (range 0-1.58 yr). In all, 22 patients (19%) were rapid progressors. Variables associated with progression by multivariate analysis included: advanced age at infection (p = 0.0001), BMI > or = 25 (p = 0.01), and ALT > 1.5 times upper limit of normal (p = 0.01). Among patients with ALT > 1.5 times upper limit of normal, these variables were advanced age at infection, BMI > or = 25, diabetes and transferrin saturation > 45. Among those with normal ALT levels, only BMI > or = 30 was predictive of progression. CONCLUSIONS: Obesity, advanced age at infection, and elevated ALT levels predict rapid disease progression, suggesting that measures aimed at weight reduction may play a significant role in hepatitis C management. The natural history of hepatitis C is independent of the presence of autoimmunity markers.

Contribution of donor age to the recent decrease in patient survival among HCV-infected liver transplant recipients.

Recurrent hepatitis occurs in the majority of patients undergoing liver transplantation for hepatitis C virus (HCV) cirrhosis, with progression to cirrhosis in up to 30% after 5 years. Based on these data, a decrease in survival can be anticipated with prolonged follow-up. Furthermore, posttransplantation HCV-fibrosis progression has been shown in recent years to increase. Our aims were (1) to describe the natural history of HCV-infected recipients, particularly to determine whether survival has decreased in recent years; (2) to compare this outcome with that observed in non-HCV-infected cirrhosis controls; and (3) to determine the factors associated with disease severity and survival. Among 522 cirrhotic patients undergoing transplantation between 1991 and 2000, 283 (54%) were infected with HCV. Yearly biopsies were performed in these recipients and at 1 and 5 years in the remainder. With similar follow-up, the percentage of deaths in the HCV(+) group was significantly higher than in the HCV- group (37% vs. 22%, P <.001), and patient survival was lower (77%, 61%, 55% vs. 87%, 76%, 70% at 1, 5, and 7 years, respectively; P =.0001). Although survival has increased in the HCV- group in recent years, it has significantly decreased in HCV recipients (P <.0001). The main cause of death among the latter was decompensated graft cirrhosis (n = 23/105, 22%), whereas that of HCV- patients was infections (n = 10/52, 19%). Reasons for the recent worse outcome in HCV+ recipients include the increased donor age and stronger immunosuppression. In conclusion, patient survival is lower among HCV+ recipients than among HCV- ones and has been decreasing in recent years. The aging of donors is a major contributor to this worse outcome.