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After liver transplantation (LT) for HCV-related cirrhosis, recurrence of HCV infection is universal and the risk of progression to cirrhosis is high. The modalities and efficacy of antiviral therapy in this indication are still controversial.

In the current study ( a pilot study) researchers present the results of 12-month combination therapy by pegylated alfa2b-interferon (PEG-IFN) and ribavirin in 20 patients.

Twenty patients entered the study (13 male and 7 female, median age 53.8 years). In 80% of patients, HCV infection was of genotype 1. The delay between LT and antiviral therapy was 28 months. The doses were progressively increased from 0.5 to 1 g/kg/week for PEG-IFN and from 400 to 1000–1200 mg/d for ribavirin. Follow-up was based on biochemical (ALT), virological (HCV-RNA) and histological (liver biopsy) examinations.

Results

Four patients (20%) were withdrawn due to adverse effects. In 6 patients the dose of PEG-IFN had to be reduced to 0.5 g/kg/week. A reduction in the dose of ribavirin in 13/16 cases was due to the onset of anemia. Histological evidence of mild acute rejection increased the immunosuppressive regimen in 5/20 patients.

At the end of the treatment, 75% of the patients had a biochemical response and 55% a virological response. The mean METAVIR score, according to activity and fibrosis, was A1.8 F2.2 before treatment and A0.3 F1.6 at the end of treatment.

In 9/20 patients, virological response persisted 6 months after the end of the treatment.

Conclusions

Our results suggest that combination therapy by PEG-IFN and ribavirin may be well tolerated and beneficial during recurrent hepatitis C in liver transplant recipients.

04/02/04

Reference
Jérôme Dumortier and others. Treatment of recurrent hepatitis C after liver transplantation: a pilot study of peginterferon alfa-2b and ribavirin combination. Journal of Hepatology 40(4): 669-674. April 2004.

Treatment of Recurrent Hepatitis C After Liver Transplantation: A Pilot Study of Peginterferon Alfa-2b and Ribavirin
 

After liver transplantation (LT) for HCV-related cirrhosis, recurrence of HCV infection is universal and the risk of progression to cirrhosis is high. The modalities and efficacy of antiviral therapy in this indication are still controversial.

Presented here are the results of a pilot study of a 12-month combination therapy with by peginterferon alfa-2b (PEG-IFN) and ribavirin in 20 patients.

Twenty patients entered the study (13 male and 7 female, median age 53.8 years). In 80% of patients, HCV infection was of genotype 1. The delay between LT and antiviral therapy was 28 months. The doses were progressively increased from 0.5 to 1 g/kg/week for PEG-IFN and from 400 to 1000–1200 mg/d for ribavirin. Follow-up was based on biochemical (ALT), virological (HCV-RNA) and histological (liver biopsy) examinations.

Results

Four patients (20%) were withdrawn due to adverse effects. In 6 patients the dose of PEG-IFN had to be reduced to 0.5 g/kg/week. A reduction in the dose of ribavirin in 13/16 cases was due to the onset of anemia. Histological evidence of mild acute rejection increased the immunosuppressive regimen in 5/20 patients.

At the end of the treatment, 75% of the patients had a biochemical response and 55% a virological response. The mean METAVIR score, according to activity and fibrosis, was A1.8 F2.2 before treatment and A0.3 F1.6 at the end of treatment. In 9/20 patients, virological response persisted 6 months after the end of the treatment.

Conclusions

These results suggest that combination therapy using PEG-IFN and ribavirin may be well tolerated and beneficial during recurrent hepatitis C in liver transplant recipients.

03/31/04

Reference
J Dumortier Treatment of recurrent hepatitis C after liver transplantation: a pilot study of peginterferon alfa-2b and ribavirin combination Journal of Hepatology  40(4): 669-674. April 2004.

New Onset Diabetes Mellitus After Liver Transplantation: The Critical Role of Hepatitis C Infection
 

Epidemiological studies suggest diabetes mellitus (DM) may be an extrahepatic manifestation of chronic hepatitis C virus (HCV) infection. Since diabetes and HCV are common in liver transplant recipients, we sought to examine the unique contribution of HCV infection to risk of de novo diabetes post-transplantation.

Using a cohort of 555 liver transplant recipients (median age 49 years, 54% males, 82% Caucasian) without preexisting diabetes from 3 U.S. centers enrolled between 1990 and 1994 and followed for a median duration of 5 years, researchers determined the incidence of de novo diabetes and the independent predictors of the development of diabetes. De novo diabetes was defined by the use of anti-diabetic medications.

De novo diabetes developed in 209/555 (37.7%) patients of whom 157 (28.3%) had transient-DM (T-DM) and 52 (9.4%) had persistent-DM (P-DM).

Among HCV-infected transplant recipients, de novo T-DM and P-DM developed in 26% and 14%, respectively. HCV was predictive of P-DM (P = .02) but not T-DM. Older age (P = .03) and tacrolimus use (P = .02) were also independent predictors of P-DM.

In conclusion, de novo diabetes is common in transplant recipients, but is typically transient in nature. However, among those developing de novo persistent diabetes, HCV is one of the most important risk factors.

This adds further support to the epidemiological data linking HCV and diabetes.

03/17/04

Reference
M Khalili and others. New onset diabetes mellitus after liver transplantation: The critical role of hepatitis C infection. Liver Transplantation

Journal of Hepatology, Vol. 40 (4) (2004) pp. 699-701
© 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
PII: S0168-8278(04)00044-3
 

Editorial

^*Corresponding author. Tel.: +49-511-532-3305; fax: +49-511-532-4896

Orthotopic liver transplantation (OLT) is an efficient treatment for patients with end-stage liver disease currently reaching 5-year survival rates of more than 70% (see www.eltr.org ). However, the improved control of many of the short-term problems after OLT shifted the focus of interest to the long-term complications. Chronic hepatitis C represents the most abundant single diagnosis in patients undergoing OLT. Therefore, recurrence of hepatitis C after OLT has been and is a major issue in transplantation medicine. In this issue of the Journal Dumortier and co-workers present their experience using combination therapy with pegylated interferon alpha and ribavirin, thus opening a new round in the fight against recurrent hepatitis C after OLT [1].

In the immunocompetent host, chronic hepatitis C is a slowly advancing disease taking decades to progress to liver cirrhosis. After OLT, recurrence of the virus is nearly universal and viral load is considerably higher than prior to transplantation [2-5]. The impact of recurrent hepatitis C on the prognosis of patients after OLT has been a point of intensive discussion for many years. Early reports found that a small proportion of patients (approx. 5%) suffer from a rapidly progressing cholestatic hepatitis similar to fibrosing cholestatic hepatitis (FCH) which had been detected in immunosuppressed patients with hepatitis B [6-8]. However, the remaining patients appeared to have a favourable prognosis and progression to cirrhosis was rarely detected [2,8]. It was the landmark work of Berenguer and co-workers, who recently demonstrated that the rate of fibrosis progression might have increased depending on the date of OLT [9]. Their results suggested that posttransplant hepatitis C has changed from a snail to a cheetah with respect to the speed of disease progression. In other words, the median time interval between OLT and detection of liver cirrhosis shortened from more than 10 years in patients transplanted in the late 1980s to around 3 years in patients transplanted in the late 1990s. Meanwhile, these results have been confirmed by other centres [10,11]. Once cirrhosis is established, signs of decompensation develop quickly [12]. Additionally, recent data suggest an impaired survival of patients with hepatitis C after OLT which is not caused by recurrence of hepatocellular carcinoma [13,14]. Various explanations have been suggested for these findings including changes in the selection of patients and in postoperative care. However, the most important factor appears to be the recent acceptance of elderly donors since there is a strong correlation between donor age and the course of recurrent hepatitis C after OLT [10,11,15]. The lack of an efficient strategy to prevent reinfection of the graft and the increasingly aggressive course of hepatitis C after OLT indicate the need for an effective antiviral therapy.

Several approaches have been proposed to prevent the progression of posttransplant hepatitis C to liver cirrhosis [16,17]. It was attempted to reduce viral load or eliminate HCV in patients on the waiting list for OLT using either standard interferon alpha monotherapy or standard interferon alpha/ribavirin combination therapy [18-20]. In treated patients, a virological response can be expected in up to one third of the patients, and 20% remain free of virus after OLT. However, many patients do not meet inclusion criteria, and serious adverse events occur frequently, mostly due to low platelet counts.

Treatment may be initiated in the first weeks after liver transplantation prior to the onset of biochemical or histological signs of recurrent hepatitis (preemptive/prophylactic therapy) [21-24]. Although effective in some patients and apparently not associated with a grossly increased rate of acute rejections, data supporting this approach are scarce. Pegylated interferons have not been used, and preemptive therapy was not directly compared to delayed treatment. Additionally, the tolerability of the treatment is limited in the early posttransplantation period. Therefore, most transplantation centres currently follow protocols that initiate treatment once signs or symptoms of recurrent hepatitis C develop.

Standard interferon alpha treatment of recurrent hepatitis C after OLT was evaluated at many centers [25-30]. The study groups were mostly small and uncontrolled. However, the overall picture is unequivocally unfavourable for standard interferon monotherapy, because viral clearance is rarely achieved. Initially, concern was raised as to the immunological safety of interferon use after OLT. Although induction of rejection was reported, careful histological evaluation prior to interferon therapy appears to keep the risk low, and severe rejection episodes are a rare event. Monotherapy using ribavirin was similarly ineffective as interferon with regard to viral clearance rates [30-34].

Treatment results improved when combination therapy with standard interferon alpha and ribavirin was introduced [35]. Seven papers with study groups of more than 25 patients have been published [36-42]. Intent-to-treat analysis showed average sustained virological response rates of around 20%. The main obstacle in achieving better results is formed by the frequent occurrence of untoward effects requiring dose reduction or even cessation of combination therapy. The most common side effects were either anaemia or leukopenia, which opened the discussion whether growth factors like erythropoetin or GSF should be used.

Many centres currently use pegylated interferon either as monotherapy or combined with ribavirin in patients with recurrent hepatitis C. However, published data on this treatment are scarce. Apart from preliminary data presented at meetings no regular papers are currently available. Now, Dumortier et al. present the Lyon data on combined treatment with pegylated interferon alpha 2b and ribavirin [1]. Of 20 patients treated, nine (45%) experienced a sustained virological response. These effects were mirrored by histological improvements. The main predictors of success were the viral genotype and the completion of the treatment course. This underlines the need for adherence of the patients to the treatment. However, the study was uncontrolled and the number of patients treated is limited. Side effects requiring dose reductions occurred in the majority of patients. Two other points regarding safety and tolerability of the treatment should be mentioned. Firstly, the protocol used an increasing dosing scheme for both ribavirin and interferon to reduce early side effects. This contrasts to the current discussion on an intensified induction phase to increase response rates. However, all but one responders showed viral clearance after 3 months of treatment. The second point is the high number of liver biopsies performed (six per patient). Acute rejection episodes were found in 20% of the patients but did not require cessation of the treatment. These data are reassuring with regard to the immunological safety of pegylated interferon in patients after liver transplantation. In summary, the data presented by Dumortier et al. support current practice at many transplant centres worldwide. Combination therapy with pegylated interferon alpha and ribavirin appears to be safe, and a substantial rate of sustained virological response appears to be achievable.

The first data using PEG-interferon/ribavirin combination therapy after liver transplantation are encouraging. However, many points remain currently unanswered and have to be addressed in further studies. The results need confirmation in a controlled study including a sufficient number of patients. An increasing number of patients has received antiviral therapy prior to and after OLT. Are there differences between non-responders and naïve patients? The optimal timing of therapy remains unclear. Should we favour preemptive therapy and how long do we need to treat? As dose reductions are required in many patients, the role of additional therapies like erythropoetin and other growth factors needs to be clarified. Even though combination therapy may not achieve sustained virological responses in the majority of the patients it needs to be evaluated whether fibrosis progression may be slowed down by continuing interferon treatment. Some of these questions are addressed by studies currently under way. We eagerly await the results of these ongoing studies

http://www1.elsevier.com/gej-ng/10/26/38/99/49/45/article.html

HCV Disease Recurrence is Earlier and More Severe in Living Donor Liver Transplantation (LDLT) Compared to Cadaveric Transplantation

The outcome of HCV recurrence in LDLT remains controversial. The objective of the current study, conducted in Spain, was to assess prognostic factors associated with severe HCV recurrence (SR) after LT.

A cohort of 117 consecutive HCV-infected patients undergoing LT from March 2000 to July 2003 was followed-up prospectively. LDLT was performed in 22 (19%) patients.  SR was defined as the presence of cirrhosis in a liver biopsy and/or clinical decompensation.

All variables potentially associated with  SR were prospectively recorded. Protocol liver biopsies were performed at 3, 12 and 24 months, and when clinically indicated. The association of these variables with SR was assessed by univariate and multivariate analysis.

Results

Pre-transplantation viral load, genotype and indication for LT were similar between recipients of a cadaveric organ and LDLT. However, the latter had younger donors (p < 0.001), less graft steatosis (p=0.06), more biliary complications  after LT  (p < 0.001) and  earlier and more severe acute hepatitis (higher ALT at 1 and 3 months; p < 0.001 and p=0.016).

After a follow-up of 664 days (77-1319), 26 (22%) patients developed SR (clinical decompensation in 12). SR occurred in 17 (18%) of 95 patients receiving a cadaveric organ and in 9 (41%) of 22 undergoing LDLT. 

SR was associated (Kaplan-Meier) with LDLT (p=0.019 ) and ALT>76 U/L 3 months after LT (p=0.023). The only variable independently associated with  SR was  LDLT (p=0.042; OR=2.39, 95%CI:1.02-5.60).

The authors conclude, “HCV disease recurrence is more aggressive in LDLT compared to cadaveric transplantation. This should be considered in LDLT programs, since [it] may ultimately compromise graft and patient survival.

Liver Unit, IDIBAPS/Hospital Clinic, Barcelona, Spain, and Liver Transplantation Unit, IDIBAPS/Hospital Clinic, Barcelona, Spain.

04/14/04

Reference
M Garcia-Retortillo and others. HEPATITIS C VIRUS (HCV) RECURRENCE IS AN EARLY AND SEVERE EVENT IN LIVING DONOR LIVER TRANSPLANTATION (LDLT). Abstract 2. 39^th EASL. April 14-18, 2004. Berlin, Germany.

Recurrent hepatitis C after orthotopic liver transplant (OLT) is associated with rapid fibrosis progression. HCV eradication with antivirals is difficult in this setting. The aim of the present study was to assess whether long-term ribavirin (RBV) monotherapy affects liver inflammation and fibrosis progression.  The study was conducted ar the Tor Vergata University in Rome, Italy.

Fifteen OLT recipients with HCV recurrent disease and a follow-up >4 years without any treatment received RBV monotherapy, up to the maximum tolerated dose, for 3 years. In each patient 6 yearly biopsies were assessed for grading and staging (Ishak), 3 before and 3 during treatment. Variations of >2 points for grading and of >1 point for staging in the last pre-treatment biopsy vs that after 3 years of RBV (end-of-treatment) were considered as significant histological changes (improvement/deterioration).

Results

Mean ribavirin dose was 353+74 mg/day. Mean grading score was 5.2+1.9 before and 4.3+1.4 after RBV (p<0.07). Fibrosis score improved in 2 patients, was unchanged in 10 and increased in 3.

Consequently, mean fibrosis score before and after 3 years RBV did not differ (2.27+1.1 vs 2.47+1.1, ns). The yearly fibrosis progression rate during the 3 years prior to treatment (excluding year one after OLT) was significantly greater than that observed during the 3 years of RBV therapy (p<0.002).

Conclusions

Long-term administration of low-dose ribavirin monotherapy is well tolerated in OLT recipients with recurrent HCV disease and associated with a significantly delay in fibrosis progression compared to a similar pre-treatment period. Extended studies are needed to assess the potential of RBV monotherapy in stabilizing liver disease in these difficult-to-treat patients.

04/28/04

Reference
R Lionetti and others. LONG-TERM RIBAVIRIN MONOTHERAPY SIGNIFICANTLY DELAYS FIBROSIS PROGRESSION IN OLT RECIPIENTS WITH RECURRENT HEPATITIS C. Abstract 144. 39^th EASL. April 14-18, 2004. Berlin, Germany.

http://www.hivandhepatitis.com/2004icr/39easl/documents/0428/042804_hcv_a.html