Liver transplantation and hepatitis C

Willems, M; Metselaar, Herold J.; Tilanus, Hugo W.; Schalm, Solko W.; Man, Rob A. de

doi:10.1111/j.1432-2277.2002.tb00132.x

Cited by 42 publications

(22 citation statements)

References 89 publications

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“…1 Recurrent infection with HCV after OLT, however, is almost universal and is a significant cause of allograft dysfunction and allograft failure. [2][3][4] Preemptive interferon therapy (prophylaxis) in the early post-transplantation period may reduce the incidence and/or severity of recurrent HCV infection. In one study, 86 patients were randomized within 2 weeks after OLT to 3 million units of interferon alfa-2b or no treatment for 1 year.…”

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confidence: 99%

Peginterferon alfa-2a for hepatitis C after liver transplantation: Two randomized, controlled trials

et al. 2005

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There is currently no effective treatment for recurrent hepatitis C after orthotopic liver transplantation (OLT). We therefore performed two randomized, controlled trials--a prophylaxis trial and a treatment trial--to evaluate the safety and efficacy of peginterferon alfa-2a in patients who had undergone OLT. The prophylaxis trial enrolled 54 patients within 3 weeks after OLT, and the treatment trial enrolled 67 patients 6 to 60 months after OLT. In each trial, patients were randomized to treatment with once weekly injections of 180 microg peginterferon alfa-2a or no antiviral treatment for 48 weeks and were followed up for 24 weeks thereafter. Peginterferon alfa-2a treated patients had significantly lower hepatitis C virus RNA levels and more favorable changes in hepatic histological features compared with untreated controls. However, only 2 treated patients in the prophylaxis trial (8%) and 3 in the treatment trial (12%) achieved a sustained virological response. In the prophylaxis trial, 8 patients (31%) in the peginterferon alfa-2a group and 9 (32%) in the untreated group were withdrawn prematurely; whereas in the treatment trial, 10 patients (30%) in the peginterferon alfa-2a group and 6 (19%) in the untreated group were withdrawn prematurely. The incidence of acute rejection was similar in the treated and untreated groups in both the prophylaxis (12% vs. 21%; P = .5) and treatment (12% vs. 0%; P = .1) trials. In conclusion, peginterferon alfa-2a treatment for 48 weeks is safe and tolerable and offers some efficacy in the post-OLT setting. Randomized controlled studies are needed to establish the efficacy of pegylated interferon and ribavirin in patients who have undergone OLT.

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confidence: 99%

Peginterferon alfa-2a for hepatitis C after liver transplantation: Two randomized, controlled trials

et al. 2005

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“…9 Interestingly, many studies note that hepatitis C patients compared with controls have not shown a reduced graft or patient survival. [11][12][13] Recently, Forman et al, using the data from UNOS, reported that HCV-positive recipients were associated with an increased rate of death (hazard ratio, 1.23), especially in female recipients, compared with non-HCV recipients. 14 What factors may be influencing a more aggressive hepatitis course after transplantation?…”

Section: Natural History Of Hcv Posttransplantationmentioning

confidence: 99%

Retransplantation for recurrent hepatitis C: Positive aspects

McCashland¹

2003

Liver Transplantation

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“…In 85% of cases, the virus establishes a chronic infection, culminating in chronic inflammation, cirrhosis, and, increasingly, hepatocellular carcinoma (HCC). Indeed, HCV is now the leading cause of HCC and is the most common reason for liver transplantation in the West (47). Treatment is presently limited to the use of type 1 interferon in combination with the nucleoside analogue ribavirin; this therapeutic regime is successful in 40 to 80% of patients, depending on virus genotype.…”

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Hepatitis C Virus NS5A-Mediated Activation of Phosphoinositide 3-Kinase Results in Stabilization of Cellular β-Catenin and Stimulation of β-Catenin-Responsive Transcription

Street

Macdonald

McCormick

et al. 2005

J Virol

133

114

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The hepatitis C virus (HCV) nonstructural NS5A protein has been shown to bind to and activate phosphoinositide 3-kinase (PI3K), resulting in activation of the downstream effector serine/threonine kinase Akt/ protein kinase B. Here we present data pertaining to the effects of NS5A-mediated Akt activation on its downstream targets. Using a recombinant baculovirus to deliver the complete HCV polyprotein to human hepatoma cells in a tetracycline-regulable fashion, we confirm that expression of the complete HCV polyprotein also activates PI3K and Akt. We further show that this results in the inhibition of the Akt substrate Forkhead transcription factor and the stimulation of phosphorylation of a second key Akt substrate, glycogen synthase kinase-3␤ (GSK-3␤). Phosphorylation of GSK-3␤ results in its inactivation; consistent with this, we show that expression of the HCV polyprotein results in the accumulation of ␤-catenin. Finally, we show that levels of ␤-catenin-dependent transcription are also elevated in the presence of the HCV polyprotein. Given the prevalence of ␤-catenin mutations in many human tumors, especially colon and hepatocellular carcinomas, these data implicate NS5A-mediated PI3K activation as a contributory factor in the increasingly common association between HCV infection and the development of hepatocellular carcinoma.Hepatitis C virus (HCV) is recognized as a major public health problem; the World Health Organization estimates that as many as 170 million individuals (approximately 3% of the world population) are infected with this virus. In 85% of cases, the virus establishes a chronic infection, culminating in chronic inflammation, cirrhosis, and, increasingly, hepatocellular carcinoma (HCC). Indeed, HCV is now the leading cause of HCC and is the most common reason for liver transplantation in the West (47). Treatment is presently limited to the use of type 1 interferon in combination with the nucleoside analogue ribavirin; this therapeutic regime is successful in 40 to 80% of patients, depending on virus genotype.The HCV genome is a single-stranded positive-sense 9.6-kb RNA molecule, comprising a single open reading frame coding for a polyprotein of ϳ3,000 amino acids flanked by untranslated regions (UTRs). The 5Ј UTR contains an internal ribosome entry sequence, allowing cap-independent initiation of translation. The polyprotein is cleaved into 10 polypeptides by cellular and viral proteinases; one of these products is the nonstructural NS5A protein. NS5A has been the focus of much intensive investigation recently with regard to its potential role both in the cytopathology of HCV infection and in mediating viral immune evasion (for a review, see reference 33). NS5A has been reported to interact with a wide range of cellular proteins involved in, among others, the interferon response and cell cycle control. These interactions result in the modulation of various transcription factors, including NF-B (40, 46), STAT3 (31, 43), and AP-1 (32); furthermore, NS5A has been reported to promote anchorage-i...

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Liver transplantation and hepatitis C

Abstract: remain good indications for liver transplantation.

Cited by 42 publications

References 89 publications

Peginterferon alfa-2a for hepatitis C after liver transplantation: Two randomized, controlled trials

Peginterferon alfa-2a for hepatitis C after liver transplantation: Two randomized, controlled trials

Retransplantation for recurrent hepatitis C: Positive aspects

Hepatitis C Virus NS5A-Mediated Activation of Phosphoinositide 3-Kinase Results in Stabilization of Cellular β-Catenin and Stimulation of β-Catenin-Responsive Transcription

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