Teresa Maria Antonini

Safety and efficacy of protease inhibitors to treat hepatitis C after liver transplantation: A multicenter experience

BACKGROUND & AIMSnProtease inhibitors (PI) with peginterferon/ribavirin have significantly improved SVR rates in HCV G1 patients. Their use to treat HCV recurrence after liver transplantation (LT) is a challenge.nnnMETHODSnThis cohort study included 37 liver transplant recipients (male, 92%, age 57 ± 11 years), treated with boceprevir (n=18) or telaprevir (n=19). The indication for therapy was HCV recurrence (fibrosis stage ≥F2 (n=31, 83%) or fibrosing cholestatic hepatitis (n=6, 16%).nnnRESULTSnEighteen patients were treatment-naive, five were relapsers and fourteen were non-responders to dual therapy after LT. Twenty-two patients received cyclosporine and fifteen tacrolimus. After 12 weeks of PI therapy, a complete virological response was obtained in 89% of patients treated with boceprevir, and 58% with telaprevir (p=0.06). The end of treatment virological response rate was 72% (13/18) in the boceprevir group and 40% (4/10) in the telaprevir group (p=0.125). A sustained virological response 12 weeks after treatment discontinuation was observed in 20% (1/5) and 71% (5/7) of patients in the telaprevir and boceprevir groups, respectively (p=0.24). Treatment was discontinued in sixteen patients (treatment failures (n=11), adverse events (n=5)). Infections occurred in ten patients (27%), with three fatal outcomes (8%). The most common adverse effect was anemia (n=34, 92%), treated with erythropoietin and/or a ribavirin dose reduction; thirteen patients (35%) received red blood cell transfusions. The cyclosporine dose was reduced by 1.8 ± 1.1-fold and 3.4 ± 1.0-fold with boceprevir and telaprevir, respectively. The tacrolimus dose was reduced by 5.2 ± 1.5-fold with boceprevir and 23.8±18.2-fold with telaprevir.nnnCONCLUSIONSnOur results suggest that triple therapy is effective in LT recipients, particularly those experiencing a severe recurrence. The occurrence of anemia and drug-drug interactions, and the risk of infections require close monitoring.

Hepatitis C virus therapy in liver transplant recipients: Response predictors, effect on fibrosis progression, and importance of the initial stage of fibrosis

Antiviral therapy after liver transplantation (LT) using interferon (IFN) and ribavirin (RBV) can achieve a sustained virological response (SVR) rate ranging from 20% to 45%. The aims of our study were to assess efficacy and tolerability of therapy, effect on fibrosis progression and the importance of the initial fibrosis stage to outcome. A total of 113 hepatitis C virus (HCV)‐infected LT patients received 133 courses of IFN (standard, n = 29, pegylated IFN [pegIFN], n = 104) and RBV (75% genotype 1). Early virological response (EVR), end‐of‐treatment (EOT), and SVR were obtained in 74%, 55%, and 38%, respectively. EVR, completion of treatment, viral load before therapy, genotype non‐1, and use of pegIFN were predictive of SVR, but only EVR remained in the multivariate analysis. SVR was obtained in 45% patients who received a second course of therapy. Paired biopsies at baseline, at EOT and at long‐term were available in 42 patients. The mean fibrosis stage remained stable in patients with SVR and increased in patients without response. Rejection episodes were observed in 6% of patients. Tolerability of therapy decrease in patients with fibrosis stage ≥3 on baseline liver biopsy. A total of 20% of them died or were retransplanted due to liver failure as opposed to 1% of patients who had fibrosis stage <3. In conclusion, IFN and RBV achieved SVR in 38% of patients. EVR is independently associated with SVR. Fibrosis stage remained stable in patients with SVR and increased in nonresponders. Fibrosis stage ≥3 was associated with a high rate of liver failure, arguing for an early introduction of antiviral therapy. Liver Transpl 14:1766–1777, 2008.

Practical management of boceprevir and immunosuppressive therapy in liver transplant recipients with hepatitis C virus recurrence.

ABSTRACT Hepatitis C virus (HCV) recurrence is the most important complication in HCV liver transplant patients. Boceprevir with pegylated interferon and ribavirin (PegIFN/RBV) enabled improvement in sustained virological response rates of patients with genotype 1 HCV. Boceprevir interacts with immunosuppressive therapy (IT) by inhibiting the cytochrome P450 3A enzyme. Our aim was to study interactions and assess the safety of boceprevir in the context of HCV recurrence. Boceprevir (800 mg three times a day) initiated after a 4-week lead-in phase was associated with cyclosporine (three patients), tacrolimus (two patients), and everolimus (one patient) in five liver transplant patients with genotype 1 HCV infection who experienced HCV recurrence. The mean follow-up period after HCV therapy was 14.8 ± 3.1 weeks. Estimated oral clearances of IT decreased on average by 50%, requiring reduced dosing regimens. Anemia occurred in all patients, with a mean fall in hemoglobin levels between baseline and week 12 of 3.12 ± 2.27 g/dl. All patients required administration of β-erythropoietin (n = 5), three needed ribavirin dose reduction, and one needed a blood transfusion. A virological response was observed in all patients (mean HCV viral load [HVL] decrease at week 12, 6.64 ± 0.35 log10 IU/ml). These preliminary results in liver transplant patients with HCV recurrence demonstrate the feasibility and safety of coadministration of boceprevir and IT.

Long-term follow-up of liver transplanted HIV/hepatitis B virus coinfected patients: perfect control of hepatitis B virus replication and absence of mitochondrial toxicity.

Background:In patients coinfected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV), evolution toward cirrhosis and its complications is more rapid and severe than in patients infected with HBV alone. The outcome of liver transplantation in HBV–HIV-coinfected patients is poorly understood in terms of survival rate, HBV reactivation and mitochondrial toxicity on the liver graft. Patients and methods:Between November 2002 and June 2007, 13 HIV-positive patients underwent liver transplantation because of end-stage liver disease due to HBV with or without coinfection with hepatitis D or C virus. These patients were prospectively followed for an average of 32 ± 5.2 months (range 10–63 months). Results:All patients were alive at the end of the follow-up period and had normal liver function. Their HBV viral load was undetectable, no cccDNA was found in the liver graft and HIV infection was nonprogressive under antiretroviral therapy. Moreover, no mitochondrial toxicity was noted in the liver graft, as assessed by the spectrophotometric analysis of respiratory chain activities and by quantifying the mitochondrial DNA copy number. Conclusion:HBV–HIV-coinfected patients can successfully undergo liver transplantation with excellent results in terms of survival, control of HBV replication after transplantation and mitochondrial toxicity.

Posttransplantation hepatitis E: transfusion-transmitted hepatitis rising from the ashes.

In developed countries, acute hepatitis E virus (HEV) infections are increasingly reported mostly due to zoonotic genotypes 3 and 4 strains (1). Risk factors for these sporadic cases include consumption of raw or undercooked infected meat or direct contact with infected animals (1). In immunocomprom

Symptomatic and proven de novo amyloid polyneuropathy in familial amyloid polyneuropathy domino liver recipients.

D. Adams, C. Lacroix, T. Antonini, P. Lozeron, C. Denier, A. M. Kreib, S. Epelbaum, F. Blandin, V. Karam, D. Azoulay, R. Adam, D. Castaing, & D. Samuel 1,3,5,6,7 French Reference Center for FAP, Université Paris Sud, Paris, France, Department of Neurology, CHU Bicetre, Paris, France, Univ Paris Sud 11, Paris, France, INSERM U788, Universite Paris Sud, Paris, France, APHP, Hôpitaux de Paris, Paris, France, CHU Paul Brousse, Centre HepatoBiliaire, Villejuif, France, and INSERM U785 Villejuif, Paris

Twenty-year protocol liver biopsies: Invasive but useful for the management of liver recipients

BACKGROUND & AIMSnMost liver transplant centres have discontinued the practice of protocol liver biopsies (LB), mainly because of the perceived lack of therapeutic benefit. This study aimed to examine the usefulness of 20-year LBs.nnnMETHODSnTen, 15, and 20-year protocol LBs from 147 patients surviving for >20 years were reviewed. Twenty-year biopsy findings were correlated with clinical data.nnnRESULTSnTwenty-year-biopsy patients (N=91) and 20-year-non-biopsy patients (N=56) were similar in terms of transplant data, adverse events, and liver function tests (LFTs). Twenty-year LBs revealed a 90% prevalence of abnormalities, among which viral chronic hepatitis (VCH) was the most common (46%). Between 15 and 20 years, hepatic structural abnormalities were the only disorder to increase (p=0.008). An individual progression of abnormalities occurred in 56% of patients. At 20 years, the negative and positive predictive values (PV) of LFTs with respect to histological abnormalities were 95% and 18%, respectively; in VCH, Fibrotest and transient elastography displayed poor discriminative ability for fibrosis (80% and 81% discordance, respectively), but were satisfactory regarding significant fibrosis (negative PV of 77.7% and 80%, respectively). A decrease in immunosuppression was less frequent (14/91 vs. 20/56, p=0.008) while an increase was more common (15/91 vs. 2/56, p=0.017) in 20-year-biopsy patients than in non-biopsy patients. Antiviral therapy was administered in seven of the 20-year biopsy patients, but in none of the non-biopsy patients (p=0.04).nnnCONCLUSIONSnTwenty-year LBs provided important histological information on graft function that was available to a limited degree from LFTs and non-invasive markers. They exerted an impact on immunosuppressive and antiviral therapies.

Therapy with boceprevir or telaprevir in HIV/hepatitis C virus co-infected patients to treat recurrence of hepatitis C virus infection after liver transplantation.

Objective:Severe hepatitis C virus (HCV) recurrence affects post-transplant survival in HIV/HCV co-infected patients. This article describes the results of triple anti-HCV therapy with boceprevir or telaprevir in seven HIV/HCV co-infected patients following liver transplantation. Methods:All patients had severe HCV recurrence [fibrosis stage ≥F2 or acute hepatitis ≥A2 (nu200a=u200a5) or fibrosing cholestatic hepatitis (nu200a=u200a2)] associated with genotype 1a (nu200a=u200a4) or 1b (nu200a=u200a3). Patients were treated with Peg-interferon/ribavirin and boceprevir (nu200a=u200a2) or telaprevir (nu200a=u200a5) immediately (nu200a=u200a3) or after a 4-week lead-in phase (nu200a=u200a4). Immunosuppression included either cyclosporine (nu200a=u200a5) or tacrolimus (nu200a=u200a2). Prior to introducing telaprevir, combined antiretroviral therapy was switched in one patient to prevent drug–drug interactions. Results:At 24 weeks after the end of treatment, sustained virological response was observed in 60% (3/5) of the patients treated with telaprevir; no responders were observed in the boceprevir group. Triple anti-HCV therapy was prematurely discontinued in six patients [treatment failure (nu200a=u200a2), infection (nu200a=u200a2), acute rejection (nu200a=u200a1) and myocardial infarction (nu200a=u200a1)]. Anaemia occurred in all patients, requiring erythropoietin, ribavirin dose reduction and red blood cell transfusions in five patients.Average cyclosporine doses were reduced by 50–84% after telaprevir initiation and by 33% after boceprevir initiation. Tacrolimus doses were reduced by 95% with telaprevir. Conclusion:Our data suggest that in HIV/HCV co-infected patients, triple anti-HCV therapy with telaprevir greatly improved efficacy despite poor tolerability. Significant decreases in cyclosporine or tacrolimus doses are necessary prior to introduction of boceprevir or telaprevir. Close monitoring is essential to prevent drug–drug interactions among antiretroviral therapy, immunosuppressive agents and anti-HCV therapy.

Acute liver failure due to antitubercular therapy: Strategy for antitubercular treatment before and after liver transplantation.

The standard antitubercular treatment (ATT), which consists of isoniazid (INH), rifampicin (RIF), ethambutol, and pyrazinamide (PZA), is the best available treatment for tuberculosis (TB). However, the hepatotoxicity of INH and PZA can be severe, and even after drug withdrawal, patients may require liver transplantation (LT). In these cases, the strategy for the treatment of TB is poorly defined. Between 1986 and 2008, 14 patients presented at our department with severe hepatitis secondary to INH and PZA treatment. Four of these patients were immunosuppressed: 2 after renal transplantation and 2 because of human immunodeficiency virus infection. In seven of the 14 patients an alternative ATT was begun on admission, which was well tolerated. Hepatitis improved spontaneously in 5 patients, and alternative ATT was continued for 9.3 ± 4.2 months; 1 patient deteriorated and underwent LT, and 1 patient died. ATT was stopped definitively in 2 patients. Six patients required urgent LT, and alternative ATT was started after transplantation and was successful. Five patients receiving RIF had an episode of acute rejection. In conclusion, hepatitis secondary to ATT can be successfully treated with alternative anti‐TB regimens. The use of RIF in LT patients may lead to acute rejection. RIF should therefore be avoided in these patients. Liver Transpl 16:1136–1146, 2010.

29 EARLY TRANSPLANTATION IMPROVES SURVIVAL OF NON-RESPONDERS TO CORTICOSTEROIDS IN SEVERE ALCOHOLIC HEPATITIS: A CHALLENGE TO THE 6 MONTH RULE OF ABSTINENCE

W72 for the three renal groups were 1.1, 1.2 and 1.4mg/dL and median change from baseline was −0.10, 0, and −0.20, respectively. Four patients with mild renal impairment at baseline had a confirmed creatinine clearance <50mL/min; these patients remain stable on treatment with one patient continuing QOD dosing. No patient had a confirmed increase in serum creatinine ≥0.5mg/dL or phosphorus <2mg/dL. None of the serious AEs (N=8) were considered related to FTC/TDF. Two patients discontinued due to AEs considered related to treatment (ALT increased and worsening ulcerative colitis). Conclusion: FTC/TDF was well tolerated through WK72 in patients with mild to moderate renal impairment post OLT with appropriate monitoring and dose adjustment. Notably, no patient has experienced HBV recurrence including the treatment group that discontinued HBIG and remained on FTC/TDF alone.