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Successful anti-hepatitis C virus therapy with telaprevir in an HIV/hepatitis C virus co-infected patient with a severe recurrence of hepatitis C virus infection on the liver graft
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AIDS Aug 26 2013 published ahead of print
Research Letter
Antonini, T.M.; Furlan, V.; Teicher, E.; Haim-Boukobza, S.; Sebagh, M.; Coilly, A.; Bonhomme-Faivre, L.; Peytavin, G.; Roque-Afonso, A.M.; Vittecoq, D.; Samuel, D.; Taburet, A.M.; Duclos-Vallee, J.C.
aAP-HP, Hopital Paul Brousse, Centre He'pato-Biliaire; bUniversity Paris-Sud, UMR-S 785; cInserm, Unite' 785, Villejuif; dAP-HP, HopitalBicetre, Pharmacie Clinique; eAP-HP, Hopital Bicetre, Service de Me'decine Interne, Immunologie et Maladies Infectieuses, Le Kremlin Bicetre; fAP-HP Hopital Paul Brousse, Service de Virologie; gAP-HP, Hopital Paul Brousse, Service
Anatomie Pathologique; hAP-HP, Hopital Paul Brousse, Pharmacie Clinique, Villejuif; iAP-HP, GH Xavier Bichat-Claude Bernard, Laboratoire de Toxicologie et Pharmacocine'tique; jUniversite' Paris, Paris; and kHepatinov, Villejuif, France.
Abstract
We report, for the first time, the outcome of anti-hepatitis C virus (HCV) triple therapy with telaprevir in an HIV/HCV co-infected transplanted patient. After liver transplantation, the patient experienced a severe HCV recurrence with fibrosing cholestatic hepatitis, and anti-HCV therapy with pegylated interferon alpha 2a, ribavirin and telaprevir was initiated. A sustained virological response was achieved after 48 weeks of anti-HCV therapy. Drug-drug interactions between antiretroviral therapy, immunosuppressive agents and anti-HCV therapy could be managed.
A 53-year-old, HIV/hepatitis C virus (HCV) (genotype 1b) co-infected woman underwent liver transplantation because of decompensated cirrhosis, a Model of End-Stage Liver Disease (MELD) score of 20 and the presence of hepatocellular carcinoma.
At the time of liver transplantation, plasma HIV viral load was undetectable [Cobas Taqman AmpliPrep/CobasTaqman v2, limit of quantification (LOQ) of 20 copies/ml; Roche Molecular Diagnostics, Mannheim, Germany) and CD4 cell count was 160 cell/ml (20%). Interleukin (IL)-28B polymorphism rs12979860 was CT for both recipient and donor. Immunosuppressive regimen was based on cyclosporine, corticosteroids and mycophenolate mofetil (MMF). Combined antiretroviral therapy (cART), including a fixed dose of abacavir/lamivudine (600 mg/300 mg), tenofovir (300 mg) and ritonavir-boosted darunavir (100 mg/800 mg) once daily, was reintroduced at day (D) 14 after liver transplantation.
Because of side effects (hypertrichosis and gingival hyperplasia), cyclosporine was switched to tacrolimus (TAC). No complications occurred during the post-liver transplantation course, but for arterial hypertension, the CD4 cell count was 82 cells/ml (18%) and the HIV viral load remained undetectable. Four months after liver transplantation, blood tests revealed raised levels of gamma-glutamyl transferase (gGT 916 IU/l), alanine aminotransferase (ALT 185 IU/l) and total bilirubin (91mmol/l); the HCV viral load was 8.66 log10 IU/ml (Abbott Real Time HCV PCR assay, LOQ of 12 IU/ml; Abbott Molecular, Illinois, USA). A liver biopsy displayed typical features of fibrosing cholestatic hepatitis (FCH) [1]. After the discontinuation ofMMF, anti-HCV therapy was initiated based on 1.5mg/kg per week of pegylated interferon alpha 2b (PEG-IFN a2b), and ribavirin (RBV) 600 mg/day. Erythropoietin (EPO) and eltrombopag
were introduced 3 weeks after the initiation of anti-HCV therapy because of the presence of anaemia (11 g/dl) and thrombocytopenia (<50 000 G/l). Following a 4-week lead-in phase, the plasma HCV viral load was 6.7 log10 IU/ml, with an improvement in the liver test parameters (gGT 583 IU/l, ALT 38 IU/l, total bilirubin 28mmol/l). Cumulated HIV genotypes showed the presence of the following resistance-associated mutations on reverse transcriptase gene: M41L, D67N, T69D, K70R, M184V, L210W, T215F, K219E on protease gene: L10I, L63P, A71T, V77I, L90M and none on the integrate gene.. HIV tropism testing performed in previous sample with detectable HIV RNA showed an R5 tropic strain. In line with the HIV genotypic susceptibility, and in order to prevent drug-drug interactions between cART, TAC and telaprevir (TVR), ritonavir-boosted darunavir was withdrawn and raltegravir (400mgtwice daily) was added to the abacavir/lamivudine/tenofovir regimen. The patient was hospitalized the day before the cART switch, for clinical monitoring and daily assays of trough blood concentrations of TAC.When a TAC steady state was achieved (3.6 ng/ml for 0.5mg twice daily), TVR was introduced (750mg
three times daily). The TAC dose was reduced by 50% 1 day before (D1) and on the day (D0) of the introduction of TVR. The oral clearance of TAC, assessed from the trough concentrations before and after TVR initiation,was 193 and 7.9 ml/min, respectively. The target TAC concentration was reached with 0.2mg administered every 72 h with an oral clearance of 9.8 ml/min. When TVR was discontinued (week 12), the steady-state dosing regimen was 2.5mg of TAC administered twice daily.
Retrospective trough plasma concentrations were determined for RBV and TVR at week (W)6, W7, W9, W10, W12 and W16 after the start of the lead-in phase. The mean trough plasma concentrations were found to be 3747 ng/ml (1806; 6028 ng/ml) and 3968 ng/ml (2995; 4496 ng/mL) for RBV and TVR, respectively. These were interpreted as being efficacious but significantly elevated.
From W4 to W48, the HCV viral load was undetectable, and liver test parameters normalized. SVR was obtained 24 weeks after stopping therapy (Fig. 1). The 2-year liver biopsy showed a portal fibrosis with some porto-portal bridging without necro-inflammatory activity (Metavir A0F2).
Fig. 1. HCV viral load kinetics according to cART and TAC treatment. (a) HCV viral load decline between baseline and W48. (b) TAC dosing regimens during HCV therapy depending on the cART. 3TC, lamivudine; ABC, abacavir; cART, combined antiretroviral therapy; DRT/r, darunavir/ritonavir; HCV, hepatitis C virus; PEG IFN, pegylated interferon; R, ribavirin; RAL, raltegravir; TAC, tacrolimus; TDF, tenofovir; TVR, telaprevir; W, week.
During the past 10 years, it has been shown that liver transplantation in HIV-infected patients is feasible. Most studies have demonstrated that patient and graft survival in transplanted HIV/HCV co-infected patients is poorer than those in HCV monoinfected patients [2-4]. The prognosis is particularly poor in the case of FCH, which represents a severe form of HCV recurrence with a 3-year survival rate of only 15%, despite anti-HCV treatment based on PEG-IFN and RBV [5]. Few, but encouraging, data are available in the literature about results of anti- HCV triple therapy with BOC or TPV in naive HIV/HCV co-infected patients (63 and 74% of SVR 24, respectively) [6,7]. Moreover, the principal problem when introducing anti-HCV therapy with BOC or TVR after liver transplantation is the interaction between the immunosuppressive therapy and boosted anti-HIV protease inhibitor [8,9]. In two recent small series, it has been shown that managing anti-HCV therapy while including BOC and TVR was feasible in the context of liver transplantation [10,11], but it is difficult to define effective and compatible HIV cART with BOC or TVR. However, the use of maraviroc has yet never been validated in transplanted HIV/HCV co-infected patients, although a rationale of its use may exist in this population [12].
We report here, for the first time, on successful anti-HCV triple therapy with TVR in an HIV/HCV co-infected liver transplant patient who experienced FCH. We
observed a complete normalization of liver function test parameters, and an extended and rapid virological response leading to a SVR 24.With respect to tolerability, the patient experienced anaemia, thrombocytopenia and neutropenia requiring the introduction of EPO, G-CSF and eltrombopag, despite a reduction of PEG-IFN and RBV doses to 45mg/week and 400 mg/day, respectively. Neither infectious nor dermatological complications were observed during this triple therapy.
As for the management of drug-drug interactions, it is not recommended to co-administer TVR with boosted HIV protease inhibitor; so darunavir/ritonavir was switched to raltegravir (a non-CYP3A substrate, devoid of interactions with TVR). On the contrary, a very potent interaction with TVR has been described with immunosuppressive therapy that includes CYP3A and Pgp substrates such as cyclosporine or TAC [13].
Triple therapy with TVR has now been shown to be effective in controlling HCV infection in HIV/HCV connected patients following liver transplantation.
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