January 7, 2013

Telaprevir & Boceprevir in Liver Transplantation

Reported by Jules Levin of NATAP

AMERICAN TRANSPLANT CONGRESS 2012 ABSTRACTS

Abstract# 1367 Poster Board #-Session: P234-III

Initial Experience Utilizing Telaprevir with Peginterferon and Ribavirin for Treatment of Hepatitis C Genotype 1 after Liver Transplantation.

S. Pungpapong, J. Murphy, T. Henry, R. Satyanarayana, B. Rosser, M. Yataco, D. Harnois, T. Patel, A. Keaveny. Transplantation, Mayo Clinic, Jacksonville, FL.

Background: Successful antiviral treatment of recurrent hepatitis C (HCV) after liver transplantation (LT) has been shown to improve graft and patient outcomes. In non-LT patients, telaprevir (TVR) combined with peginterferon and ribavirin (PR) is approved to treat HCV genotype 1, resulting in signifi cantly higher sustained virological response. There is no reported experience of TVR+PR in LT recipients.

Methods: A clinical protocol to treat HCV genotype 1 after LT with TVR+PR was initiated. LT recipients who met specifi c inclusion criteria were invited to participate. Cyclosporine (CyA) has less interaction with TVR, compared to tacrolimus. Therefore, maintenance immunosuppression was changed to CyA-based regimen (if not already on). Close monitoring of trough CyA levels was required during the first 10-14 days of starting TVR.

Results: Enrollment is ongoing and to date 7 patients (5 genotype 1a; 2 Blacks; 4 TT, 3 CT IL28B polymorphism; 3 null responders, 3 partial responders, 1 poor tolerance to previous PR treatment) were started on TVR+PR, then followed to wk2-14 (mean 8; 6 patients thru wk4, 3 patients thru wk12). At the steady state, CyA dose was adjusted to 50-100% of the original q12hr dose, and interval was reduced to q24hr. No evidence of severe CyA toxicity was observed except mild renal insufficiency. At wk4, 5/6 patients (83%) had HCV RNA<1,000 IU/mL. At their last visits, 4 patients (57%) had undetectable HCV RNA (fi rst at wk1, 5, 9, 12). Due to subtherapeutic CyA levels, 1 patient had biopsy-proven moderate acute rejection at wk2 (resolved with intravenous steroids), but remained on TVR+PR and achieved undetectable HCV RNA at wk12. Due to significant anemia, 1 patient developed unstable angina at wk3 requiring coronary angiography with 1-vessel angioplasty and TVR discontinuation, but remained on PR and achieved undetectable HCV RNA at wk9. Five patients required erythropoietin and 2 patients received filgrastim.

Conclusions: In our initial experience utilizing TVR+PR to treat HCV genotype 1 after LT, 1/6 patients (17%) achieved undetectable HCV RNA by wk4 (RVR) and 3/3 patients (100%) achieved undetectable HCV RNA by wk12 (cEVR). Adjustment of CyA dose and interval was required. Cytopenias were common. Ongoing follow-up would provide additional insights into the safety and effi cacy of TVR+PR to treat HCV genotype 1 in LT recipients.

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Abstract# 1369 Poster Board #-Session: P236-III

Post Liver Transplant Therapy with Telaprevir for Recurrent Hepatitis C.
A. P. de Oliveira Pereira, H. J. Shin, A. Safdar, H. Tobias, B. Gelb, G. Morgan, T. Diflo, A. Winnick, L. Teperman. Transplant Surgery, NYU- School of Medicine, New York, NY.

Background: The combination of peginterferon-α (PegINF-α) and ribavirin (RIBV) has been the most effective treatment for hepatitis C virus (HCV) for the past decade.However, only 36-50% of genotype 1 HCV achieve sustained virologic response (SVR). Telaprevir, a protease inhibitor in combination with PegINF-α and RIBV, was approved by the FDA in May 2011 for treatment of genotype 1 HCV. Our study aims to evaluate its use on recurrent HCV (rHCV) patients post OLT.

Methods: Since June 2011, six rHCV patients post OLT have received triple therapy with PegINF-α (45-180mcg/week), RIBV(200-800mg/day) and telaprevir (2250mg/day). Doses of PegINF-α and RIBV were adjusted based on each patient's tolerance. All patients were genotype 1 and diagnosed with rHCV by liver biopsy. Immunosuppression regimen was tacrolimus 0.5mg/week and everolimus 0.25mg every 3 days, with closely monitored drug levels. Results: Four male and two female patients, median age 63.7, had rHCV diagnosed 1 to 39 months post OLT. Histology was grade 2-3 rHCV with fibrosis (stage 2-4). Two patients had the fibrosing cholestatic variant (FCV).Five patients tolerated telaprevir. One patient had to stop taking telaprevir due to skin rash and headache after 1 week of therapy. One patient achieved a 3-log reduction (168 from 1,000K IU/ml) after 2weeks on therapy and underwent appendectomy on the 16th day, but remained compliant. One of the patients with FCV, achieved 3-log (734 from 1,010K IU/ml) reduction in viral load within 1 week, became fungemic, and failed therapy after missing 3 doses. He has, however, clinically improved. The 2nd patient with FCV, died of sepsis 1 week after completely clearing virus. Two patients successfully obtained SVR after 5 weeks of therapy (from 2,790K and from 167K IU/ml, respectively). One patient had persistent SVR after 12 week course of therapy.

Conclusion: Triple combination therapy has shown a potent effect on HCV reduction in patients who tolerated therapy. This new therapy might have a role in improving both graft and patient survival. As drug tolerance is pivotal to completing this therapy course, it is necessary to determine the optimal timing of therapy and the management of adverse effects. Further study is ongoing.

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Abstract# 1370 Poster Board #-Session: P237-III

Pharmacokinetic Effects of Boceprevir Co-Administration on Cyclosporine Exposure in Liver Transplant Recipients.

T. Sam,1 E. Tichy,1 S. Emre,2 M. Schilsky.3 1Pharmacy, Yale-New Haven Hospital; 2Surgery, Yale School of Medicine; 3Medicine, Yale School of Medicine.

Background: A previous report in healthy volunteers revealed signifi cant drug-drug interactions between telaprevir (TVR) and the calcineurin inhibitors (CNI), but the impact of boceprevir (BOC) on CNI pharmacokinetics is unknown. Furthermore, these protease inhibitors (PI) have yet to be studied in liver transplant recipients (LTRs).

Objective: We report our early experience with BOC co-administration in 3 LTRs with HCV recurrence maintained on cyclosporine (CSA).

Method: Following a two week lead-in phase of peginterferon and ribavirin, BOC (800mg q8h) was started in three LTRs. Cyclosporine peak and trough levels were closely followed during BOC initiation to guide cyclosporine dosing. CSA concentration dose ratios (CDRs) were calculated dividing CSA blood level (ng/ml) by the previous daily CSA dose (mg/kg) and their units were (ng/ml)/(mg/kg).

Results: Prior to BOC initiation, all three patients were receiving CSA 100mg q12h, with resulting CSA trough concentrations ranging between 53 and 76ng/ml. Extrapolating from previously reported TVR data, CSA dose was pre-emptively reduced for patient one and two to 25mg q12h (75% dose reduction). By day 19 of BOC therapy, both patients required CSA dose increase up to 75mg q12h, 75% of the pre-BOC dose, with resulting CSA trough of 102 and 143ng/ml, respectively (target 100-150ng/ml). For patient three, the pre-BOC CSA dose of 100mg q12h was maintained post-BOC initiation. By day 15, patient three required a 100% upward dose titration to 200mg q12h, with resulting CSA trough of 96ng/ml (target 100ng/ ml). Mean CSA CDR amongst the three patients rose from 26.7 prior to BOC to 37.8 (ng/ml)/(mg/kg) post BOC initiation, an increase in CSA CDR by approximately 1.42 fold. In summary, BOC co-administration with CSA in LTRs resulted in a relatively minor increase in CSA blood concentrations.

HCV1

Conclusion: Minimal dose modification of CSA is needed when BOC is administered to LTRs. However, CSA therapeutic drug level monitoring is still warranted.

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Abstract# 1377 Poster Board #-Session: P244-III

Boceprevir, Peginterferon and Ribavirin (PEGIFN/RIB) as Triple Antiviral Therapy for Severe Recurrent Hepatitis C Post Liver Transplant: An Early Single Center Experience.

M. Schilsky,1,3 T. Sam,2 E. Tichy,2 C. Caldwell,1 S. Jakab,1 S. Emre.3 1Medicine, Yale School of Medicine; 2Pharmacy, Yale-New Haven Hospital; 3Surgery, Yale School of Medicine.

Background: Hepatitis C virus (HCV) protease inhibitors (PIs) have changed the paradigm of HCV treatment but use of PIs has not been recommended in posttransplant as safety and efficacy data are lacking.

Objective: We report our early experience with anti-HCV triple therapy, consisting of PEGIFN/RIB and boceprevir (BOC), in 3 liver transplant recipients (LTRs) with HCV recurrence.

Study Group and Methods: Study group consisted of post liver transplant (n=2) and post liver and kidney transplant (n=1) patients with recurrent HCV; 2 had a fibrosing cholestatic hepatitis (FCH) variant and the other stage 2-3 fibrosis on liver biopsy. Treatment was begun with PEGIFN/RIB for 2 weeks and then BOC (800mg q8h) was added. All 3 were maintained on cyclosporine (CSA) based immunosuppression, which was adjusted based on CSA drug level monitoring. Parameters monitored throughout therapy included HCV viral load, liver tests, CSA levels, and screening for side effects.

Results: Patient one achieved undetectable HCV viral load by day 19 of BOC. Patient two experienced greater than a 2 log decrease in HCV viral load by day 19 of BOC with a significant improvement in liver tests (direct and total bilirubin went from 3.1 to 0.77mg/dl and 4.83 to 1.45mg/dl, respectively). In contrast, patient three had a delayed biochemical response but showed improved histology. The only side effect experienced from BOC was fatigue that did not require therapy discontinuation. None had evidence of rejection or CSA toxicity. In summary, triple therapy with BOC resulted in positive outcomes in viral response and liver function in 2 cases, and initial histological improvement in a third with FCH.

HCV2

Conclusion: Our experience demonstrates that triple therapy with BOC offers promising early results in the treatment of severe recurrent genotype 1 HCV in LTRs.

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Abstract# 1372 Poster Board #-Session: P239-III

Telaprevir Can Be Used Safely with Concomitant Tacrolimus in the Post-Transplant Setting.

C. C. Rogers,1 D. R. Stevens,1 M. Kim,1 T. Ghaziani,2 R. Malik,2 M. P. Curry.2 1Department of Pharmacy, Beth Israel Deaconess Medical Center; 2Department of Medicine, Beth Israel Deaconess Medical Center.

Treatment of recurrent hepatitis c virus(HCV) post-transplant (post-tx) with PEGinterferon(PEG-IFN) and ribavirin(RBV) is poorly tolerated with sustained viral response rates(SVR) of < 30%. Addition of telaprevir(TP) to PEG-IFN/RBV pretransplant results higher SVRs. Use of TP with tacrolimus(FK) is challenging due to the significant drug-drug interaction. Blunted FK peaks and altered AUC's have been reported in pts on protease inhibitors and FK. This case series describes the first 2 cases of successful post-tx initiation of TP with concomitant FK.

Results: Patient (pt) 1 started PEG-IFN/RBV 5 weeks post-tx for aggressive HCV recurrence. Despite 3 months of PEG-IFN/RBV and 2 months of interferon alfacon-1 the pt developed severe cholestatic hepatitis (peak T bili 17.8). A biopsy revealed stage 2 fibrosis at 6 months post tx. The pt was admitted for initiation of TP.

HCV3

Figure 1 illustrates the titration of FK around TP initiation in addition to AST, ALT and T bilirubin. The last FK dose was given 4 hours prior to initiating TP to avoid both drugs peaking at the same time. HCV viral load remains undetectable after 10 weeks of therapy. Pt 2 started PEG-IFN/RBV 6 weeks post-tx for aggressive HCV recurrence. TP was initiated 6 months later for lack of response to IFN/RBV evidenced by progression to stage 2 fibrosis. TP was initiated in pt 2 with close monitoring on the in-patient setting. Of note, pt 2 had a FK level of 3.9 necessitating a FK dose increase to 2mg BID 3 days prior to admission. FK trough on admission was 8.3 and 11.2 at TP initiation. Similar to pt 1, TP and the fi nal FK dose were administered 4 hours apart. The 12 hour FK level was 16.3, this fell to 8.9 5 days later. FK 0.5mg BIW was started the next day with levels durring the first week of 6.5 and 6.8.

Conclusion: TP can safely be administered post-tx with careful monitoring and FK dose adjustment. The FK target was increased by 30% to minimize the risk of rejection and IFN induced immune mediated graft injury while on TP. Longer follow-up is needed to determine if TP use post-tx is benefi cial.

DISCLOSURE: Curry, M. P.: Other, Consultant, Vertex.

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Abstract# LB01

Initial Experience with Telaprevir for Treating Hepatitis C Virus in Liver Recipients: Virologic Response, Safety, and Tolerability.

J. R. Burton, Jr, G. T. Everson. Division of Hepatology, University of Colorado, Denver, Aurora, CO.

Introduction: Telaprevir (TPV)/peginterferon (P)/ribavirin (R) (triple therapy, TT) significantly improves rates of sustained virological response in patients with genotype 1 chronic HCV. TPV inhibits CYP450 3A4, which alters metabolism of calcineurin inhibitors. TT has not been studied in liver recipients.

Methods: Demographic, clinical and virologic data were collected retrospectively. Patients were switched to cyclosporine (CsA) and mycophenolate mofetil (MMF) for immunosuppression, monitored for rejection, and then treated with PR using a low-accelerating dose regimen. Once patients achieved maximum tolerated doses for PR, TPV was introduced and the dose of CsA was reduced to 25% of total daily dose and given every other day. Subsequent doses of CsA were adjusted to maintain a 2 hr post-dose CsA level (C2) of 500 ng/ml. After completing 12 weeks of TT, patients are scheduled to receive an additional 36 weeks of PR. Epogen to maintain Hgb >8 g/dL and G-CSF to maintain ANC >500/μL were used.

Results:Twelve patients have received at least 4 weeks of TT (mean 11, 4-25 weeks). Mean time from LT to TT was 60 mos (7-137). Ten had at least fibrosis stage ≥2 and 4 patients had clinical or biopsy evidence of cirrhosis. Nine underwent pre-LT HCV treatment, all non-responders. Six were on antiviral therapy prior to CsA/MMF switch. Mean HCV RNA (IU/ml) prior to starting TPV was 2.4x106 (55-15x106). Mean 1 week HCV RNA was 1895 (0-19,400). By week 4, 11/12 had HCV RNA <43. Two patients developed presumed TPV resistance (rising HCV RNA >1000 IU/ ml after initial decline <1000 IU/ml) and TT was stopped. Mean C2 levels (ng/ml) during weeks 1-4 were 412, 468, 421 and 363, respectively. Mean daily CsA dose (mg/d) prior to TT and during weeks 1-4 were 187, 32, 45, 58 and 66, respectively. Mean hemoglobin (g/dL) prior to TT was 12.8 (10.8-14.9) and dropped to 10.5 g/dL (8.3-12.5) during first 4 weeks of TT. During TT, 5 patients have received total of 28 units of blood, 3 were hospitalized, none experienced rash and none had evidence of acute cellular rejection.

Conclusions: CsA-based immunosuppression and C2 monitoring effectively maintains immunosuppression and prevents rejection during TT for recurrent HCV. Rates of early virologic response with TT exceed those previously published using PR alone. Anemia is a signifi cant problem, but rash events are rare. TPV-based TT is manageable and may enhance virologic responses in liver recipients.

DISCLOSURE: Burton, Jr, J. R.: Grant/Research Support, Vertex Pharmaceuticals. Everson, G. T.: Grant/Research Support, Vertex Pharmaceuticals.

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