Reply to: “Frequent plasma cell hepatitis during telaprevir-based triple therapy for hepatitis C after liver transplantation”
Authors: Audrey Coilly, Mylène Sebagh, Jean-Charles Duclos-Vallée
Journal: Journal of Hepatology (2013)

Safety and efficacy of protease inhibitors to treat hepatitis C after liver transplantation: A multicenter experienceJournal of HepatologyVol. 60Issue 1PreviewProtease 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. Full-Text PDF Frequent plasma cell hepatitis during telaprevir-based triple therapy for hepatitis C after liver transplantationJournal of HepatologyVol. 60Issue 4PreviewTo the Editor: Full-Text PDF Open Access To the Editor:We much appreciate Dr Ikegami and colleagues’ comments on our study on the use of a first generation protease inhibitor-based regimen to treat hepatitis C (HCV) recurrence after liver transplantation (LT) [[1]Coilly A. Roche B. Dumortier J. Leroy V. Botta-Fridlund D. Radenne S. et al.Safety and efficacy of protease inhibitors to treat hepatitis C after liver transplantation: a multicenter experience.J Hepatol. 2014; 60: 78-86Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar]. One comment concerned the lack of occurrence of plasma cell hepatitis (PHC) in our series of 37 patients. Dr Ikegami reported on 9 patients treated with telaprevir (TVR), peginterferon α2b (PegIFN) and ribavirin (RBV) in a context of HCV recurrence after living donor LT. PHC occurred in 33.3% of patients (3/9) during triple therapy, compared with 6.7% (7/105) during standard PegIFN/RBV. We have developed some arguments to explain the difference between these two different findings.A low immunosuppressive regimen is a risk factor for the development of PCH [[2]Aguilera I. Sousa J.M. Praena J.M. Gomez-Bravo M.A. Nunez-Roldan A. Choice of calcineurin inhibitor may influence the development of de novo immune hepatitis associated with anti-GSTT1 antibodies after liver transplantation.Clin Transplant. 2011; 25: 207-212Crossref PubMed Scopus (19) Google Scholar]. All patients in Dr Ikegami’s letter received cyclosporine (CsA) ± mycophenolate mofetil (MMF). Data concerning targeted trough blood concentrations (TBC) of CsA, and the delay between triple therapy and LT, were lacking. All PHC cases reported by Dr Ikegami occurred after the discontinuation of TVR (weeks 21, 31, and 12). Despite biweekly monitoring, the mean CsA TBC in patient 3 was low after week 12 (from 53 to 86 ng/ml). Drug-drug interactions between PI and calcineurin inhibitors have always been the main challenge when using PI after LT. In the first instance, we focused on the PI initiation period to demonstrate its feasibility in terms of practical management [[3]Coilly A. Furlan V. Roche B. Barau C. Noël C. Bonhomme-Faivre L. et al.Practical management of boceprevir and immunosuppressive therapy in liver transplant recipients with hepatitis C virus recurrence.Antimicrob Agents Chemother. 2012; 56: 5728-5734Crossref PubMed Scopus (46) Google Scholar]. We also looked carefully at the time of PI discontinuation. In our study, TBC were monitored daily and CsA doses were also adjusted daily to reach the target range. It was necessary to increase the CsA doses by 47% after TVR discontinuation [[1]Coilly A. Roche B. Dumortier J. Leroy V. Botta-Fridlund D. Radenne S. et al.Safety and efficacy of protease inhibitors to treat hepatitis C after liver transplantation: a multicenter experience.J Hepatol. 2014; 60: 78-86Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar]. In this context, HCV clearance might have an impact on PHC occurrence with triple therapy, but drug-drug interactions are more likely to be responsible for the excess risk found by Ikegami et al.One observation in Dr Ikegami’s letter was particularly surprising, and concerned the favorable outcome of PHC in all patients. This contrasted with the usually poor prognosis of PHC in a context of HCV recurrence. According to Fiel et al., patients who were not treated or were receiving corticosteroids had a negative outcome. Cirrhosis was seen to develop in 60% of patients (4). According to Dr Ikegami, patients 1 and 2 were treated with steroid pulses and an increase in or addition of mycophenolate mofetil (MMF). For patient 1, we could hypothesize that acute cellular rejection (ACR) justified such a treatment. And as for patient 3, MMF and low-dose corticosteroids (5 mg) were added to CsA.The prevalence of PHC may vary, depending on the diagnosis criteria applied. Most studies on PHC have considered that this diagnosis is based on three criteria: (1) abnormality of liver tests, (2) increased levels of immunoglobulin G and/or specific antibodies of auto-immune hepatitis, (3) compatible histological features. Dr Ikegami does not mention any serological data. Furthermore, we have some concerns about the histological findings. The authors considered that the diagnosis was based on the presence of centrilobular and portal necrosis and a prominent (>30%) plasma cell (PC) aggregation, as previously described by Fiel et al. [[4]Fiel M.I. Agarwal K. Stanca C. Elhajj N. Kontorinis N. Thung S.N. et al.Posttransplant plasma cell hepatitis (de novo autoimmune hepatitis) is a variant of rejection and may lead to a negative outcome in patients with hepatitis C virus.Liver Transpl. 2008; 14: 861-871Crossref PubMed Scopus (95) Google Scholar]. In patient 1, PHC was associated with ACR. The differential diagnosis between these entities can be difficult. In severe ACR, a severe portal necro-inflammatory activity may mimic hepatitis. The infiltrate may be made up of PC, but without proper PCH. In order to clarify the histological features of PCH, we recently reported on a scoring system based on centrilobular changes such as necro-inflammatory activity (NIA) and the centrilobular PC ratio. The positive predictive value of the association of severe centrilobular NIA and a PC ratio of up to 30% was >90% [[5]Sebagh M. Castillo-Rama M. Azoulay D. Coilly A. Delvart V. Allard M.A. et al.Histologic findings predictive of a diagnosis of de novo autoimmune hepatitis after liver transplantation in adults.Transplantation. 2013; 96: 670-678Crossref PubMed Scopus (20) Google Scholar]. In fact, we currently use these criteria to diagnose PCH.To conclude, we agree with Dr Ikegami that PCH is a potential complication of a TVR-based antiviral regimen. For as long as an interferon-based regimen is used after LT, hepatologists should be alert to possibilities of PHC occurrence. Close monitoring of drug-drug interactions is warranted, particularly soon after PI initiation and also at the time of PI discontinuation. We also think that using stringent criteria based on serological markers and histological features is crucial to preventing a misdiagnosis of PHC.Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. To the Editor: We much appreciate Dr Ikegami and colleagues’ comments on our study on the use of a first generation protease inhibitor-based regimen to treat hepatitis C (HCV) recurrence after liver transplantation (LT) [[1]Coilly A. Roche B. Dumortier J. Leroy V. Botta-Fridlund D. Radenne S. et al.Safety and efficacy of protease inhibitors to treat hepatitis C after liver transplantation: a multicenter experience.J Hepatol. 2014; 60: 78-86Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar]. One comment concerned the lack of occurrence of plasma cell hepatitis (PHC) in our series of 37 patients. Dr Ikegami reported on 9 patients treated with telaprevir (TVR), peginterferon α2b (PegIFN) and ribavirin (RBV) in a context of HCV recurrence after living donor LT. PHC occurred in 33.3% of patients (3/9) during triple therapy, compared with 6.7% (7/105) during standard PegIFN/RBV. We have developed some arguments to explain the difference between these two different findings. A low immunosuppressive regimen is a risk factor for the development of PCH [[2]Aguilera I. Sousa J.M. Praena J.M. Gomez-Bravo M.A. Nunez-Roldan A. Choice of calcineurin inhibitor may influence the development of de novo immune hepatitis associated with anti-GSTT1 antibodies after liver transplantation.Clin Transplant. 2011; 25: 207-212Crossref PubMed Scopus (19) Google Scholar]. All patients in Dr Ikegami’s letter received cyclosporine (CsA) ± mycophenolate mofetil (MMF). Data concerning targeted trough blood concentrations (TBC) of CsA, and the delay between triple therapy and LT, were lacking. All PHC cases reported by Dr Ikegami occurred after the discontinuation of TVR (weeks 21, 31, and 12). Despite biweekly monitoring, the mean CsA TBC in patient 3 was low after week 12 (from 53 to 86 ng/ml). Drug-drug interactions between PI and calcineurin inhibitors have always been the main challenge when using PI after LT. In the first instance, we focused on the PI initiation period to demonstrate its feasibility in terms of practical management [[3]Coilly A. Furlan V. Roche B. Barau C. Noël C. Bonhomme-Faivre L. et al.Practical management of boceprevir and immunosuppressive therapy in liver transplant recipients with hepatitis C virus recurrence.Antimicrob Agents Chemother. 2012; 56: 5728-5734Crossref PubMed Scopus (46) Google Scholar]. We also looked carefully at the time of PI discontinuation. In our study, TBC were monitored daily and CsA doses were also adjusted daily to reach the target range. It was necessary to increase the CsA doses by 47% after TVR discontinuation [[1]Coilly A. Roche B. Dumortier J. Leroy V. Botta-Fridlund D. Radenne S. et al.Safety and efficacy of protease inhibitors to treat hepatitis C after liver transplantation: a multicenter experience.J Hepatol. 2014; 60: 78-86Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar]. In this context, HCV clearance might have an impact on PHC occurrence with triple therapy, but drug-drug interactions are more likely to be responsible for the excess risk found by Ikegami et al. One observation in Dr Ikegami’s letter was particularly surprising, and concerned the favorable outcome of PHC in all patients. This contrasted with the usually poor prognosis of PHC in a context of HCV recurrence. According to Fiel et al., patients who were not treated or were receiving corticosteroids had a negative outcome. Cirrhosis was seen to develop in 60% of patients (4). According to Dr Ikegami, patients 1 and 2 were treated with steroid pulses and an increase in or addition of mycophenolate mofetil (MMF). For patient 1, we could hypothesize that acute cellular rejection (ACR) justified such a treatment. And as for patient 3, MMF and low-dose corticosteroids (5 mg) were added to CsA. The prevalence of PHC may vary, depending on the diagnosis criteria applied. Most studies on PHC have considered that this diagnosis is based on three criteria: (1) abnormality of liver tests, (2) increased levels of immunoglobulin G and/or specific antibodies of auto-immune hepatitis, (3) compatible histological features. Dr Ikegami does not mention any serological data. Furthermore, we have some concerns about the histological findings. The authors considered that the diagnosis was based on the presence of centrilobular and portal necrosis and a prominent (>30%) plasma cell (PC) aggregation, as previously described by Fiel et al. [[4]Fiel M.I. Agarwal K. Stanca C. Elhajj N. Kontorinis N. Thung S.N. et al.Posttransplant plasma cell hepatitis (de novo autoimmune hepatitis) is a variant of rejection and may lead to a negative outcome in patients with hepatitis C virus.Liver Transpl. 2008; 14: 861-871Crossref PubMed Scopus (95) Google Scholar]. In patient 1, PHC was associated with ACR. The differential diagnosis between these entities can be difficult. In severe ACR, a severe portal necro-inflammatory activity may mimic hepatitis. The infiltrate may be made up of PC, but without proper PCH. In order to clarify the histological features of PCH, we recently reported on a scoring system based on centrilobular changes such as necro-inflammatory activity (NIA) and the centrilobular PC ratio. The positive predictive value of the association of severe centrilobular NIA and a PC ratio of up to 30% was >90% [[5]Sebagh M. Castillo-Rama M. Azoulay D. Coilly A. Delvart V. Allard M.A. et al.Histologic findings predictive of a diagnosis of de novo autoimmune hepatitis after liver transplantation in adults.Transplantation. 2013; 96: 670-678Crossref PubMed Scopus (20) Google Scholar]. In fact, we currently use these criteria to diagnose PCH. To conclude, we agree with Dr Ikegami that PCH is a potential complication of a TVR-based antiviral regimen. For as long as an interferon-based regimen is used after LT, hepatologists should be alert to possibilities of PHC occurrence. Close monitoring of drug-drug interactions is warranted, particularly soon after PI initiation and also at the time of PI discontinuation. We also think that using stringent criteria based on serological markers and histological features is crucial to preventing a misdiagnosis of PHC. Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.