Sofosbuvir-based Interferon-Free Direct Acting Antiviral Regimens for Heart Transplant Recipients With Chronic Hepatitis C Virus Infection

Clinical Infectious Diseases, Jan 2018

We assessed the effectiveness and safety of sofosbuvir (SOF) combined with ledipasvir (LDV) or daclatasvir (DCV) in 12 heart transplant recipients with chronic hepatitis C virus (HCV). The sustained virologic response (SVR12) rate was 100% [95% confidence interval [CI]: 75.8%–100%]. All patients tolerated treatment well without interruption, death, or serious adverse events.

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Sofosbuvir-based Interferon-Free Direct Acting Antiviral Regimens for Heart Transplant Recipients With Chronic Hepatitis C Virus Infection

Abstract We assessed the effectiveness and safety of sofosbuvir (SOF) combined with ledipasvir (LDV) or daclatasvir (DCV) in 12 heart transplant recipients with chronic hepatitis C virus (HCV). The sustained virologic response (SVR12) rate was 100% [95% confidence interval [CI]: 75.8%–100%]. All patients tolerated treatment well without interruption, death, or serious adverse events. hepatitis C virus, heart transplantation, direct acting antiviral agent (See the Editorial Commentary by Weinberg and Reddy on pages 293–5). Hepatitis C virus (HCV) infection is common in patients receiving organ transplantation. The reported prevalence of HCV infection among heart transplant recipients ranges from 7% to 18% [1, 2]. Several studies have indicated that the survival is reduced in heart transplant recipients with HCV infection, regardless of acquisition of HCV pre- or post-heart transplantation [1–6]. Treatment of HCV infection after heart transplantation by interferon (IFN) monotherapy or IFN plus ribavirin (RBV) therapy is associated with an increased risk of graft rejection, cardiac arrhythmia, cardiotoxicity, and worsening coronary ischemia [7]. The use of IFN-free direct acting antiviral agents (DAAs) has confirmed the excellent efficacy and safety for ordinary patients with chronic HCV infection. Two case reports showed that HCV-infected heart transplant recipients were successfully treated with daclatasvir (DCV) plus simeprevir (SMV) for 24 weeks and sofosbuvir (SOF) plus SMV for 12 weeks, respectively [8, 9]. Until now, there are no case series to evaluate the effectiveness and safety of IFN-free DAAs for heart transplant recipients with chronic HCV infection. We reported our experience in HCV-infected heart transplant recipients receiving SOF-based IFN-free DAAs. MATERIALS AND METHODS Patients Between July 2015 and February 2017, chronic HCV-infected heart transplant recipients who received SOF-based IFN-free DAAs at the National Taiwan University Hospital (NTUH) and NTUH Yun-Lin Branch were prospectively enrolled. All patients were aged ≥ 20 years and had chronic HCV infection, defined as detectable HCV antibody (anti-HCV; Abbott HCV EIA 2.0, Abbott Laboratories, Abbott Park, Illinois) and quantifiable serum HCV RNA (Cobas TaqMan HCV Test v2.0, Roche Diagnostics GmbH, Mannheim, Germany; lower limit of quantification [LLOQ]: 25 IU/mL) for ≥ 6 months. Patients were excluded from the study if they had decompensated cirrhosis or chronic kidney disease (CKD) stage 4 or 5. The study was approved by the NTUH Institutional Review Board and was conducted in accordance with the principles of Declaration of Helsinki and the International Conference on Harmonization for Good Clinical Practice. All patients provided written informed consent for the study. Study Design Baseline demographic data, hemogram, serum biochemical profiles (albumin, bilirubin, aspartate aminotransferase, alanine aminotransferase, creatinine), anti-HCV, hepatitis B virus (HBV) surface antigen (HBsAg) (Abbott Architect HBsAg qualitative assay, Abbott Laboratories, Abbott Park, Illinois), HCV RNA, HCV genotype (Abbott RealTime HCV Genotype II, Abbott Laboratories, Abbott Park, Illinois) and anti-HIV (Abbott Architect HIV Ag/Ab Combo, Abbott Laboratories, Abbott Park, Illinois) were evaluated for all patients. Each patient received transient elastography (FibroScan®, Echosens, Paris, France) to assess hepatic fibrosis. Patients received ledipasvir 90 mg plus SOF 400 mg (LDV/SOF) fixed-dose combination (Harvoni, Gilead Sciences, Carrigtohill, Co. Cork, Ireland) once daily for 12 weeks if they were infected with HCV genotype 1, and DCV 60 mg (Daklinza, Bristol-Myers Squibb, Mount Vernon, Indiana) once daily plus SOF 400 mg (Sovaldi, Gilead Sciences, Carrigtohill, Co. Cork, Ireland) (DCV/SOF) once daily for 12 weeks if they were infected with HCV genotype 2 or 6. All patients received on-treatment effectiveness assessment by HCV RNA and ALT levels, and safety assessment for constitutional and laboratory adverse events (AEs) every 2 weeks. For patients who completed 12 weeks of treatment or prematurely discontinued treatment, they received off-therapy effectiveness assessment for HCV RNA and ALT levels every 4 weeks until 12 weeks. The electrocardiogram (ECG) was performed monthly to monitor significant abnormalities. The estimated glomerular filtration rate (eGFR) was serially assessed by Cockcroft-Gault equation. The potential drug-drug interactions (DDIs) between DAAs and concomitant medications were checked by HEP Drug Interaction Checker as proposed by the University of Liverpool. The endpoint of study was sustained virologic response (SVR12), defined as serum HCV RNA level < LLOQ 12 weeks after the end of treatment. Statistical Analyses All analyses were performed using Statistical Program for Social Sciences (SPSS Statistics Version 23.0, IBM, Armonk, New York). The baseline patient characteristics were shown in median (range) and percentages when appropriate. The effectiveness of viral responses was shown in number and percentages with 95% confidence interval (CI). The on-treatment constitutional and laboratory AEs were shown in number and percentages when appropriate. RESULTS Patient Characteristics Twelve heart transplant recipients were enrolled in the study. The median age was 55 years, and 7 (58.3%) patients were male. Seven (58.3%), 4 (33.3%), and 1 (8.3%) patients were infected with HCV-1b, HCV-2, and HCV-6, respectively. The median log10 HCV RNA level was 6.34. Eight (76.7%) patients had a fibrosis stage of ≤ F2 (Table 1). There were no contraindicated DDIs between the prescribed immunosuppressants and the SOF-based DAAs. Table 1. Baseline Demographic and Clinical Characteristicsa Characteristic Patients (N = 12) Age, years, median (range) 55 (38, 62) Male 7 (58.3) Treatment-naive 10 (83.3) HCV infection   Prior to heart transplantation 7 (58.3)  De novo infection after heart transplantationb 5 (41.7) Time interval from heart transplantation to DAA treatment, months, median (range) 50 (13, 116) HCV genotype   1b 7 (58.3)  2 4 (33.3)  6 1 (8.3) DAA regimen for HCV   LDV/SOF for 12 weeks 7 (58.3)  DCV/SOF for 12 weeks 5 (41.7) HBV coinfection 0 (0) HIV coinfection 0 (0) BMI, kg/m2, median (range) 24.5 (20.1, 28.4) Hemoglobin level, g/dL, median (range) 14.2 (11.7, 16.9) Leukocyte count, 109 cells/L, median (range) 5.8 (2.8, 9.8) Platelet count, 109 cells/L, median (range) 178 (86, 223) Albumin, g/dL, median (range) 4.2 (3.0, 4.7) Total bilirubin, mg/dL, median (range) 0.8 (0.4, 2.2) Direct bilirubin, mg/dL, median (range) 0.2 (0.1, 0.6) AST, U/L, median (range) 76 (25, 436) ALT, U/L, median (range) 114 (24, 456) Creatinine, mg/dL, median (range) 1.1 (0.6, 1.3) eGFR, mL/min/1.73 m2, median (range)c 83.2 (46.6, 107.9) HCV RNA, log10 IU/mL, median (range) 6.34 (4.68, 7.59) Stage of hepatic fibrosis (METAVIR)d   F0-1 5 (41.7)  F2 3 (25.0)  F3 1 (8.3)  F4 3 (25.0) Immunosuppressant   Prednisone 6 (50.0)  Cyclosporine 1 (8.3)  Tacrolimus 9 (75.0)  Sirolimus 2 (16.7)  Mycophenolate mofetil 8 (66.7)  Everolimus 5 (41.7)  Characteristic Patients (N = 12) Age, years, median (range) 55 (38, 62) Male 7 (58.3) Treatment-naive 10 (83.3) HCV infection   Prior to heart transplantation 7 (58.3)  De novo infection after heart transplantationb 5 (41.7) Time interval from heart transplantation to DAA treatment, months, median (range) 50 (13, 116) HCV genotype   1b 7 (58.3)  2 4 (33.3)  6 1 (8.3) DAA regimen for HCV   LDV/SOF for 12 weeks 7 (58.3)  DCV/SOF for 12 weeks 5 (41.7) HBV coinfection 0 (0) HIV coinfection 0 (0) BMI, kg/m2, median (range) 24.5 (20.1, 28.4) Hemoglobin level, g/dL, median (range) 14.2 (11.7, 16.9) Leukocyte count, 109 cells/L, median (range) 5.8 (2.8, 9.8) Platelet count, 109 cells/L, median (range) 178 (86, 223) Albumin, g/dL, median (range) 4.2 (3.0, 4.7) Total bilirubin, mg/dL, median (range) 0.8 (0.4, 2.2) Direct bilirubin, mg/dL, median (range) 0.2 (0.1, 0.6) AST, U/L, median (range) 76 (25, 436) ALT, U/L, median (range) 114 (24, 456) Creatinine, mg/dL, median (range) 1.1 (0.6, 1.3) eGFR, mL/min/1.73 m2, median (range)c 83.2 (46.6, 107.9) HCV RNA, log10 IU/mL, median (range) 6.34 (4.68, 7.59) Stage of hepatic fibrosis (METAVIR)d   F0-1 5 (41.7)  F2 3 (25.0)  F3 1 (8.3)  F4 3 (25.0) Immunosuppressant   Prednisone 6 (50.0)  Cyclosporine 1 (8.3)  Tacrolimus 9 (75.0)  Sirolimus 2 (16.7)  Mycophenolate mofetil 8 (66.7)  Everolimus 5 (41.7)  Abbreviations: ALT: alanine aminotransferase; AST: aspartate aminotransferase; BMI: body mass index; DAA: direct acting antiviral agent; DCV: daclatasvir; eGFR: estimated glomerular filtration rate; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; LDV: ledipasvir; RNA: ribonucleic acid; SOF: sofosbuvir. aValues are numbers (percentages) unless otherwise indicated. Percentages may not add up to 100% because of rounding. bHCV-uninfected recipients with newly acquired HCV infection from HCV-infected donors. cDetermined by Cockcroft-Gault equation. dDetermined by transient elastography (FibroScan®, Echosens, Paris, France). The reference range of hepatic fibrosis by transient elastography was as follows: F0–F1(≤ 7.0 kPa), F2 (7.1–9.4 kPa), F3 (9.5–12.4 kPa), F4 (≥ 12.5 kPa). View Large Table 1. Baseline Demographic and Clinical Characteristicsa Characteristic Patients (N = 12) Age, years, median (range) 55 (38, 62) Male 7 (58.3) Treatment-naive 10 (83.3) HCV infection   Prior to heart transplantation 7 (58.3)  De novo infection after heart transplantationb 5 (41.7) Time interval from heart transplantation to DAA treatment, months, median (range) 50 (13, 116) HCV genotype   1b 7 (58.3)  2 4 (33.3)  6 1 (8.3) DAA regimen for HCV   LDV/SOF for 12 weeks 7 (58.3)  DCV/SOF for 12 weeks 5 (41.7) HBV coinfection 0 (0) HIV coinfection 0 (0) BMI, kg/m2, median (range) 24.5 (20.1, 28.4) Hemoglobin level, g/dL, median (range) 14.2 (11.7, 16.9) Leukocyte count, 109 cells/L, median (range) 5.8 (2.8, 9.8) Platelet count, 109 cells/L, median (range) 178 (86, 223) Albumin, g/dL, median (range) 4.2 (3.0, 4.7) Total bilirubin, mg/dL, median (range) 0.8 (0.4, 2.2) Direct bilirubin, mg/dL, median (range) 0.2 (0.1, 0.6) AST, U/L, median (range) 76 (25, 436) ALT, U/L, median (range) 114 (24, 456) Creatinine, mg/dL, median (range) 1.1 (0.6, 1.3) eGFR, mL/min/1.73 m2, median (range)c 83.2 (46.6, 107.9) HCV RNA, log10 IU/mL, median (range) 6.34 (4.68, 7.59) Stage of hepatic fibrosis (METAVIR)d   F0-1 5 (41.7)  F2 3 (25.0)  F3 1 (8.3)  F4 3 (25.0) Immunosuppressant   Prednisone 6 (50.0)  Cyclosporine 1 (8.3)  Tacrolimus 9 (75.0)  Sirolimus 2 (16.7)  Mycophenolate mofetil 8 (66.7)  Everolimus 5 (41.7)  Characteristic Patients (N = 12) Age, years, median (range) 55 (38, 62) Male 7 (58.3) Treatment-naive 10 (83.3) HCV infection   Prior to heart transplantation 7 (58.3)  De novo infection after heart transplantationb 5 (41.7) Time interval from heart transplantation to DAA treatment, months, median (range) 50 (13, 116) HCV genotype   1b 7 (58.3)  2 4 (33.3)  6 1 (8.3) DAA regimen for HCV   LDV/SOF for 12 weeks 7 (58.3)  DCV/SOF for 12 weeks 5 (41.7) HBV coinfection 0 (0) HIV coinfection 0 (0) BMI, kg/m2, median (range) 24.5 (20.1, 28.4) Hemoglobin level, g/dL, median (range) 14.2 (11.7, 16.9) Leukocyte count, 109 cells/L, median (range) 5.8 (2.8, 9.8) Platelet count, 109 cells/L, median (range) 178 (86, 223) Albumin, g/dL, median (range) 4.2 (3.0, 4.7) Total bilirubin, mg/dL, median (range) 0.8 (0.4, 2.2) Direct bilirubin, mg/dL, median (range) 0.2 (0.1, 0.6) AST, U/L, median (range) 76 (25, 436) ALT, U/L, median (range) 114 (24, 456) Creatinine, mg/dL, median (range) 1.1 (0.6, 1.3) eGFR, mL/min/1.73 m2, median (range)c 83.2 (46.6, 107.9) HCV RNA, log10 IU/mL, median (range) 6.34 (4.68, 7.59) Stage of hepatic fibrosis (METAVIR)d   F0-1 5 (41.7)  F2 3 (25.0)  F3 1 (8.3)  F4 3 (25.0) Immunosuppressant   Prednisone 6 (50.0)  Cyclosporine 1 (8.3)  Tacrolimus 9 (75.0)  Sirolimus 2 (16.7)  Mycophenolate mofetil 8 (66.7)  Everolimus 5 (41.7)  Abbreviations: ALT: alanine aminotransferase; AST: aspartate aminotransferase; BMI: body mass index; DAA: direct acting antiviral agent; DCV: daclatasvir; eGFR: estimated glomerular filtration rate; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; LDV: ledipasvir; RNA: ribonucleic acid; SOF: sofosbuvir. aValues are numbers (percentages) unless otherwise indicated. Percentages may not add up to 100% because of rounding. bHCV-uninfected recipients with newly acquired HCV infection from HCV-infected donors. cDetermined by Cockcroft-Gault equation. dDetermined by transient elastography (FibroScan®, Echosens, Paris, France). The reference range of hepatic fibrosis by transient elastography was as follows: F0–F1(≤ 7.0 kPa), F2 (7.1–9.4 kPa), F3 (9.5–12.4 kPa), F4 (≥ 12.5 kPa). View Large Effectiveness of Sofosbuvir-Based Interferon-free Direct Acting Antiviral Agents One (8.3%) and 10 (83.3%) patients had serum HCV RNA level < LLOQ at weeks 2 and 4 of treatment. The serum HCV RNA levels were 28 IU/mL and 68 IU/mL in 2 patients with week 4 detectable HCV RNA, respectively. Between weeks 6 and 12 of treatment, all (100%) patients had serum HCV RNA level < LLOQ. During 12 weeks of off-therapy follow-up, no patients relapsed. The SVR12 rate was 100% [95% CI: 75.8%–100%]. Safety of Sofosbuvir-Based Interferon-free Direct Acting Antiviral Agents Eight (66.7%) patients had at least one AE. No patients had serious adverse events, death, or treatment discontinuation due to AEs. Most patients with constitutional symptoms were mild and resolved with or without medications (Supplementary Table 1). One patient with duodenal ulcer bleeding and anemia (hemoglobin level: 9.6 g/dL) at week 4 of treatment was managed with endoscopic therapy. One patient with baseline ALT level of 456 IU/mL had an ALT level of 123 U/L at week 2 of treatment. After week 2 of treatment, the patients’ ALT levels were within normal limit. Among the 5 patients receiving everolimus, 1 patient receiving LDV/SOF needed to titrate the dosage to keep within the target range of serum concentration after DAA treatment. There was no myocardial infraction, myocarditis, pericarditis, or graft rejection during the course of treatment. With regard to ECG monitoring, we did not find prolonged QT corrected interval, prolonged PR interval, bradyarrhythmia, or tachyarrhythmia. For renal safety, there was no significant change of the eGFR. DISCUSSION In this study, we demonstrated that treatment by LDV/SOF or DCV/SOF was efficacious and safe for heart transplant recipients with chronic HCV infection. Our patients had a high rate of serum HCV RNA level < LLOQ after 4 weeks of DAA treatment, which was comparable to the ordinary HCV-infected patients receiving the same regimens. Although 11 and 2 patients remained viremic at weeks 2 and 4 of treatment, all of them achieved SVR12, indicating that the on-treatment viral kinetics may play a minor role in predicting off-therapy viral responses in patients receiving LDV/SOF or DCV/SOF [10]. Furthermore, all patients completed the assigned treatment without experiencing serious adverse events or deaths. Based on the excellent safety and effectiveness of SOF-based IFN-free DAA regimens for heart transplant recipients, the healthcare providers should be active to treat these patients to reduce the recipients’ mortality and morbidity. The cardiac surgeons may also expand the use of HCV-infected heart donors to increase the organ pool for the uninfected heart recipients because treatment with LDV/SOF or DCV/SOF was also efficacious and safe for recipients with newly acquired HCV infection from HCV-infected donors (de novo HCV infection) [11, 12]. In contrast to the significant DDIs between HCV NS3 protease inhibitors and various kinds of immunosuppressants, most immunosuppressants can be safety co-administered with LDV/SOF and DCV/SOF. Because co-administration of LDV or DCV may increase the serum levels of everolimus through the inhibition of P-glycoprotein (P-gp), close monitoring of serum everolimus concentrations should be done. Only 1 patient in our study receiving everolimus needed dosage titration, indicating that co-administration of everolimus with LDV/SOF or DCV/SOF was safe under close drug monitoring. In addition to no observed serious AEs or death, most patients who had constitutional AEs were mild in severity and did not need treatment interruption. With regard to laboratory AEs, the event rates were generally low and were considered not related to DAA regimens. All recipients had no significant changes of cardiac rhythm and eGFR by DAA treatment, implying that SOF-based DAAs may have low probability to cause cardiac or renal deterioration. Our study had 4 limitations. First, the patient number was relatively small, and more data are needed to confirm our findings. Second, we did not have data with regard to the effectiveness and safety in heart transplant recipients with HCV-1a, 3, 4, or 5 infection, or those with decompensated cirrhosis or severe renal impairment. Third, although the SVR rates range from 60% to 98% in ordinary HCV-2 patients receiving SOF plus RBV for 12 weeks, our HCV-2 recipients did not receive such regimen due to the concern of severe anemia [12–15]. In contrast, a recent report showed that the SVR rate of DCV/SOF was 100% in HCV-2 patients who cannot tolerate RBV [16]. Fourth, we did not treat HCV-6 recipients by LDV/SOF because the study was conducted before the approval of LDV/SOF for HCV-6 infection by Food and Drug Administration (FDA). In conclusion, treatment by LDV/SOF or DCV/SOF is highly efficacious for heart transplant recipients with chronic HCV infection. Furthermore, the safety profiles are excellent for these patients. Supplementary Data Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author. Notes Author contributions. C. H. L, Y. S. C., S. S. W., C. J. L., T. H. S., H. C. Y., C. M. H., P. J. C., D. S. C., and J. H. K. collected the data. C. H. L., Y. S. C., S. S. W., C. J. L., and J. H. K. analyzed and interpreted the data. C. H. L., Y. S. C., S. S. W., P. J. C., D. S. C., and J. H. K. were responsible for the concept and design of the study. C. H. L., and J. H. K. drafted the manuscript. All authors critically reviewed the manuscript and approved the final version. Acknowledgements. The authors thank the patients involved in the study; Hui-Ju Lin, and Po-Chung Liu for clinical data management; the 7th Core Lab of National Taiwan University Hospital and the 1st Common Laboratory of National Taiwan University Hospital, Yun-Lin Branch for instrumental and technical support. Financial support. The work was supported by grants from the National Taiwan University Hospital, Taiwan (105-P09). Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. Fagiuoli S , Minniti F , Pevere S et al.  HBV and HCV infections in heart transplant recipients . J Heart Lung Transplant   2001 ; 20 : 718 – 24 . Google Scholar Crossref Search ADS PubMed   2. 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Liu, Chen-Hua, Chen, Yih-Sharng, Wang, Sheoi-Shen, Liu, Chun-Jen, Su, Tung-Hung, Yang, Hung-Chih, Hong, Chun-Ming, Chen, Pei-Jer, Chen, Ding-Shinn, Kao, Jia-Horng. Sofosbuvir-based Interferon-Free Direct Acting Antiviral Regimens for Heart Transplant Recipients With Chronic Hepatitis C Virus Infection, Clinical Infectious Diseases, 2018, 289-292, DOI: 10.1093/cid/cix787