Direct-acting antiviral therapy for hepatitis C virus infection in the kidney transplant recipient
2018; Elsevier BV; Volume: 93; Issue: 3 Linguagem: Inglês
10.1016/j.kint.2017.10.024
ISSN1523-1755
AutoresDonald F. Chute, Raymond T. Chung, Meghan E. Sise,
Tópico(s)HIV/AIDS drug development and treatment
ResumoHepatitis C virus infection (HCV) is a common comorbidity in patients who have undergone kidney transplantation and is associated with increased morbidity and mortality compared with recipients who do not have chronic HCV infection. Because interferon-α-based therapies can precipitate acute rejection, they are relatively contraindicated after kidney transplantation. Thus, the majority of kidney transplant recipients with HCV remain untreated. There are now all-oral, interferon-free direct-acting antiviral therapies for HCV infection that are extremely effective and well tolerated in the general population. Recent reports in the literature demonstrate that direct-acting antiviral therapies effectively cured HCV in 406 of 418 kidney transplant recipients (97%); the majority were treated with sofosbuvir-based regimens. Smaller numbers of kidney transplant recipients have been treated with paritaprevir-ritonavir, ombitasvir and dasabuvir, elbasvir-grazoprevir, or glecaprevir-pibrentasvir with excellent success. Direct-acting antiviral therapies were well tolerated and did not increase the rate of acute rejection. The latest advances include approval of regimens that can treat patients with advanced allograft dysfunction (eGFR < 30 ml/min per 1.73 m2) and "pan-genotypic" regimens that have activity against all 6 major genotypes of HCV. This review summarizes what is known about the epidemiology of HCV infection in kidney transplant recipients, and presents the landscape of direct-acting antiviral therapies and areas in need of further investigation. Hepatitis C virus infection (HCV) is a common comorbidity in patients who have undergone kidney transplantation and is associated with increased morbidity and mortality compared with recipients who do not have chronic HCV infection. Because interferon-α-based therapies can precipitate acute rejection, they are relatively contraindicated after kidney transplantation. Thus, the majority of kidney transplant recipients with HCV remain untreated. There are now all-oral, interferon-free direct-acting antiviral therapies for HCV infection that are extremely effective and well tolerated in the general population. Recent reports in the literature demonstrate that direct-acting antiviral therapies effectively cured HCV in 406 of 418 kidney transplant recipients (97%); the majority were treated with sofosbuvir-based regimens. Smaller numbers of kidney transplant recipients have been treated with paritaprevir-ritonavir, ombitasvir and dasabuvir, elbasvir-grazoprevir, or glecaprevir-pibrentasvir with excellent success. Direct-acting antiviral therapies were well tolerated and did not increase the rate of acute rejection. The latest advances include approval of regimens that can treat patients with advanced allograft dysfunction (eGFR < 30 ml/min per 1.73 m2) and "pan-genotypic" regimens that have activity against all 6 major genotypes of HCV. This review summarizes what is known about the epidemiology of HCV infection in kidney transplant recipients, and presents the landscape of direct-acting antiviral therapies and areas in need of further investigation. Hepatitis C virus (HCV) infection affects between 5% to 15% of kidney transplant (KT) recipients in the developed world,1Baid-Agrawal S. Schindler R. Reinke P. et al.Prevalence of occult hepatitis C infection in chronic hemodialysis and kidney transplant patients.J Hepatol. 2014; 60: 928-933Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 2Mitwalli A.H. Alam A. Al-Wakeel J. et al.Effect of chronic viral hepatitis on graft survival in Saudi renal transplant patients.Nephron Clin Pract. 2006; 102: c72-c80Crossref PubMed Scopus (38) Google Scholar, 3Fissell R.B. Bragg-Gresham J.L. Woods J.D. et al.Patterns of hepatitis C prevalence and seroconversion in hemodialysis units from three continents: the DOPPS.Kidney Int. 2004; 65: 2335-2342Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar rates that are up to 10-fold higher than in the general population.4Martin P. Fabrizi F. Hepatitis C virus and kidney disease.J Hepatol. 2008; 49: 613-624Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar HCV infection is associated with worse graft and patient survival,5Carpio R. Pamugas G. Danguilan R. et al.Outcomes of renal allograft recipients with hepatitis C.Transplant Proc. 2016; 48: 836-839Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 6Scott D.R. Wong J.K. Spicer T.S. et al.Adverse impact of hepatitis C virus infection on renal replacement therapy and renal transplant patients in Australia and New Zealand.Transplantation. 2010; 90: 1165-1171Crossref PubMed Scopus (121) Google Scholar, 7Mahmoud I.M. Elhabashi A.F. Elsawy E. et al.The impact of hepatitis C virus viremia on renal graft and patient survival: a 9-year prospective study.Am J Kidney Dis. 2004; 43: 131-139Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar and has been extremely difficult to cure after transplant due to the poor efficacy, intolerable side effects, and risk of acute rejection associated with interferon-α (IFN) and ribavirin use. Direct-acting antiviral therapies (DAAs) have revolutionized the management of HCV infection. These agents target viral proteins essential for viral replication and do not rely on the host's immune response. Current DAA regimens approved by the Food and Drug Administration (FDA) are IFN-free and are able to achieve cure rates of upwards of 95%.8Afdhal N. Zeuzem S. Kwo P. et al.Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection.New Engl J Med. 2014; 370: 1889-1898Crossref PubMed Scopus (1428) Google Scholar, 9Roth D. Nelson D.R. Bruchfeld A. et al.Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study.Lancet. 2015; 386: 1537-1545Abstract Full Text Full Text PDF PubMed Scopus (538) Google Scholar, 10Feld J.J. Jacobson I.M. Hezode C. et al.Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection.N Engl J Med. 2015; 373: 2599-2607Crossref PubMed Scopus (804) Google Scholar Clinical trials and real-world data have demonstrated excellent cure rates in liver transplant recipients, suggesting that immunosuppression does not decrease the effectiveness of DAAs, nor are there unacceptable interactions with transplant medications.11Brown Jr., R.S. O'Leary J.G. Reddy K.R. et al.Interferon-free therapy for genotype 1 hepatitis C in liver transplant recipients: Real-world experience from the hepatitis C therapeutic registry and research network.Liver Transpl. 2016; 22: 24-33Crossref PubMed Scopus (96) Google Scholar There is now increasing data that DAAs can also be successfully used in KT recipients with low rates of adverse events and without increasing the rate of acute rejection. In this review, we discuss the effect of chronic HCV infection in the KT recipient, the safety and efficacy of historical and novel HCV therapies in KT recipients, the optimal timing of HCV treatment in patients on the KT waiting list, the use of DAAs to cure HCV infection after transplantation from an HCV-infected donor to an HCV uninfected recipient, and finally, areas in need of further study. Chronic HCV infection has been independently associated with a number of adverse outcomes in KT recipients, including increased risk of acute rejection, chronic allograft nephropathy, diabetes, and de novo glomerulonephritis.6Scott D.R. Wong J.K. Spicer T.S. et al.Adverse impact of hepatitis C virus infection on renal replacement therapy and renal transplant patients in Australia and New Zealand.Transplantation. 2010; 90: 1165-1171Crossref PubMed Scopus (121) Google Scholar, 12Fernández I. Muñoz-Gómez R. Pascasio J.M. et al.Efficacy and tolerability of interferon-free antiviral therapy in kidney transplant recipients with chronic hepatitis C.J Hepatol. 2017; 66: 718-723Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 13Mahmoud I.M. Sobh M.A. El-Habashi A.F. et al.Interferon therapy in hemodialysis patients with chronic hepatitis C: study of tolerance, efficacy and post-transplantation course.Nephron Clin Pract. 2005; 100: c133-c139Crossref PubMed Scopus (55) Google Scholar, 14Cruzado J.M. Carrera M. Torras J. et al.Hepatitis C virus infection and de novo glomerular lesions in renal allografts.Am J Transplant. 2001; 1: 171-178Crossref PubMed Scopus (149) Google Scholar, 15Fabrizi F. Messa P. Martin P. et al.Hepatitis C virus infection and post-transplant diabetes mellitus among renal transplant patients: a meta-analysis.Int J Artif Organs. 2008; 318: 675-682Crossref Scopus (43) Google Scholar Mahmoud and colleagues found a substantially increased risk of chronic allograft nephropathy in transplant recipients with ongoing HCV viremia compared with those who had been treated with IFN prior to transplantation (40.6% vs. 5.6%, P = 0.009).13Mahmoud I.M. Sobh M.A. El-Habashi A.F. et al.Interferon therapy in hemodialysis patients with chronic hepatitis C: study of tolerance, efficacy and post-transplantation course.Nephron Clin Pract. 2005; 100: c133-c139Crossref PubMed Scopus (55) Google Scholar Cruzado et al. demonstrated a nearly 8-fold increase in the rate of biopsy-proven de novo membranoproliferative glomerulonephritis after KT in HCV-infected patients.14Cruzado J.M. Carrera M. Torras J. et al.Hepatitis C virus infection and de novo glomerular lesions in renal allografts.Am J Transplant. 2001; 1: 171-178Crossref PubMed Scopus (149) Google Scholar Chronic HCV infection increases insulin resistance, and a meta-analysis of more than 30,000 unique KT recipients showed that the relative risk of developing post-transplant diabetes mellitus was 2.73-fold higher (95% confidence interval [CI] 1.94–3.83) in HCV-infected KT recipients.15Fabrizi F. Messa P. Martin P. et al.Hepatitis C virus infection and post-transplant diabetes mellitus among renal transplant patients: a meta-analysis.Int J Artif Organs. 2008; 318: 675-682Crossref Scopus (43) Google Scholar Taking into account all of the above risks, a retrospective study of 834 kidney transplant recipients with a 10-year follow-up period showed a substantial decrease in overall graft survival of HCV-infected compared with uninfected KT recipients (65% ± 5% vs. 85% ± 3%, P = 0.001).16Mathurin P. Mouquet C. Poynard T. et al.Impact of hepatitis B and C virus on kidney transplantation outcome.Hepatology. 1999; 29: 257-263Crossref PubMed Scopus (500) Google Scholar Meta-analyses have demonstrated a 1.56-fold (95% CI 1.35–1.80) relative risk of graft loss and 1.79-fold (95% CI 1.57–2.03) relative risk for mortality when compared with uninfected KT recipients.16Mathurin P. Mouquet C. Poynard T. et al.Impact of hepatitis B and C virus on kidney transplantation outcome.Hepatology. 1999; 29: 257-263Crossref PubMed Scopus (500) Google Scholar, 17Fabrizi F. Martin P. Dixit V. et al.Hepatitis C virus antibody status and survival after renal transplantation: meta-analysis of observational studies.Am J Transplant. 2005; 5: 1452-1461Crossref PubMed Scopus (210) Google Scholar, 18Hanafusa T. Ichikawa Y. Kishikawa H. et al.Retrospective study on the impact of hepatitis C virus infection on kidney transplant patients over 20 years.Transplantation. 1998; 66: 471-476Crossref PubMed Scopus (187) Google Scholar The majority of studies have shown that survival differences that exist between HCV-infected and uninfected KT recipients do not typically manifest until more than 10 years of follow-up.16Mathurin P. Mouquet C. Poynard T. et al.Impact of hepatitis B and C virus on kidney transplantation outcome.Hepatology. 1999; 29: 257-263Crossref PubMed Scopus (500) Google Scholar, 19Legendre C. Garrigue V. Le Bihan C. et al.Harmful long-term impact of hepatitis C virus infection in kidney transplant recipients.Transplantation. 1998; 65: 667-670Crossref PubMed Scopus (232) Google Scholar Despite reductions in graft and overall survival, it is still unequivocally clear that patients with HCV benefit from KT compared with remaining on dialysis on the wait-list.20Bloom R.D. Sayer G. Fa K. et al.Outcome of hepatitis C virus-infected kidney transplant candidates who remain on the waiting list.Am J Transplant. 2005; 5: 139-144Crossref PubMed Scopus (93) Google Scholar In a study of 315 HCV-infected KT candidates on the wait-list, Bloom et al. found a significantly higher survival rate among transplanted patients when compared with their HCV-infected counterparts who remained on the wait-list.20Bloom R.D. Sayer G. Fa K. et al.Outcome of hepatitis C virus-infected kidney transplant candidates who remain on the waiting list.Am J Transplant. 2005; 5: 139-144Crossref PubMed Scopus (93) Google Scholar Because IFN was linked to acute graft rejection, the majority of KT recipients chronically infected with HCV remained untreated after transplant. In fact, the 2008 KDIGO guidelines for the management of HCV recommended treatment of HCV only in KT recipients who had pressing indications for therapy, such as clinically and histologically worsening liver disease.21Gordon C.E. Balk E.M. Becker B.N. et al.KDOQI US commentary on the KDIGO clinical practice guideline for the prevention, diagnosis, evaluation, and treatment of hepatitis C in CKD.Am J Kidney Dis. 2008; 52: 811-825Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar Beyond the risk of rejection, IFN-based therapies are poorly efficacious, causing flu-like symptoms, neuropsychiatric side effects, and provoking autoimmunity.22Wei F. Liu J. Liu F. et al.Interferon-based anti-viral therapy for hepatitis C virus infection after renal transplantation: an updated meta-analysis.PLoS One. 2014; 9: e90611Crossref PubMed Scopus (30) Google Scholar Ribavirin, which is added to IFN therapy to improve the likelihood of cure, often causes anemia by provoking hemolysis, and is also ideally avoided after KT.23Feld J.J. Jacobson I.M. Sulkowski M.S. et al.Ribavirin revisited in the era of direct-acting antiviral therapy for hepatitis C virus infection.Liver Int. 2017; 37: 5-18Crossref PubMed Scopus (64) Google Scholar The few studies of IFN-based therapies in KT recipients have yielded disappointing results. Wei et al. recently summarized the literature with a meta-analysis of 12 studies covering 140 KT recipients who received IFN-based therapy for chronic HCV infection.22Wei F. Liu J. Liu F. et al.Interferon-based anti-viral therapy for hepatitis C virus infection after renal transplantation: an updated meta-analysis.PLoS One. 2014; 9: e90611Crossref PubMed Scopus (30) Google Scholar IFN monotherapy cured 6 of 48 (12.5%) patients. Combination therapy with IFN-α and ribavirin or pegylated IFN and ribavirin cured 11 of 33 (33%) and 24 of 59 (41%) patients, respectively. Twenty-one percent dropped out due to side effects; graft dysfunction was the most frequent adverse event requiring discontinuation. The rates of rejection varied from 0% to 40%, with a total of 10 of the 140 treated patients experiencing acute rejection. For these reasons, in parts of the world where DAA therapies are not yet available to treat HCV, pegylated IFN and ribavirin combination therapy should be used only to treat patients with high mortality risk from decompensated liver disease or severe manifestations of cryoglobulinemic glomerulonephritis. Ribavirin monotherapy cannot cure HCV in KT recipients; however, ribavirin monotherapy has been shown to improve proteinuria and histopathological changes in post-transplant glomerulopathy.24Kamar N. Sandres-Saune K. Selves J. et al.Long-term ribavirin therapy in hepatitis C virus-positive renal transplant patients: effects on renal function and liver histology.Am J Kidney Dis. 2003; 42: 184-192Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 25Fontaine H. Vallet-Pichard A. Equi-Andrade C. et al.Histopathologic efficacy of ribavirin monotherapy in kidney allograft recipients with chronic hepatitis C.Transplantation. 2004; 78: 853-857Crossref PubMed Scopus (52) Google Scholar HCV is divided into 6 distinct genotypes, each with multiple subtypes, accounting for structural differences in the HCV genome. The response to treatment varies greatly by genotype. DAAs target viral proteins associated with replication, including NS3-4A protease, NS5A protein, and NS5B polymerase (Figure 1). The general approach for curative treatment is to target multiple components of the viral replicative machinery with agents from 2 or more classes and inhibit them for 8 to 24 weeks; this is sufficient to achieve cure in the vast majority (>95%). Treatment duration is generally determined by the potency of the regimen, genotype, and whether the patient has cirrhosis or prior HCV treatment experience. Early drug development focused on genotype 1 infection, because it is the most common in the United States and worldwide, and there are multiple combinations of DAAs that can be used to effectively treat genotype 1 infection (Table 1). In the last 12 months, "pan-genotypic" therapies that effectively function against the major viral genotypes 1 through 6 have been approved by the FDA.10Feld J.J. Jacobson I.M. Hezode C. et al.Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection.N Engl J Med. 2015; 373: 2599-2607Crossref PubMed Scopus (804) Google Scholar, 26Gane E. Lawitz E. Pugatch D. et al.Glecaprevir and pibrentasvir in patients with HCV and severe renal impairment.N Engl J Med. 2017; 377: 1448-1455Crossref PubMed Scopus (283) Google Scholar All patients can now be treated with DAA therapies that are IFN-free. It is worth noting that even the small numbers of patients in whom first-line DAA regimens fail can be successfully re-treated with combinations of newer, more potent agents.27de Lédinghen v, Laforest C, Hédoze C, et al. Retreatment with sofosbuvir plus grazoprevir/elbasvir plus ribavirn of patients with hepatitis c virus genotype 1 or 4 who previously failed a NS5A or NS3-containing regimen. ANRS HC34 REVENGE. Clin Infect Dis. https://doi.org/10.1093/cid/cix916.Google Scholar, 28Bourliere M. Gordon S.C. Ramji A. et al.Sofosbuvir/Velpatasvir/Voxilaprevir for 12 weeks as a Salvage regimen in NS5A inhibitor-experienced patients with genotype 1–6 infection: the phase 3 POLARIS-1 study.Hepatology. 2016; 64: 1-136PubMed Google ScholarTable 1FDA-approved direct-acting antiviral combinationsDAA combinationGenotypeAvailable transplant dataInteraction with CNISafety if eGFR < 30Sofosbuvir-simeprevir (SOF-SIM)1Used in multiple retrospective series in KT and LT recipientsCSA ↑↑ SIM AUC combination not recommendedSOF not approved if GFR < 30TAC ↑ SIM AUC, monitor levelsSIM largely hepatically metabolizedSofosbuvir-daclatasvir (SOF-DAC)1–3Case series in KT recipientsNo interactions, no dose adjustment, monitor levelsSOF not approved if GFR < 30Recommended regimen in LT recipients ± ribavirinDAC largely hepatically metabolizedSofosbuvir-ledipasvir (SOF-LDV)1, 4Prospective RCT in KT, also used in retrospective series30Colombo M. Aghemo A. Liu H. et al.Treatment with ledipasvir–sofosbuvir for 12 or 24 weeks in kidney transplant recipients with chronic hepatitis C virus genotype 1 or 4 infection: a randomized trial.Ann Intern Med. 2017; 166.2: 109-117Crossref Scopus (139) Google ScholarNo dose adjustments, monitor levelsSOF not approved if GFR < 30Recommended regimen in LT recipients ± ribavirinLDV largely hepatically metabolizedOmbitasvir-paritaprevir-ritonavir + dasabuvir (PrOD)110 cases reported12Fernández I. Muñoz-Gómez R. Pascasio J.M. et al.Efficacy and tolerability of interferon-free antiviral therapy in kidney transplant recipients with chronic hepatitis C.J Hepatol. 2017; 66: 718-723Abstract Full Text Full Text PDF PubMed Scopus (73) Google ScholarRitonavir ↑↑ in CSA and TAC AUCSafe and effective in advanced/ESRD on hemodialysis46Gane E.J. Sola R. Cohen E. et al.RUBY-II: efficacy and safety of a ribavirin-free ombitasvir/paritaprevir/ritonavir+/-dasabuvir regimen in patients with severe renal impairment or end-stage renal disease and HCV genotypes 1a or 4 infection.Hepatology. 2016; 63: 470A-471AGoogle Scholar, 58Pockros P.J. Reddy K. Mantry P. et al.LO1: Safety of ombitasvir/paritaprevir/ritonavir plus dasabuvir for treating HCV GT1 infection in patients with severe renal impairment or end-stage renal disease: The RUBY-I study.J Hepatol. 2015; 62: S257Abstract Full Text PDF PubMed Google ScholarOmbitasvir-paritaprevir-ritonavir (PrO)4Grazoprevir-elbasvir (GRZ-ELB)1, 4Used in 18 KT recipients with 1 potentially related SAE55Reese P.P. Abt P.L. Blumberg E.A. et al.Transplanting hepatitis C-positive kidneys.N Engl J Med. 2015; 373: 303-305Crossref PubMed Scopus (125) Google Scholar, 57Durand C. Brown D. Wesson R. et al.EXPANDER-1: Exploring renal transplants using hepatitis-C Infected donors for HCV-negative recipients.Am J Transplant. 2017; 17Google ScholarCSA ↑↑ GRZ-ELB AUC, combination not recommendedSafe and effective in advanced/ESRD on hemodialysis9Roth D. Nelson D.R. Bruchfeld A. et al.Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study.Lancet. 2015; 386: 1537-1545Abstract Full Text Full Text PDF PubMed Scopus (538) Google ScholarNo reports in LTGRZ-ELB ↑ TAC AUC, no a priori dose adjustments, monitor levelsSofosbuvir-velpatasvir (SOF-VEL)Pan-GenotypicNo current reports of use in KT or LT recipientsNo dose adjustments, monitor levels, minimal dataSOF not approved if GFR < 30VEL largely hepatically metabolizedGlecaprevir-pibrentasvir (GLE-PIB)Pan-GenotypicStudied in a prospective trial of 100 transplant recipients (20 KT, 80 LT)31Reau N. Kwo P. Rhee S. et al.LBO-03-MAGELLAN-2: safety and efficacy of glecaprevir/pibrentasvir in liver or renal transplant adults with chronic hepatitis C genotype 1–6 infection.J Hepatol. 2017; 66: S90-S91Abstract Full Text PDF Google ScholarCSA ↑ GLE-PIB, monitor levelsSafe and effective in advanced/ ESRD on hemodialysis26Gane E. Lawitz E. Pugatch D. et al.Glecaprevir and pibrentasvir in patients with HCV and severe renal impairment.N Engl J Med. 2017; 377: 1448-1455Crossref PubMed Scopus (283) Google ScholarTacrolimus requires no dose adjustment, monitor levelsAUC, area under curve; CNI, calcineurin inhibitor; CSA, cyclosporine; DAA, direct-acting antiviral; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; FDA, Food and Drug Administration; KT, kidney transplant; LT, liver transplant; RCT, randomized controlled trial; SIM, simeprevir; TAC, tacrolimus. Open table in a new tab AUC, area under curve; CNI, calcineurin inhibitor; CSA, cyclosporine; DAA, direct-acting antiviral; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; FDA, Food and Drug Administration; KT, kidney transplant; LT, liver transplant; RCT, randomized controlled trial; SIM, simeprevir; TAC, tacrolimus. Recommended therapies for patients with advanced allograft dysfunction include 1 of only 3 regimens approved for patients with estimated glomerular filtration rate (eGFR) < 30 ml/min per 1.73 m2 (Table 1). Sofosbuvir, a NS5B polymerase inhibitor, is renally eliminated and not approved for those with eGFR < 30 ml/min per 1.73 m2. There are now only a few situations in which ribavirin is still used in conjunction with DAAs. Ribavirin may still be needed in simultaneous liver-kidney transplant recipients or used to enhance therapy in patients with coexistent decompensated cirrhosis.29AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. Available at: http://www.hcvguidelines.org. Accessed June 16, 2017.Google Scholar To date, there have been 2 prospective clinical trials using DAAs in KT recipients (Table 2). Colombo et al. randomized 114 adult patients at least 6 months after KT to receive 12 or 24 weeks of sofosbuvir-ledipasvir 400 mg/90 mg combination therapy.30Colombo M. Aghemo A. Liu H. et al.Treatment with ledipasvir–sofosbuvir for 12 or 24 weeks in kidney transplant recipients with chronic hepatitis C virus genotype 1 or 4 infection: a randomized trial.Ann Intern Med. 2017; 166.2: 109-117Crossref Scopus (139) Google Scholar The majority (75%) had genotype 1b, 16.5% had genotype 1a, and 8.5% had genotype 4 infection. Median age was 53 (range 25–75), 94% were white, 58% were male, 15% had compensated cirrhosis, and 69% were treatment-naïve. All patients had eGFR ≥ 40 ml/min per 1.73 m2 at the time of screening. All 114 patients were cured. In the MAGELLAN-2 trial, 80 liver transplant recipients and 20 KT recipients received glecaprevir-pibrentasvir.31Reau N. Kwo P. Rhee S. et al.LBO-03-MAGELLAN-2: safety and efficacy of glecaprevir/pibrentasvir in liver or renal transplant adults with chronic hepatitis C genotype 1–6 infection.J Hepatol. 2017; 66: S90-S91Abstract Full Text PDF Google Scholar The population was mostly white (78%) and male (75%), with a median age of 60 (range 39–78). Patients had genotype 1 to 6 infection, and all but 2 patients (98%) were cured.Table 2Summary of studies of DAA use in kidney transplant recipientsAuthor, journal/conferenceRegimen used, numberSVRAdditional informationColombo, Annals of Intern Med30Colombo M. Aghemo A. Liu H. et al.Treatment with ledipasvir–sofosbuvir for 12 or 24 weeks in kidney transplant recipients with chronic hepatitis C virus genotype 1 or 4 infection: a randomized trial.Ann Intern Med. 2017; 166.2: 109-117Crossref Scopus (139) Google ScholarSOF-LDV, 114100%18% required CNI adjustment1 patient had persistent decline in renal functionMorales, Clinical Transplantation40Morales A.L. Liriano-Ward L. Tierney A. et al.Ledipasvir/sofosbuvir is effective and well tolerated in postkidney transplant patients with chronic hepatitis C virus.Clin Transplant. 2017; 31Crossref PubMed Scopus (23) Google ScholarSOF-LDV, 3284%25% required CNI adjustment1 virologic failure, 4 deaths, none attributed to DAAs1 borderline rejectionaIn the patient with borderline rejection, BANFF class IIa rejection had been noted prior to initiating DAAs, and creatinine improved at the end of treatment.Reau, EASL Meeting, Amsterdam, Netherlands, 201731Reau N. Kwo P. Rhee S. et al.LBO-03-MAGELLAN-2: safety and efficacy of glecaprevir/pibrentasvir in liver or renal transplant adults with chronic hepatitis C genotype 1–6 infection.J Hepatol. 2017; 66: S90-S91Abstract Full Text PDF Google ScholarGLE-PIB, 2098%bOverall SVR was 98 of 100 patients. Only 20 of the patients were KT recipients, and 80 were liver transplant recipients.Data available only in abstract formKamar, Transplantation35Kamar N. Marion O. Rostaing L. et al.Efficacy and safety of sofosbuvir-based antiviral therapy to treat hepatitis C virus infection after kidney transplantation.Am J Transplant. 2016; 16: 1474-1479Crossref PubMed Scopus (163) Google ScholarSOF-LDV, 9SOF-LDV-RBV, 1SOF-SIM, 6SOF-SIM-RBV, 1SOF-DAC, 4SOF-RBV, 3SOF-PEG-RBV, 1100%No serious adverse eventsTacrolimus trough levels decreased during therapySawinsky, Transplantation32Sawinski D. Kaur N. Ajeti A. et al.Successful treatment of hepatitis C in renal transplant recipients with direct-acting antiviral agents.Am J Transplant. 2016; 16: 1588-1595Crossref PubMed Scopus (174) Google ScholarSOF-SIM, 9SOF-LDV, 7SOF-RBV, 3SOF-DAC, 1100%45% required CNI adjustmentsNo episodes of rejectionLin, PLOS One37Lin M.V. Sise M.E. Pavlakis M. et al.Efficacy and safety of direct acting antivirals in kidney transplant recipients with chronic hepatitis C virus infection.PLoS One. 2016; 11: e0158431Crossref PubMed Scopus (84) Google ScholarSOF-SIM, 9SOF-SIM-RBV, 3SOF-LDF, 7SOF-LDV-RBV, 1SOF-RBV, 492%No CNI adjustments2 episodes of worsening proteinuria with collapsing FSGS on biopsyFernandez, J Hepatol12Fernández I. Muñoz-Gómez R. Pascasio J.M. et al.Efficacy and tolerability of interferon-free antiviral therapy in kidney transplant recipients with chronic hepatitis C.J Hepatol. 2017; 66: 718-723Abstract Full Text Full Text PDF PubMed Scopus (73) Google ScholarSOF-LDV, 30SOF-LDV-RBV, 29SOF-DAC, 16SOF-DAC-RBV, 2OBV-PTV-r-DSV, 8OBV-PTV-r-DSV-RBV, 2SOF-SIM, 5SOF-SIM/RBV, 3SMV-DCV, 2SMV-DCV-RBV, 4SOF-RBV, 298%3 episodes of acute humoral rejectionGrade 2/3 anemia in 33% with RBV vs. 15% RBV-free55% required CNI dose adjustment16% experienced increase in serum creatinine > 25% on therapyLubetzky, Transplantation36Lubetzky M. Chun S. Joelson A. et al.Safety and efficacy of treatment of hepatitis C in kidney transplant recipients with directly acting antiviral agents.Transplantation. 2017; 101: 1704-1710Crossref PubMed Scopus (56) Google ScholarSOF-LDV, 21SOF-LDV-RBV, 3SOF-RBV, 2SOF-DAC, 297%19% had worsening proteinuria during/shortly after therapy6% had eGFR decline below 20 ml/min6% required CNI adjustmentBhamidimarri, Transpl Int34Bhamidimarri K.R. Ladino M. Pedraza F. et al.Transplantation of kidneys from hepatitis C-positive donors into hepatitis C virus-infected recipients followed by early initiation of direct acting antiviral therapy: a single-center retrospective study.Transplant Int. 2017; 30: 865-873Crossref PubMed Scopus (47) Google ScholarSOF-LDV-RBV, 19SOF-LDV, 4SOF-SIM, 1SOF-DAC, 196%52% required CNI adjustment4 cases of antibody-mediated rejection on DAA treatment7 of 19 on RBV experienced anemiaGallegos-Orozco, Cureus33Gallegos-Orozco J.F. Kim R. Thiesset H.F. et al.Early results of pilot study using hepatitis C virus (HCV) positive kidneys to transplant HCV infected patients with end-stage renal disease allowing for successful interferon-free direct acting antiviral therapy after transplantation.Cureus. 2016; 8: e890PubMed Google ScholarSOF-LDV (RBV), 5SOF-DAC,1100%cStudy included 7 patients, but only 6 had b
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