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New drugs for HCV treatment in solid organ transplantation Xavier Forns Liver Unit Hospital Clínic May 23-35, 2019. Efficacy results of pangenotypic regimens in transplant recipients Antiviral therapy and safety issues of in transplant recipients
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New drugsfor HCV treatment in solidorgan transplantation Xavier Forns Liver Unit Hospital Clínic May 23-35, 2019
Efficacyresults of pangenotypicregimens in transplant recipients • Antiviral therapy and safety issues of in transplant recipients • HCV positive donorsforsolidorgan transplant recipients • Results of antiviral therapy in recipients of HCV NAT positive donors • Virologicalissues in recipients of HCV NAT positive donors
Efficacyresults of pangenotypicregimens in transplant recipients • Antiviral therapy and safety issues of in transplant recipients • HCV positive donorsforsolidorgan transplant recipients • Results of antiviral therapy in recipients of HCV NAT positive donors • Virologicalissues in recipients of HCV NAT positive donors
Efficacy of pangenotypicregimens in real life SOF/VEL GLE/PIB Efficacy of SOF/VEL in real life cohort (North America and EU). N=5541 patients Study Population Receiving On-Label Glecaprevir/Pibrentasvir. SVR12 data N=998 SVR12 (ITT) SVR12 (mITT) • Mangia A, et al. ILC 2019; GS-03 • Cornberg M, et al. ILC 2019; GS-07
Efficacy of pangenotypicregimens in transplant recipients everolimus sirolimus Glecaprevir/Pibrentasvir 12 weeks (n=100) tacrolimus cyclosporine Reau et al Hepatology. 2018
Efficacy of pangenotypicregimens in liver transplant recipients Sofosbuvir/Velpatasvir12 sem (n=79) Agarwal K et al J Hepatol 2018
Efficacyresults of pangenotypicregimens in transplant recipients • Antiviral therapy and safety issues of in transplant recipients • HCV positive donorsforsolidorgan transplant recipients • Results of antiviral therapy in recipients of HCV NAT positive donors • Virologicalissues in recipients of HCV NAT positive donors
DDA and druginteractions in the transplant setting Tacrolimus Drug CsA MMF Everolimus SOF/VEL G/P Drug SOF/VEL Caspofungin Amphotericin B Anidulafungin Valciclovir Fluconazol G/P Valaciclovir Drug SOF/VEL Atorvastatin Tenofovir DF Entecavir G/P Potential interaction No interaction Drugs should not be coadministered http://hep-druginteractions.org/interactions.aspx
Renal failure and Glecaprevir/Pibrentasvir Multicenter, open-label, phase 3 trialassessingglecaprevir/pibrentasvir for 12 weeks in adults who had HCV genotype 1-6 and severe renal impairment SVR12 (ITT) Gane et al NEJM 2017
Renal failure and sofosbuvir-basedregimens Observational cohort of patientswith renal failurewhorecievedSOF-basedregimens. FoureGFRmeasurementsduringtherapy 75% hadlessthan 0.3 mg/dLincrease in creatininelevels at any time Median eGFRdidnotchange Sise et al Clinc J Am SocNephrol 2017
Impact of DAA on livertransplantationwaitinglists All Descompensated CHC HCV NASH HBV Flemming et al Hepatology 2017
Impact of DAA on livertransplantationwaitinglists OCATT: Proportion of anti-HCV positive patientsenlisted in Catalonia (2008-2016) Crespo et l J Hepatol 2018
Efficacyresults of pangenotypicregimens in transplant recipients • Antiviral therapy and safety issues of in transplant recipients • HCV positive donorsforsolidorgan transplant recipients • Results of antiviral therapy in recipients of HCV NAT positive donors • Virologicalissues in recipients of HCV NAT positive donors
Increase in anti-HCVpotentialdonors • In the USA deathsduetoopioidoverdosehaveincreased up to 200% since 2000. As a consequence, a largenumber of anti-HCV positive potentialdonors are available. • Drasticreduction of donorage Stewart OPTN 2017, Levistly et al Am J Transpl 2017, Cotter et al Hepatology 2019
Anti-HCVpositivedonors: definition • The term “anti-VHC positive” donorisconfusing and shouldnotbeused. • The term “HCV-viremic donor” includes the NAT results and, thus, differentiates the presence of viremia from its absence, allowing for improved communication regarding infection transmission risk. • HCV transmissionfrom a non viremic anti-HCV positive donoris excepcional, whereastransmissionfrom a viremicdonorsisalmost universal (independently of the transplantedorgan). Levistky et al (AST) AJT2017
Anti-HCV negativehighriskdonors Anti-HCV negativedonorswithsome of the followingriskfactors (< 12 monthsbeforedonation) are associatedwith a highrisk of “window” period and HCV-RNA shouldbetested. • People who have had sex with a person known or suspected to have HIV, HBV, or HCV infection • Men who have had sex with men (MSM) or women who have had sex with a man with a history of MSM behavior • People who have had sex in exchange for money or who have had sex with a person who injected drugs • A child who is < 18 months of age and born to a mother known to be infected with HCV • People who have injected drugs by intravenous, intramuscular, or subcutaneous route for nonmedical reasons • People who have been in lockup, jail, prison, or a juvenile correctional facility for more than 72 consecutive hours • People who have been newly diagnosed with STD, or have been treated STD • People who have been on hemodialysis Levistky et al (AST) AJT2017; Seem et al Public Health Reports 2013
Increased use of HCV viremicdonorsover time • Data fromScientific Registry of Transplant Recipientshaveshown a continuousincrease in the utilization of suchdonors. 11.270 DNAT - /R- 4748 DNAT - /R+ 87 DNAT + /R- 753 DNAT + /R+ Cotter et al Hepatology 2019
Historical Outcomes Following Transplant of “HCV-positive” Donors • In non-hepatic transplantation, recipients with HCV have demonstrated worse outcomes when receiving from HCV-“positive” versus HCV-negative donors; in hepatic transplantation, outcomes have been similar. • The use of HCV antibody status as opposed to viremia in designating donors as HCV-“positive” limits the applicability of these prior findings to the current DAA era. Levistky et al (AST) AJT2017
Efficacyresults of pangenotypicregimens in transplant recipients • Antiviral therapy and safety issues of in transplant recipients • HCV positive donorsforsolidorgan transplant recipients • Results of antiviral therapy in recipients of HCV NAT positive donors • Virologicalissues in recipients of HCV NAT positive donors
Kidneytransplantationfrom HCV viremicdonorsto non infectedrecipients 38 anti-HCV negativepatientscandidatesfor KT HCV on day 3 post-Tx ranged from15 IU/mL to 193.000 million IU/mL. SVR12 in 10 patients 14 acceptprotocol 10 recievekidneyfrominfecteddonor (genotype 1) Grazoprevir-Elbasvir (12 w.) startedday3 post-KT The median time from eligibility on the waiting list for hepatitis C–infected kidneys to transplantation was 58 days Goldberg et al, NEJM 2017
Kidneytransplantationfrom HCV viremicdonorsto non infectedrecipients 10 HCV negativecandidates (no living donor) • Donor genotypes were 1a (n=3), 1a/3 mix (n=1), 2 (n=2), and in 4 cases HCV genotype could not be determined due to insufficient HCV RNA • 5 recipientsseroconvertedto anti-HCV Any HCV genotype Grazoprevir/Elbasvir (firstdose pre-transplant) G1: GZV/EBV 12 weeks *G2/3: GZV/EBV + SOF 12 weeks Lowlevel HCV-RNA in 5 *Viral load and HCV genotypewasavailableduring the firstdays post-KT. If G3, SOF wasadded. If G1a RBV wasadded and treatment extended to 16 weeksif RAS. Durand et al Ann Inter Med 2018
Seroconversionaftertransplantation of HCV Ab+/NAT - organs • 32 HCV negativepatientswhoreceivedkidneyallograftsfrom 25 HCV Ab+/NAT- donors • Mean follow-up 10 months • 14 (44%) patientsbecame anti-HCV + • Allwere HCV-RNA - Similar experiencewithotherorgans Immnecellsfromtransplantedorgans? De Vera et al Am J Transpl 2018
Hearttransplantationfrom HCV viremicdonorsto non infectedrecipients 20 candidatessigninformconsent HCV on day 3 post-Tx ranged from 25 IU/mL to 40 million IU/mL.All G1a. SVR12 in 9 patient (1 died on day 79) 10 receive a heartfrominfecteddonor (genotype 1)* Grazoprevir-Elbasvir (12 w)** startedday 3 post-HT if HCV-RNA positive *Genotype testing during the organ allocation process ** RBV added and treatment 16 w. if G1a with RAS McLean et al Am J Transpl 2019
Liver transplantationfrom HCV viremicdonorsto non infectedrecipients Seven (70%) recipientshad a prior diagnosis of HCV and had achieved SVR Receptor All recipients had documented HCV viremia within 4 days of LT Donor Regimen: SOF/VEL (6) SOF/LDV (3) SOF/DAC (1) Duration: 12 weeks(7) 24 weeks(3) Start at: 43 days post-LT (20-59). Allachieved SVR Kwong et al Am J Transpl 2018
Excellent Initial Outcomes Following Liver Transplant of HCV-ViremicDonors Cox regression analysis comparing HCV-negative LT recipients who received an HCV RNA–positive versus an HCV-RNA–negative liver. Cox regression analysis comparing HCV-positive LT recipients who received an HCV RNA–positive versus an HCV-RNA–negative liver. Cotter et al Hepatology 2019
Efficacyresults of pangenotypicregimens in transplant recipients • Antiviral therapy and safety issues of in transplant recipients • HCV positive donorsforsolidorgan transplant recipients • Results of antiviral therapy in recipients of HCV NAT positive donors • Virologicalissues in recipients of HCV NAT positive donors
Use of donorswhofailedprevious DAA treatment. 545subjects re-treated with GLE/PIB for 12 weeks:assess association between RAS and SVR VEL (pM) LDV (pM) • SVR not affected by presence of NS3 or NS5A L31/Y93 • P32del: SVR in 1 of 4 (25%) versus 191/197 (97%) in WT (p=0.0002) EBV (pM) RBV (µM) SOF (nM) GZV (nM) Nitta el al Scientific Reports 2019 Kurosaki M, et al. ILC 2019; PS-180
Increase in anti-HCVpotentialdonors Anti-HCV prevalence in Catalonia Total: 3328 Lens et al AEEH 2018