Management of hepatitis C in kidney transplant patients: on the cusp of change.

Department of Surgery, University of California,San Francisco, CA Corresponding author: Peter G. Stock,Peter.Stock@ucsfmedctr.orgReceived 29 April 2014, revised 15 May 2014 andaccepted for publication 17 May 2014The impact of hepatitis C virus (HCV) and humanimmunodeﬁciency virus (HIV) infections on the short- andlong-term outcomes of kidney transplant (KT) recipientshave been clouded by the multitude of donor and recipientfactors that inﬂuence graft and patient survival. In anelegant analysis using the Scientiﬁc Registry of TransplantRecipients(SRTR)database,Xiaetal(1)removedthedonorvariables from consideration by comparing outcomes inkidney recipients of paired deceased donor kidneys. In thisanalysis, the outcomes of the kidney transplanted into arecipient with HCV, HIV or HIV/HCV coinfection wascompared to the outcomes of the paired-kidney trans-planted into a recipient without these viral infections. Byutilizing a large database and eliminating the deceaseddonor variables, the study was able to show that HCVinfection had a statistically signiﬁcant negative effect onboth death censored graft survival and patient survival.Interestingly, HIV infection did not affect patient or graftsurvival, although those with HIV/HCV coinfection hadthe poorest survival rates. The report by Xia et al (1) isimportant and timely, given the recent approval of the ﬁrstinterferon-free regimen for treatment of HCV and withseveral other direct-acting antiviral (DAA) drug combina-tions against HCV anticipated soon. For the ﬁrst time,transplant physicians have the ability to intervene andminimize the detrimental inﬂuence of hepatitis C onposttransplant outcomes.A higher rate of graft loss among HCV-viremic kidneyrecipients compared with uninfected recipients has beendemonstrated in other prospective cohort studies and priorSRTR analyses (2). Both direct and indirect effects of HCVare at play. The most frequent pathology is recurrent or denovo membranoproliferative glomerulonephritis, the lattermost frequently associated with cryoglobulinemia (3).Diabetes, a well-established extrahepatic manifestation ofHCV infection, occurs at higher rates in KT recipients withHCV compared with uninfected recipients and maycontribute to progression of recurrent kidney disease (4).Finally, due to concerns regarding the effects of immuno-suppression on HCV and/or HIV diseases, minimization ofimmunosuppressionmaycontributetohigherratesofgraftlossduetorejection.GiventhemyriadofpossiblewaysthatHCV inﬂuences graft outcomes both in HCV and HIV/HCVinfected KT recipients, eradication of HCV prior to or soonafter KT would be ideal, with the expectation that HCV-related causes of graft loss would be minimized.The study by Xia et al (1) identiﬁed a twofold higher risk foracuterejectionintheHIV/HCVcoinfectedkidneyrecipients,though this was marginally signiﬁcant, possibly related tolimited sample size. The ﬁnding of higher rejection ratesamongHIVtransplantrecipientshasbeenshowninseveralstudies (5–7) and the potential negative impact of rejectiontreatment on hepatitis C progression is well recognized.The etiology of the higher incidence of rejection observedin the HIV-infected kidney recipients is multifactorial.Although immune dysregulation likely contributes to thehigher rates of rejection, complex pharmacokinetic inter-actions between antiretroviral drugs and immunosuppres-sive drugs are also an important factor. Speciﬁcally,inhibition of the cytochrome P450 system by proteaseinhibitors makes it challenging to achieve adequateexposure to the calcineurin inhibitors. Importantly, thehigher incidence of rejection observed in HIV-infectedtransplant recipients were abrogated by using integraseinhibitor-basedantiretroviraltherapy,andavoidingproteaseinhibitors as part of the antiretroviral therapy (8). For thisreason, many centers are recommending switching tointegrase inhibitor-based antiretroviral therapy prior totransplantation. Although thymoglobulin induction therapyis another strategy to minimize rejection, lymphocytedepletionintheUSmulticentertrialinHIV-infectedpatientsresulted in twofold increases in infection rates in the KTrecipients (5). Furthermore, lymphocyte depletion in theHIV/HCVcoinfectedrecipientscouldexacerbatehepatitisCinfection. For all these reasons, the best strategy tominimize rejection is to prevent the pharmacokineticinteractions leading to poor immunosuppression exposureby using integrase inhibitor-based antiretroviral therapy.Based on the signiﬁcantly poorer outcome observed in theanalysis by Xia et al (1), future management of the