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Hepatitis C Virus Infection in Chronic Kidney Disease

Marco Ladino, Fernando Pedraza, and David Roth

Division of Nephrology and Hypertension, University of Miami Miller School of Medicine and the Miami Veterans Administration Hospital, Miami, Florida

ABSTRACT Soon after the virus (HCV) was identified in 1989, it was recognized that diagnosis and treatment of HCV infec- the prevalence of infection in patients with ESRD far exceeded that in the general tion.6 It was evident to the KDIGO in- population. Infection with HCV predisposes to the hepatic complications of vestigators that patients with CKD and and hepatocellular carcinoma. However, important extrahepatic manifestations patients with ESRD had been system- include immune complex glomerular disease, accelerated progression of CKD, atically excluded from all of the phase increases in cardiovascular event risk, and lymphoproliferative disorders. Advances 3 HCV treatment trials and as a conse- in understanding the molecular biology of HCV have ushered in a new era in the quence, that they represented a popula- treatment of this infection. Second generation direct–acting antiviral agents have tion with a substantial unmet clinical revolutionized therapy, with sustained virologic response rates (undetectable viral need. load 12 weeks after completing therapy) of .90% in most patients. Studies using This review will focus on HCV in- direct-acting antivirals in patients with CKD and those on dialysis are showing ex- fection in patients with CKD, patients cellent safety and efficacy as well. In this context, it is imperative that nephrologists with ESRD, and patients with transplants become familiar with this literature, reviewed here, so that the important decisions, and summarizes new information per- including which patients should be treated and the optimal timing to initiate ther- taining to the use of direct–acting anti- apy, are vetted in association with the compounding issues of CKD, ESRD, and viral (DAA) agents in these patients. The kidney transplantation. availability of safe and effective antiviral medications requires the development J Am Soc Nephrol 27: 2238–2246, 2016. doi: 10.1681/ASN.2016010030 of treatment paradigms that take into account the unique needs of this patient population. In the quarter century that has passed Early reports noted prevalence rates as since hepatitis C virus (HCV) was iden- high as 25% in urban hemodialysis units tified,1 an extensive literature has de- in the United States and in excess of 50% THE HCV fined the epidemiology, viral kinetics, in less developed countries. Moreover, it and clinical manifestations of this infec- was unequivocally shown that HCV was HCV is a small (50 nm) enveloped virus tion. Soon after its discovery, HCV was transmissible by kidney transplantation that was first isolated and cloned in recognized to be a public health issue of (KT)9 as well as within dialysis units as a 1989.1 It has a positive single–stranded global significancethatisestimatedto consequence of a breakdown of univer- RNA with approximately 9600 nucleo- affect approximately 170 million indi- sal precautions.10 HCV infection was tides11 and a genome composed of struc- viduals worldwide,2–5 many of whom also shown to be the etiology of most cases tural and nonstructural proteins (Figure 1). remain undiagnosed. Furthermore, it of what had previously been referred to Seven genotypes have been identified, has become clear that the consequences as essential mixed cryoglobulinemia with each divided into subtypes and of HCV infection extend well beyond as well as some cases of idiopathic strains.12,13 Genotypes 1–3aredistributed the , defining more of a systemic membranoproliferative GN.7,10 disease with a multitude of clinical Recognizing that an extensive litera- Published online ahead of print. Publication date 6–8 consequences. ture had accumulated on the effect and available at www.jasn.org. As different populations of patients treatment of HCVin patientswithkidney fi Correspondence: Dr. David Roth, 1120 NW 14th werescreened for anti-HCVantibodies, it disease, the rst Kidney Disease Improv- Street, Room 813, Miami, FL 33136. Email: d.roth@ became evident that the prevalence of ing Global Outcomes (KDIGO) work- miami.edu

HCV infection in patients with ESRD far group was organized in 2007 with a focus Copyright © 2016 by the American Society of exceeded that of the general population. on developing clinical guidelines for the Nephrology

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Studies have consistently shown that HCV infection is associated with an increased mortality in patients with ESRD.25–29 In a meta-analysis by Fabrizi et al.,26 the relative risk of mortality was 1.35 (95% confidence interval, 1.25 to 1.47) among HCV-infected patients with ESRD. Analysis of cause-specific death showed an increased burden of car- diovascular risk, supporting the concept that HCV is a systemic disease with im- portant extrahepatic consequences.26 Of interest, transplanting an anti-HCV– positive patient with ESRD is accompa- nied by a significantly decreased risk of death compared with remaining on the waiting list. This survival benefitis largely attributable to a decrease in car- fi Figure 1. The HCV genome and target sites of action for the direct acting antiviral agents. diovascular events within the rst year 30 Combining agents with different mechanisms of viral interference has resulted in the post-transplant. Thus, although it is – achievement of very high sustained viral response rates. NTR, nontranslated region. important to recognize that HCV infected kidney recipients have an increased hazard ratio for death, trans- globally, with 1a and 1b being the most (SVR12) would diminish the rate of de- plant continues to offer these patients a common (60% of the infections world- cline in GFR. significantly improved survival com- wide). Genotype 1a is the dominant geno- Infection with HCV has been impli- pared with remaining on dialysis.25–29,31 type in northern Europe and North cated as being causative in most patients America, whereas 1b is distributed world- with mixedcryoglobulinemia andseveral HCV and KT wide. In contrast, genotypes 2 (Europe and histologic forms of glomerular injury, HCV infection is the primary cause of Mediterranean region), 3 (Asia), 4 (Middle including membranoproliferative and liver disease in KT recipients32; however, East and central Africa), 5 (South Africa), membranous GN.7,20 Patients coinfec- it has also been associated with impor- 6 (Asia) and 7 (Central Africa) have a ted with HIV have been reported to tant extrahepatic manifestations that penetration that is more geographically have an increased mortality and overall contribute to increased morbidity and specific.11,13 worse prognosis.21,22 mortality after transplantation.33 HCV- infected recipients are at increased risk HCV in the Patient with ESRD of de novo and recurrent membranous HCV IN PATIENTS WITH KIDNEY The prevalence of HCV in patients with nephropathy, membranoproliferative DISEASE ESRD has always exceeded that of the GN,34–36 and transplant glomerulopathy.37 general population, and transmission of Infection with HCV has also been asso- HCV and CKD the virus within dialysis clinics has been ciated with an increased risk for insulin Patients with CKD have a higher prev- unequivocally shown.10 The risk of resistance and diabetes mellitus in wait- alence of HCV infection compared with transmission is an ongoing hazard as listed candidates and kidney recipients, the general population.10 Recent studies emphasized in a recent Centers for Dis- similar to that reported for the general suggest that HCV-infected patients with ease Control and Prevention (CDC) population.38–43 Although prospective CKD have an accelerated rate of kidney health advisory that noted an increased studies are lacking, it is reasonable to as- function loss and an increased risk of number of acute HCV infection events sume that the increased incidence of progressing to ESRD.14–19 In one study, among patients undergoing mainte- diabetes in the HCV–infected KT Molnar et al.19 showed that HCV- nance hemodialysis.23 Lapses in univer- candidate/recipient would translate into infected patients with CKD had an in- sal precautions were identified at these an increased burden of cardiovascular creased mortality and an accelerated dialysis clinics, emphasizing the need event risk. rate of progression to ESRD, raising the for continuously improving infection The presence of anti-HCVantibody is important question of whether treating control practices and environmental dis- associated with lower patient and graft to obtain a sustained virologic response infection procedures accompanied by survival among KT recipients.44,45 In a defined as an undetectable viral load adherence to recommended CDC HCV large meta-analysis, Fabrizi et al.44 12 weeks after completion of treatment screening protocols.24 showed a significant increase in both

J Am Soc Nephrol 27: 2238–2246, 2016 Hepatitis C Virus in CKD 2239 BRIEF REVIEW www.jasn.org mortality and graft loss among HCV- Additional experience with sofosbuvir Ombitasvir is an inhibitor of the nonstruc- infected recipients. However, in a retro- in HCV-infected patients with CKD tural protein 5A (NS5A), whereas paritap- spective study of 230 patients, Roth has been reported from the HCV-TAR- revir is a nonstructural protein 3/4A et al.31 showed that KT in HCV-infected GET Study, a longitudinal real world protease inhibitor that is combined with patients conferred a long–term survival observational study of DAAs.56 SVR12 low-dose ritonavir to boost paritaprevir benefit compared with remaining on the rates of 85%–90% were achieved across drug levels.61 These three drugs are ad- waitlist. Thus, chronic HCV infection all patient groups; however, increased ministered with dasabuvir, an inhibitor should not be considered a contraindi- adverse events were reported in pa- of the nonstructural protein 5B RNA– cation to KT, because the long–term tients with more advanced kidney dis- dependent RNA polymerase (NS5B). survival advantage associated with trans- ease (eGFR,45 ml/min). Current This combination was studied in the plantation can still be shown in these guidelines from the American Associ- RUBY-I Trial, a multicenter, phase 3b patients.31,46–49 ation for the Study of Liver Disease study assessing the safety and efficacy (AASLD) recommend that sofosbuvir of the three-dimensional regimen in pa- only be considered as an option for pa- tients with CKD stage 4/5.62 In prelim- DAA AGENTS IN PATIENTS WITH tients with creatinine clearance of ,30 inaryreports,17of17patientsachieved CKD ml/min when expert opinion is obtained an SVR12, and no treatment–related before initiating therapy.57 serious adverse events were noted. Patients achieving an SVR12 are consid- No dose adjustments of ombitasvir- ered cured of the infection. Using the Simeprevir paritaprevir/ritonavir and dasabuvir are latest generation DAAs, rates of SVR12 in Simeprevir is a nonstructural protein required in patients with advanced CKD; clinical trials conducted in the general 3/4A protease inhibitor that is metabo- however, insufficient data are available population exceed 90% across all geno- lized in the liver (.90%) with insignifi- to recommend their use in patients on types, with the lowest response rates cant renal clearance (,1%). The drug is dialysis. being reported in cirrhotics and patients highly protein bound, and it is not with genotype 3. The evolution from IFN- cleared by dialysis; thus, no dosing ad- Daclatasvir based therapy to DAAs is a remarkable justments are required for patients with Daclatasvir is a nonstructural protein 5A accomplishment of the last decade and CKD or ESRD.58 Limited data are (NS5A) inhibitor that blocks both RNA offers the possibility of life-saving treat- available on the safety and efficacy of replication and virion assembly. As a ment for millions of patients.50,51 simeprevir in the CKD and ESRD consequence of the drugs hepatic me- population. Bhamidimarri et al.54 re- tabolism, no dosing adjustments are DAAs ported the use of full-dose simeprevir necessary in patients with CKD.63 Sofosbuvir combined with half-dose sofosbuvir in Daclatasvir has been used mostly in Sofosbuvir is a nucleotide analog NS5B patients with advanced CKD/ESRD. combination with sofosbuvir for pa- polymerase inhibitor that targets the This combination was found to be well tients with genotype 3 infection.64 In a nonstructural protein 5B RNA– tolerated, with limited adverse events study including patients with mild to dependent RNA polymerase, thus effec- and excellent efficacy. moderate CKD and ESRD, daclatasvir tively terminating viral replication was well tolerated with good efficacy.65 (Figure 1, Table 1). Sofosbuvir is a pro- Ledipasvir drug that is phosphorylated into the Ledipasvir is a nonstructural protein Grazoprevir and Elbasvir active metabolite GS-461203, with subse- 5A inhibitor (NS5A) that is marketed Grazoprevir is a nonstructural protein quent dephosphorylation into the inactive in combination with sofosbuvir 3/4A protease inhibitor (NS3/4A) that has metabolite GS-331007.52 Sofosbuvir and (Harvoni).59,60 The drug is hepatically been combined with the nonstructural GS-331007 are cleared by the kidneys, metabolized with minimal renal clear- protein5A(NS5A)inhibitorelbasvir. This resulting in significant accumulation of ance, and as a consequence, the AASLD product (Zepatier) recently received both in patients with CKD.53 In this con- does not recommend dose adjustments Food and Drug Administration approval text, the safety and efficacy of sofosbuvir for patients with CKD or ESRD.57 How- for the treatment of HCV genotypes 1 in patients with advanced CKD or ESRD ever, because it is prepared in combina- and 4 infection and should be available have not been established, and the drug tion with sofosbuvir, caution must be in the United States within several is not recommended for use in patients used in patients with GFR,30 ml/min. months. Both grazoprevir and elbasvir with a creatinine clearance of ,30 ml/min. are highly protein bound and thus, not Nevertheless, two recent studies using Ombitasvir-Paritaprevir-Ritonavir and cleared by dialysis.66 Additionally, they open-label treatment with simeprevir Dasabuvir (3D Regimen) rely on hepatic metabolism and do not and dose-adjusted sofosbuvir in patients The combination of ombitasvir/ accumulate in patients with reduced with advanced CKD/ESRD showed paritaprevir (ritonavir boosted) and kidney function. This combination safety and high rates of SVR12.54,55 dasabuvir is marketed as Viekira Pak. was studied in the C-SURFER Trial,

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Table 1. DAA agents Medication Dose Clearance Target of Action Use in CKD Stages 4 and 5 Sofosbuvir 400 mg daily Renal =81%; NS5B eGFR=15–29 ml/min: not recommended; GI=15% eGFR,15 ml/min: not recommended; limited data available Simeprevir 150 mg daily Renal ,1%; NS3A/4A eGFR=15–29 ml/min: dose adjustment not required; GI=91% eGFR,15 ml/min: not recommended; limited data available Ledipasvir 90 mg daily Renal =1%; NS5A eGFR=15–29 ml/min: dose adjustment not required; GI=86% eGFR,15 ml/min: not recommended Ombitasvir/paritaprevir/ 12.5/75/50 mg 32 tablets; Renal ,2%; NS5A/NS3A/ eGFR=15–29 ml/min: dose adjustment not required; ritonavir; dasabuvir 250 mg 32 tablets GI=90% 4A/CYP3A; NS5B eGFR,15 ml/min: dose adjustment not required; not studied in patients on dialysis; limited data Grazoprevir/elbasvir 100/50 mg daily Renal ,1% NS3/4A NS5A eGFR=15–29 ml/min: dose adjustment not required; eGFR,15 ml/min: dose adjustment not required; dialysis population studied Daclatasvir 60 mg daily; used Renal =7%; NS5A eGFR=15–29 ml/min: dose adjustment not required; with sofosbuvir GI=88% eGFR,15 ml/min: dose adjustment not required GI, gastrointestinal. the first prospective, randomized study of Special Considerations fibrosis who have a living donor should DAAs that focused exclusively on HCV- HCV Infection in the KT Candidate receive DAAs before transplant to achieve infected patients with CKD and HCV-in- All patients being evaluated for KT SVR12. For the patient without a living fected patients with ESRD.67 In this phase should be screened for HCV infection. donor, there are two options available at 3 trial, 224 patients with HCV genotype 1 The KDIGO guidelines recommended the time of listing. In one scenario, the infection and stage 4 or 5/5D CKD were ELISA testing in geographic regions patient can delay DAA treatment (thus randomly assigned to an immediate treat- with a low prevalence of HCV followed remaining viremic), with the intention ment group (n=111) or a deferred treat- with nucleic acid testing confirmation of of receiving a kidney from an HCV- ment group (n=113) that initially all positive results. Initial testing with positive donor. Of note, this option is received placebo and then, was offered nucleic acid testing was recommended in not available at all transplant centers, and active therapy. Data from an intensive regions with a high prevalence of HCV.6 an informed consent should be obtained. pharmacokinetic group (n=11) showed An accurate assessment of the extent of This approach has been accompanied by no requirement for dose adjustment in liver injury is necessary in all KT candi- significantly reduced waiting times com- patients on hemodialysis. Treatment dates with active viral replication. Liver pared with those for HCV-negative kid- with Zepatier resulted in SVR12s of biopsy has always been considered the neys.75 In this scenario, DAA therapy can 99%, with a low adverse event profile gold standard; however, there are now be initiated in the post-transplant period. and no significant safety signals in this several noninvasive tests that have We would recommend waiting 2–3 CKD population.67,68 shown promise in making this determi- months post-transplant to achieve stable nation. These methods rely on distinct kidney function and immunosuppressive Velpatasvir but complementary approaches: a bio- dosing (see below). The primary objective Velpatasvir is a nonstructural protein 5A logic method that quantifies serum lev- of transplanting a kidney from an HCV- (NS5A) inhibitor with antiviral activity els of biomarkers of fibrosis and a positive donor would be to shorten wait- against genotypes 1–6.69 Two studies physical approach that measures liver ing times and make transplantation more have shown that velpatasvir combined stiffness by ultrasound or magnetic res- available by using kidneys that are often with sofosbuvir provided high rates of onance elastography (FibroTest and discarded.76 If this option was not avail- SVR12 in patients with all genotypes, in- FibroScan).72 Validation of these surro- able, the patient would be confronted cluding the difficult to treat patients with gate markers of liver fibrosis in the patient with a waiting times that can often exceed genotype 3.70,71 As has been the case in with ESRD will be needed. A 5 years. In this case, consideration should most pivotal trials of HCV infection in should be considered in inconclusive cases be given to pretransplant treatment with the general population, patients with or if there is a suggestion of advanced fibro- DAAs to achieve an SVR12, thus limiting kidney disease were not included in sis (stage 3/4) on the noninvasive testing. the risk of progressive liver injury. In this these studies; thus, there are no data on We have been using a management scenario, the patient can wait to receive a the safety and efficacy of this combina- paradigm73,74 (Figure 2) similar to the kidney from an uninfected donor or con- tion in patients with CKD and patients one proposed by Sawinski et al.73 Pa- sider transplantation of a kidney from an with ESRD.71 tients with METAVIR stages 0–2liver HCV-infected donor, with early initiation

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fibrosing cholestatic hepatitis using current DAAs.80–83 These results are en- couraging; however, we await confirma- tion of these outcomes in kidney recipients. The second option for the HCV– infected transplant candidate would be to treat with DAAs before transplant. As mentioned earlier, this would be a rea- sonable plan for the patient with a living donor. This might also be an advisable approach for the patient with more ad- vanced histologic liver injury (stage 3/4 liver disease with early cirrhosis) and without a living donor. These patients must be carefully evaluated to determine if a kidney-alone transplant is advisable or if a combined liver transplant/KT is necessary. Much of this decision will hinge on whether the patient has pre- served synthetic liver function and/or portal hypertension.74 At our center, these Figure 2. Suggested paradigm for the management of the HCV-infected pretransplant patients have transjugular measurement candidate. Critical decision points include whether the patient has a living donor and the of hepatic venous pressure gradient. Pa- extent of liver fibrosis. The option to accept a kidney from a HCV positive donor could tients with a gradient #12 mmHg significantly shorten wait times. HVPG, hepatic venous pressure gradient; Neg, negative; with normal platelet count and syn- Pos, positive; SVR, sustained virologic response; DAA, direct antiviral agent. thetic liver function are treated with DAAs to achieve an SVR12 and subse- of DAAs in the post-transplant period. against the knowledge that not all pa- quently, listed to receive a kidney from In a similar context, there is increased tients achieve an SVR with DAA treat- an HCV-negative donor. This will re- interest in transplanting kidneys from ment, and there is no certainty that quire the usual waiting times on the positive donors into negative recipients payers will approve this costly therapy list; however, it seems prudent not to followed by early initiation of DAAs after transplantation. transplant a cirrhotic patient with active post-transplant. Reese et al.76 discussed Any discussion of knowingly infecting viral replication. Each of these options this perspective in a recent editorial and a patient with HCV at the time of trans- must be carefully reviewed with the pa- propose this as a reasonable consider- plant must be with full understanding of tient, because the treatment strategy ation for uninfected patients with high the accompanying risk of fibrosing chole- will have a significant effect on the pa- risk of health deterioration because of static hepatitis, an aggressive form of HCV tient’s clinical course.73,76 Furthermore, dialysis (elderly, cardiovascular morbid- seen after liver transplantation or KT the decision to use a hepatic venous ity, or access failure) or those with dis- during the period of maximal immuno- pressure gradient of #12 as a component advantageous blood types. Any decision suppression.78 This was a serious concern of this decision is not on the basis of pro- in this regard must be balanced against during the IFN/ribavirin era when SVRs spective studies and should not to be con- data suggesting that uninfected patients were low, and the treatment was associ- sidered the standard of care. Successfully that receive HCV-positive kidneys have ated with an increased risk of renal allo- establishing a paradigm for the use of increased mortality.77 Furthermore, the graft rejection.79 These concerns may be kidneys from anti-HCV–positive donors ethics of knowingly infecting a patient diminished by recent data from liver re- will likely increase the number of pa- with HCV must be carefully weighed cipients showing successful treatment of tients transplanted by using kidneys

Table 2. Use of DAAs with immunosuppressive agents Immunosuppressant SOF and LDV OMV, PTV, r, and DSV SMV SOF Cyclosporin No changes in levels ↑ Cyclosporin levels (r) ↑ Levels of both cyclosporin and SMV No changes in levels Tacrolimus No changes in levels ↑ Tacrolimus levels (r) ↓ Tacrolimus levels; monitor levels closely No changes in levels Sirolimus No changes in levels ↑ Sirolimus levels (r) ↑ or ↓ Levels of sirolimus No changes in levels SOF, sofosbuvir; LDV, ledipasvir; OMV, ombitasvir; PTV, paritaprevir; r, ritonavir; DSV, dasabuvir; SMV, simeprevir.

2242 Journal of the American Society of Nephrology J Am Soc Nephrol 27: 2238–2246, 2016 www.jasn.org BRIEF REVIEW that are currently being discarded and/or extrahepatic manifestations. Although with hepatitis C virus infection. NEnglJMed328: not being harvested.76,84 patients with CKD had been largely 465–470, 1993 8. Morales JM, Kamar N, Rostaing L: Hepatitis C excluded from most phase 3 DAA trials, and renal disease: Epidemiology, diagnosis, HCV Treatment in the KT Recipient data are now becoming available that pathogenesis and therapy. Contrib Nephrol For the last two decades, the treatment of raise hopes for a cure in the patient with 176: 10–23, 2012 HCV infection in the post-transplant ESRD and the KT recipient. In this 9. Pereira BJ, Milford EL, Kirkman RL, Levey AS: settinghasnotbeenanoptioninlarge context, it will be essential that nephrol- Transmission of hepatitis C virus by organ – part because of the unacceptable risk of ogists become familiar with the different transplantation. NEnglJMed325: 454 460, 1991 rejection associated with the use of IFN- DAAs and their drug-drug interactions 10. Martin P, Fabrizi F: Hepatitis C virus and 84–87 based regimens. Furthermore, the and provide guidance on the optimal kidney disease. JHepatol49: 613–624, 2008 IFNs are poorly tolerated, and SVR rates timing for the initiation of therapy. Patients 11. Jang JY, Chung RT: Chronic hepatitis C. Gut are only in the 45%–50% range.88 As a with kidney disease and HCV infection Liver 5: 117–132, 2011 consequence of this poor efficacy and have waited decades for this opportunity, 12. Nakano T, Lau GM, Lau GM, Sugiyama M, fi Mizokami M: An updated analysis of hepatitis high adverse event pro le, treatment of andasisoftenthecasewithothercomor- C virus genotypes and subtypes based on HCV infection in the KT candidate and bidities, they will expect the nephrologist to the complete coding region. Liver Int 32: recipient has often been deferred. orchestrate the nuances of the treatment 339–345, 2012 In the era of DAAs, there are several decisions that will be necessary. 13. Murphy DG, Sablon E, Chamberland J, important caveats when opting to treat Fournier E, Dandavino R, Tremblay CL: post-transplantation. There are potential Hepatitis C virus genotype 7, a new geno- DISCLOSURES type originating from central Africa. JClin drug-drug interactions that must be con- Microbiol 53: 967–972, 2015 sidered. Both the calcineurin inhibitors M.L. and F.P. have no financial disclosures. D.R. 14. 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