Hepatitis C Virus Infection in Chronic Kidney Disease
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BRIEF REVIEW www.jasn.org 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 hepatitis C 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 cirrhosis 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 liver, 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 2238 ISSN : 1046-6673/2708-2238 JAmSocNephrol27: 2238–2246, 2016 www.jasn.org BRIEF REVIEW 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).