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Higher risk of renal disease in chronic hepatitis C patients: Antiviral therapy survival benefit in patients on hemodialysis

Open AccessPublished:December 09, 2017DOI:https://doi.org/10.1016/j.jhep.2017.12.003

      Highlights

      • Increased risk of chronic kidney disease and dialysis dependency in patients with hepatitis C.
      • Antiviral treatment improved survival of patients with hepatitis C on hemodialysis.
      • High hepatitis C treatment rate in hemodialysis patients in Sweden.

      Background & Aims

      Several studies have shown that chronic hepatitis C (CHC) infection has a negative impact on kidney function, as well as survival, in patients with chronic kidney disease (CKD) or on hemodialysis. The aim of this nationwide registry study was to describe renal disease in Swedish patients with CHC.

      Methods

      In the present study, patients were identified for CHC (B18.2) and CKD (N18) according to the International Classification of Diseases (ICD)-10 in the nationwide Swedish inpatient care day surgery (1997–2013) and non-primary outpatient care (2001–2013) patient registries. Hemodialysis was defined using the procedure code in the non-primary outpatient care. For each patient, up to five non-CHC diagnosed age/sex/place of residency-matched comparators were drawn from the general population at the time of diagnosis. Follow-up started at the date of CHC diagnosis and patients accrued person-time until, whichever came first, death, emigration or December 31st, 2013.

      Results

      Between 2001 and 2013, 42,522 patients received a CHC diagnosis. Of these patients, 2.5% (1,077/45,222) were diagnosed with CKD during 280,123 person-years, compared with 0.7% (1,454/202,694) in the matched general population comparators (1,504,765 person-years), resulting in a standardized incidence ratio (SIR) of 4.0. There was a 3.3–7.0-fold risk of patients with CHC requiring hemodialysis. Overall, 17% of patients with CHC receiving hemodialysis were treated for CHC; 24% in the treated cohort died compared with 56% of the untreated cohort (p <0.0001), with antiviral treatment improving survival with an odds ratio of 3.901 (p = 0.001).

      Conclusions

      The results from this nationwide registry study showed that patients with CHC are at a higher risk of developing CKD. Furthermore, hepatitis C treatment seemed to improve survival for patients with CHC on hemodialysis compared with untreated patients.

      Lay summary

      Hepatitis C is an infectious disease that mainly infects the liver, but has also been shown to have negative effects on other organs. This nationwide study demonstrates an increased risk of hepatitis C patients developing reduced kidney function and the need for dialysis. The study also showed improved survival in dialysis patients who received antiviral treatment.

      Graphical abstract

      Keywords

      Introduction

      Hepatitis C virus (HCV) infection is a major cause of viral hepatitis with a global seroprevalence estimated to be greater than 185 million.
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      Approximately 75% to 85% of patients with HCV infection develop a chronic hepatitis C (CHC) infection.
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      A 70% higher risk of chronic kidney disease (CKD) (defined as an estimated glomerular filtration rate of <60 ml/min/1.73 m2) has been observed in HCV seropositive patients compared to seronegative patients.
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      In a nationwide study from Taiwan, Chen and colleagues showed that HCV is a causal risk factor for CKD beyond traditional risk factors.
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      Worldwide, diabetes mellitus is the most common cause of end-stage renal disease, and in patients with diabetes, the presence of HCV adds to the risk of CKD and end-stage renal disease.
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      In the transplant setting the presence of HCV has repeatedly been shown to be an independent risk factor for poorer patient and graft survival.
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      The prevalence of anti-HCV positive patients on long-term dialysis in northern Europe is less than 5%, approximately 10% in most of southern Europe and the United States, and between 10% and 70% in many countries of the developing world.
      • Fabrizi F.
      Hepatitis C Virus infection and dialysis: 2012 update.
      The treatment of patients with CHC infection on hemodialysis using interferon (IFN)-α with or without ribavirin (RBV) has been cumbersome because of an increased risk of adverse events and a lack of expertise in treating this special population. In a recent large international observational study (Dialysis Outcomes and Practice Patterns Study [DOPPS] phase I-IV), it was noted that only 1.0% of patients with CHC infection on hemodialysis had received antiviral treatment.
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      Hepatitis C infection is very rarely treated among hemodialysis patients.
      After the approval of sofosbuvir (SOF)-based, IFN-free, all-oral direct acting antivirals (DAAs) in 2014, there has been an extraordinary improvement in treatment outcome, with high cure rates in patients with CHC infection and normal kidney function. As SOF is renally excreted, the safety of SOF has not been fully assessed in renally impaired patients.

      Gilead. Product insert for Sovaldi Prescribing information, 2014

      In fact, as reported from an even larger observational study conducted in patients with CHC on hemodialysis between 2012–2015 (DOPPS phase V), even after the introduction of DAAs the antiviral treatment rate only increased to 2.1% with only a limited number of patients actually treated with DAAs.
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      The same report pointed out that HCV infection among patients on hemodialysis is associated with higher risk of death, hospitalization, anemic complications, and worse quality-of-life scores, thereby highlighting the urgent need for effective HCV treatment in this population. However, recent approvals of the SOF-free DAAs dasabuvir, ombitasvir/paritaprevir/ritonavir with or without RBV, and elbasvir/grazoprevir have been shown to be well-tolerated in patients with genotype 1 CHC and CKD 4 or 5 (including hemodialysis), with virologic cure rates of above 90%, in both single-arm and placebo-controlled studies.
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      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.
      Moreover, it was recently shown that 98% of patients with genotype 1 to 6 CHC and CKD stage 4 or 5 (including hemodialysis) treated with a recently approved combination containing glecaprevir/pibrentasvir achieved a sustained virologic response.
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      Glecaprevir and pibrentasvir in patients with HCV and severe renal impairment.
      The aim of the present study was to describe the prevalence of CKD and hemodialysis among patients with CHC infection in the nationwide Swedish registries. A secondary objective was to assess the effect of HCV therapy on outcome in patients on hemodialysis, given that Sweden has had highly engaged specialized centers treating these patients since the late 1990s.
      • Bruchfeld A.
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      • Schvarcz R.
      Ribavirin treatment in dialysis patients with chronic hepatitis C virus infection–a pilot study.

      Patients and methods

      Setting

      Patient information is continuously collected into nationwide registries using the unique personal identification number provided to all persons residing in Sweden. The present study used information from the National Patient Register, the Cancer Register, the Prescribed Drug Register, the Cause of Death Register, and the Total Population Register. The National Patient Register contains all inpatient (1987–2013) and non-primary outpatient care (2001–2013) visits, but not primary care visits. It includes information on main and contributory diagnoses based on the International Classification of Diseases (ICD-9, 1987–1996; ICD-10, 1997–2013). For all newly diagnosed cancer cases, it is mandatory to report information such as the site of tumor, histologic type, basis, and date of diagnosis to the Cancer Registry (1958–2013). In the Prescribed Drug Register, all prescribed and dispensed drugs used in ambulatory care are registered using Anatomic Therapeutic Chemical (ATC) codes. Information on dates, drugs, and costs for all pharmacy dispensations of prescriptions in Swedish pharmacies (2005–2013) are registered, although in-hospital use of drugs is not always entered into the register.
      • Büsch K.
      • Waldenström J.
      • Lagging M.
      • Aleman S.
      • Weiland O.
      • Kövamees J.
      • et al.
      Prevalence and comorbidities of chronic hepatitis C: a nationwide population-based register study in Sweden.
      The Total Population Registry contains data on place of residence, vital, and migration status (up to December 31, 2013). The Causes of Death Register contains date and cause of death according to ICD-10. Marital status was retrieved from the longitudinal integrated database for health insurance and labor market studies (LISA). The Swedish personal identity number was used to link individuals between registers.

      Study population

      This cohort has recently been described elsewhere.
      • Büsch K.
      • Waldenström J.
      • Lagging M.
      • Aleman S.
      • Weiland O.
      • Kövamees J.
      • et al.
      Prevalence and comorbidities of chronic hepatitis C: a nationwide population-based register study in Sweden.
      In brief, CHC was defined as a B18.2 (ICD-10) listed by a physician in the Swedish National Patient Register. Since the non-primary outpatient care registry was not available before 2001, the present study restricted the study period from 2001 through 2013 (n = 42,522) to ensure the most complete coverage for all patients. Up to five comparators (n = 202,694) from the general population were matched by age, sex, and county of residence to each patient at the same index date as the respective CHC case (date of first registration of a CHC-related diagnosis). The study was approved by the Regional Ethics Committee, Karolinska Institutet, Stockholm, Sweden.

      Assessments

      The risks for diseases, procedures, or mortality were expressed as standardized ratios, where the number of observed events was divided by the number of expected events in the CHC cohort based on the events per person-years in the comparator cohort. Disease incidences were shown as standardized incidence ratios (SIRs), procedure events were shown as standardized utilization ratios (SURs), and mortalities were shown as standardized mortality ratios (SMRs). For all standardized ratios, 95% CIs were calculated.
      When a patient is diagnosed with CHC, the patient is investigated for other diseases of interest. As part of this investigation, kidney function was monitored, which might have resulted in an increased number of CKD diagnoses compared with the comparator cohort that was not under the same scrutiny during this time period. In order to avoid this surveillance bias, we introduced a six-month lag period between CHC and CKD diagnoses as a sensitivity analysis; in other words, patients with a CKD diagnosis within six months of inclusion were removed from the data set. This left 42,095 patients with CHC infection, with a corresponding 200,639 comparators in the sensitivity analysis.

      Definition of outcomes

      Treatment of HCV was defined as ≥1 dispensed drug prescription for pegylated IFN-α, RBV, or first-generation NS3/4A protease inhibitors (telaprevir or boceprevir; ATC codes: L03AB11, L03AB60, L03AB61, J05AB04, J05AE11, J05AE12). The registry was available from 2005–2013. The procedure code for hemodialysis (DR016) was not used before 2005, and the Prescribed Drug Registry was only available from 2005. Therefore, neither HCV treatment nor hemodialysis between 2001 and 2004 could be assessed in the present study. The number of patients on hemodialysis in Sweden (2,285 to 2,881 patients between 2010 and 2013) was retrieved from the annual report by the Swedish Kidney Registry.

      SNR. SNR Årsrapport 2014_Webb.pdf. 2014.

      A patient was considered to have diabetes if he or she had either ≥1 registered physician visit with an accompanying diabetes code (ICD-10: E10-E14) or ≥1 dispensed drug to treat diabetes (ATC: A10).

      Statistical methods

      Data handling was performed using SAS (version 9.4; SAS Institute, Cary, NC, USA) and data analyses were conducted using SPSS (version 21; IBM Corp, Armonk, NY, USA). Factors associated with survival of patients with CHC infection on hemodialysis were analyzed using a univariate regression analysis and presented as odds ratios (ORs). A stepwise multivariate regression model was used to assess factors that were independently associated with survival. The survival hazard ratio (HR) for patients not receiving HCV treatment adjusted for the factors independently associated with survival was calculated using a Cox regression model. A Kaplan-Meier survival curve was performed to visualize survival over time and was analyzed using a log-rank test. A Fine-Gray regression model was used to estimate the proportional hazard sub-distribution for CKD and end-stage renal disease (ESRD)-caused death, while accounting for the competing risk of other causes of death.
      • Fine J.P.
      • Gray R.J.
      A proportional hazards model for the subdistribution of a competing risk.
      ICD-10 codes considered associated with CKD and ESRD in the analysis are indicated by ∗ in Table S4. Fisher’s exact test was used to test statistical significance of contingency tables. Mann-Whitney U test was used to test differences of medians. All reported p values are two-sided.

      Results

      Chronic kidney disease

      The characteristics of patients with CHC infection with (n = 1,077) or without (n = 41,445) a CKD diagnosis, as well as all patients with CHC infection on hemodialysis (n = 268) are shown (Table 1). Between 2001 and 2013, 2.5% of the Swedish patients with CHC infection (n = 1,077) had a reported CKD diagnosis. This is higher than would have been expected when comparing with the matched comparator cohort (3.84 cases per 1,000 person-years vs. 0.97 cases per 1,000 person-years in the CHC cohort and comparator cohorts, respectively), resulting in an SIR of 4.0 (95% CI 3.7–4.2; Table 2). As a sensitivity analysis to avoid surveillance bias, we also analyzed the SIR after exclusion of all patients with CHC infection and a CKD diagnosis within six months of the initial CHC diagnosis. After the introduction of this lag period, the higher risk of CKD in the CHC cohort still remained significant, with the lower 95% CI not crossing 1 (SIR 2.5; 95% CI 2.3–2.7; Table 2). In addition, the CHC cohort had an increased risk of being diagnosed with acute or unspecific kidney failure, kidney cancer, kidney transplantation, cryoglobulinemia, and diabetes mellitus. These increased risks remained even after applying the lag period between CHC and CKD diagnosis (Table 2).
      Table 1Characteristics of patients with CHC.
      No CKD diagnosis

      (n = 41,445)
      CKD diagnosis

      (n = 1,077)
      Hemodialysis

      (n = 268)
      Person-years273,426.26,696.61,816.1
      Mean observation time (95% CI)6.60 (6.56–6.64)6.22 (5.98–6.46)6.78 (6.35–7.20)
      Death7,340 (18%)559 (52%)135 (50%)
      SMR5.66.910.4
      Acute kidney failure (N17
      ICD-10 codes.
      )
      630 (2%)215 (20%)81 (30%)
      Chronic kidney disease (N18
      ICD-10 codes.
      )
      -1,077 (100%)254 (95%)
      Unspecified kidney failure (N19
      ICD-10 codes.
      )
      132 (0.1%)228 (21%)81 (30%)
      Kidney disease (N17
      ICD-10 codes.
      -N19
      ICD-10 codes.
      )
      738 (2%)1,077 (100%)265 (99%)
      Kidney transplantation (Z94.0
      ICD-10 codes.
      )
      141 (0.3%)199 (19%)86 (32%)
      Kidney cancer (180.0
      ICD-7 codes.
      /180.9
      ICD-7 codes.
      )
      35 (0.1%)6 (0.6%)3 (1%)
      Diabetes mellitus (E10-E14
      ICD-10 codes.
      /A10
      ATC codes.
      )
      116 (43%)460 (43%)116 (43%)
      Sex (male)27,328 (66%)744 (69%)186 (69%)
      Marital status
       Married8,481 (20%)403 (37%)94 (35%)
       Unmarried23,342 (56%)287 (36%)55 (21%)
       Divorced8,872 (21%)237 (22%)108 (40%)
       Widow750 (2%)50 (5%)11 (4%)
      Country of origin
       Sweden33,177 (80%)793 (74%)178 (66%)
       Europe4,714 (11%)159 (15%)47 (18%)
       Other3,553 (8.6%)125 (12%)41 (16%)
       Information missing1 (<0.1%)00
      Year of birth (grouped)
       <19496,775 (16%)513 (48%)93 (35%)
       1950–196922,936 (55%)505 (47%)152 (57%)
       1970–198911,038 (27%)55 (5%)22 (8%)
       1990<696 (2%)4 (0.4%)1 (0.4%)
      ATC, Anatomical Therapeutic Chemical; CHC, chronic hepatitis C; ICD, International Classification of Diseases; SMR, standardized mortality ratio.
      1 ICD-10 codes.
      2 ICD-7 codes.
      3 ATC codes.
      Table 2Standard incidence ratios for the CHC cohort.
      No lag period6-month lag period between CHC and CKD diagnosis
      Obs.Exp.SIR95% CIObs.Exp.SIR95% CI
      Acute kidney failure (N17
      ICD-10 codes.
      )
      845139.16.15.7–6.5789135.95.85.4–6.2
      Chronic kidney disease (N18
      ICD-10 codes.
      )
      1,077270.74.03.7–4.2650264.82.52.3–2.7
      Unspecified kidney failure (N19
      ICD-10 codes.
      )
      36069.65.24.7–5.727267.74.03.5–4.5
      Kidney disease (N17
      ICD-10 codes.
      -N19
      ICD-10 codes.
      )
      1,815387.04.74.5–4.91,388264.83.73.5–3.9
      Kidney cancer (180.0
      ICD-7 codes.
      /180.9
      ICD-7 codes.
      )
      4124.01.81.2–2.33823.91.61.1–2.2
      Kidney transplantation (Z94.0
      ICD-10 codes.
      )
      34049.36.96.2–7.712649.02.62.2–3.1
      Cryoglobulinemia (D89.1)
      ICD-10 codes.
      470.4129.194.8–171.6440.4121.688.3–163.2
      Diabetes mellitus (E10-E14
      ICD-10 codes.
      /A10
      ATC codes.
      )
      5,0112,587.21.91.9–2.04,8482,548.11.91.8–2.0
      ATC, Anatomical Therapeutic Chemical; CHC, chronic hepatitis C; CKD, chronic kidney disease; Exp., expected; ICD, International Classification of Diseases; Obs., observed; SIR, standardized incidence ratio.
      1 ICD-10 codes.
      2 ICD-7 codes.
      3 ATC codes.
      During the study period, 7,899 deaths (19%) occurred in the CHC cohort and 7,517 deaths (4%) occurred in the comparator cohort, resulting in a SMR of 5.6. A total of 559 of the 1,077 patients with CHC infection and a CKD diagnosis died during the study period (52%; SMR of 6.9). After introducing the six-month lag period, 46.0% of patients with CHC and CKD died (SMR of 5.7). The most common cause of death by ICD-10 chapter was diseases of the circulatory system (Chapter IX I00-I99) for all patients with CHC infection and CKD (29%), as well as after the introduction of the six-month lag period (28%). The five most common specific causes of death were CHC (8%, B18.2), followed by acute myocardial infarction (6%, I21.9), CKD (5%, N18.9), unspecific kidney failure (4%, N19), and diabetes mellitus with renal complications (3%, E14.2) (Table S1). The most common cause of death (43%) for patients with a CKD diagnosis in the comparator cohort was also was diseases of the circulatory system (Chapter IX I00-I99). The five most common specific causes of death in this cohort were acute myocardial infarction (11%, I21.9), chronic ischemic heart disease (4%, I25.9), diabetes mellitus with renal complications (3%, E14.2), CKD (3%, N18.9), and atherosclerotic heart disease (2%; I25.1) (Table S2). The median age of death for the patients with CHC and CKD was 62 years and the corresponding age of death for the CKD patients in the comparator cohort was 66 years (p <0.0001; Mann-Whitney U test).

      Hemodialysis

      The requirement for hemodialysis was more common in the CHC cohort, where 268 patients with CHC infection required treatment with hemodialysis compared with the expected 38.1 patients based on the comparator cohort (all patients, SUR of 7.0; 95% CI 6.2–7.9; with a six-month lag period, SUR of 3.3; 95% CI 2.7–3.9). The characteristics of patients with CHC infection requiring hemodialysis are shown (Table 1). The average observation time from hemodialysis initiation to death or end of study was 2.89 years. Almost all of these patients (254/268) received a CKD (N18) diagnosis; 30% of these patients (81/268) received an acute kidney disease diagnosis (N17) and 30% (81/268) received an unknown kidney disease diagnosis (N19). Of the 14 patients on hemodialysis without a CKD diagnosis, 11 (79%) received an acute kidney diagnosis between 2005 and 2013. For unknown reasons, three hemodialysis patients had not received a kidney failure diagnosis (N17-N19) at any time during the study period. The SMR for the patients requiring hemodialysis was 10.4 (SMR of 11.7 after the six-month lag period). The annual prevalence of CHC infection among patients on hemodialysis in Sweden was between 3% and 4% for the years 2010–2013 (Table S3).

      HCV treatment of hemodialysis patients

      Seventeen percent (45/268) of the patients with CHC infection requiring hemodialysis received IFN-based HCV treatment, of which 60% (27/45) received HCV treatment after initiation of hemodialysis (Fig. S1). Treatment was significantly associated with a favorable outcome; 24% (11/45) of the treated hemodialysis patients died during the study period compared with 56% (124/223) of the untreated patients (p = 0.0001; Fisher’s exact test). However, being treated either before or after hemodialysis initiation did not have an impact on survival (p = 0.1; Fisher’s exact test). The most common cause of death by ICD-10 chapter in both the HCV treated and untreated patients on hemodialysis were diseases of the circulatory system (Chapter IX, I00-I99 ICD-10), with diseases of the circulatory system being the main cause of death for 33 of the 124 untreated patients on hemodialysis (27%) and for 4 of the 11 HCV treated patients (36%) (Table S4). The five most common specific causes of death for untreated patients on hemodialysis were unspecific CKD (N18.9; 6%; n = 8), unspecific kidney failure (N19; 6%; n = 8), unspecific myocardial infarction (I21.9; 6%; n = 7), CHC (B18.2; 5%; n = 6), and unspecific diabetes mellitus with renal complications (5%; n = 6). Interestingly, none of these causes were listed as a specific cause of death in patients treated for HCV on hemodialysis (full list of causes of death in this cohort are provided [Table S4]). The most common cause of death (46%) for hemodialysis patients in the comparator cohort was diseases of the circulatory system (Chapter IX I00-I99). The five most common specific causes of death in this cohort were acute myocardial infarction (13%, I21.9), hypertensive renal disease with renal failure (5%, I12.0), diabetes mellitus with renal complications (4%, E14.2), unspecific diabetes mellitus with multiple complications (4%, E14.7), dilated cardiomyopathy (4%, I42.0), nontraumatic intracerebral hemorrhage (4%, I61.9), and CKD (4%, N18.9) (Table S5). The median age of death for patients with CHC needing hemodialysis was 59 years and 65 years for the patients needing hemodialysis in comparator controls (p = 0.004; Mann-Whitney U test).
      The cumulative unadjusted survival for patients with CHC on hemodialysis starting from initiation of hemodialysis and grouped depending on whether the patient received HCV treatment or not is shown (Fig. 1A). The patients on hemodialysis receiving HCV treatment had a significantly higher rate of survival (p <0.0001, log-rank test). Besides HCV treatment, patients that received kidney transplantation also showed a significant improvement in cumulative survival (Fig. 1B, p <0.0001). Interestingly, being treated for HCV was associated with improved survival benefit both in patients who had not received a kidney transplantation (Fig. 1C, p = 0.002) and in patients who had undergone kidney transplantation (Fig. 1D, p = 0.02).
      Figure thumbnail gr1
      Fig. 1Kaplan-Meier survival curve for CHC patients on HD. Patients grouped by (A) HCV treatment or (B) kidney transplantation. Kaplan-Meier survival curve for HD patients grouped by HCV treatment depending on if the patient (C) had not or (D) had received kidney transplantation. Time started at HD initiation. Log-rank test was used. CHC, chronic hepatitis C; HCV, hepatitis C virus; HD, hemodialysis.
      Analyzing parameters associated with an increased chance of survival using a univariate regression model showed that younger age at hemodialysis initiation (OR 0.965; p = 0.004), receiving either kidney transplantation (OR 2.720; p = 0.001) or HCV treatment (OR 3.901; p = 0.001), or an acute kidney failure diagnosis (OR 2.611; p = 0.002) were all significantly associated with survival in patients on hemodialysis (Table 3). All four factors also independently predicted survival when using a multivariate regression analysis (Table 3). The increased mortality risk for untreated patients with CHC on hemodialysis remained significant (HR 2.874; 95% CI 1.541–5.358; p = 0.001) after adjusting for kidney transplantation, age, and acute kidney disease in a multivariate analysis. Both kidney transplantation and younger age have previously been shown to be favorable predictors of survival.
      • Bruchfeld A.
      • Wilczek H.
      • Elinder C.G.
      Hepatitis C infection, time in renal-replacement therapy, and outcome after kidney transplantation.
      Among the patients with CHC infection and a CKD diagnosis, without an acute kidney failure diagnosis, 55% (102/184) died during the study. Forty percent of patients with CHC infection with both a CKD and an acute kidney failure diagnosis died (28/70) and 27% of patients with CHC infection with an acute kidney failure diagnosis but without a CKD diagnosis (3/11) died (p = 0.0008; Fisher’s exact test). After accounting for the competing risk of CKD and ESRD related death in patients with CHC on hemodialysis, the sub-HR for not treating HCV was 4.250 (95% CI 1.045–17.275; p = 0.04).
      Table 3Univariate and multivariate analysis of factors associated with survival in patients with CHC requiring HD.
      UnivariateMultivariate
      OR95% CIp valueOR95% CIp value
      Acute kidney failure (N17
      ICD-10 codes.
      )
      2.6111.412–4.8290.0022.5181.394–4.5470.002
      Chronic kidney disease (N18
      ICD-10 codes.
      )
      0.8770.237–3.2440.8
      Unspecified kidney failure (N19
      ICD-10 codes.
      )
      0.6550.358–1.2000.2
      Kidney transplantation (Z94.0
      ICD-10 codes.
      )
      2.7201.472–5.0260.0012.9761.649–5.3790.0003
      Kidney cancer (180.0
      ICD-7 codes.
      /180.9
      ICD-7 codes.
      )
      2.1960.189–25.5280.5
      Cryoglobulinemia (D89.1)
      ICD-10 codes.
      0.3900.020–7.5930.5
      Diabetes mellitus (E10-E14
      ICD-10 codes.
      /A10
      ATC codes.
      )
      0.9410.543–1.6330.8
      Sex (male)1.3290.729–8.8500.3
      HCV treatment (n = 45)3.9011.720–8.8500.0013.5471.634–7.7930.001
      Age at HD initiation0.9650.942–0.9890.0040.9660.943–0.9890.004
      ATC, Anatomical Therapeutic Chemical; CHC, chronic hepatitis C; HCV, hepatitis C virus; HD, hemodialysis; ICD, International Classification of Diseases; OR, odds ratio.
      1 ICD-10 codes.
      2 ICD-7 codes.
      3 ATC codes.

      Discussion

      Chronic infection with HCV can be both a cause and a potential complication of kidney disease. In the CKD setting, there has been a decline in HCV transmission in recent years, particularly after the implementation of universal infection control precautions by dialysis centers, as recommended by Kidney Disease Improving Global Outcomes (KDIGO) guidelines.
      • KDIGO
      Guideline 3: Preventing HCV transmission in hemodialysis units.
      Overall, this has led to a reduction of iatrogenic HCV transmission.
      • Lanini S.
      • Easterbrook P.J.
      • Zumla A.
      • Ippolito G.
      Hepatitis C: global epidemiology and strategies for control.
      However, HCV still remains a challenge in the CKD population. Guidelines have recommended HCV eradication in transplant candidates because of the risk of worse graft and patient outcome, as well as the previous limitation of treatment options after transplantation. However, CHC infection has not been a contraindication for renal transplantation, as it has been shown that compared with patients remaining on the waiting list, kidney transplantation improves survival in patients with HCV infection.
      • Roth D.
      • Gaynor J.J.
      • Reddy K.R.
      • Ciancio G.
      • Sageshima J.
      • Kupin W.
      • et al.
      Effect of kidney transplantation on outcomes among patients with hepatitis C.
      Although, apart from the pre-transplant setting, HCV treatment has in general not been prioritized based on CKD status and risk of progression.
      This study showed the frequency of CHC infection among patients on hemodialysis in Sweden to be less than 5%, which is in line with previous estimates in northern Europe.
      • Fabrizi F.
      Hepatitis C Virus infection and dialysis: 2012 update.
      Our data also supported earlier findings of an increased risk of CKD and dialysis dependency in patients with CHC.
      • Fissell R.B.
      • Bragg-Gresham J.L.
      • Woods J.D.
      • Jadoul M.
      • Gillespie B.
      • Hedderwick S.A.
      • et al.
      Patterns of hepatitis C prevalence and seroconversion in hemodialysis units from three continents: The DOPPS.
      • Park H.
      • Chen C.
      • Wang W.
      • Henry L.
      • Cook R.L.
      • Nelson D.R.
      Chronic hepatitis C increases the risk of chronic kidney disease (CKD) while effective HCV treatment decreases the incidence of CKD.
      However, the most striking finding of the present study is the significant survival benefit of treating HCV in patients with CHC infection on hemodialysis, and that this benefit remained significant after controlling for age, acute kidney failure diagnosis, and kidney transplantation. Internationally, the HCV treatment rate in patients with CHC infection on hemodialysis has been reported to be strikingly low;
      • Goodkin D.A.
      • Bieber B.
      • Gillespie B.
      • Robinson B.M.
      • Jadoul M.
      Hepatitis C infection is very rarely treated among hemodialysis patients.
      • Goodkin D.A.
      • Bieber B.
      • Jadoul M.
      • Martin P.
      • Kanda E.
      • Pisoni R.L.
      Mortality, hospitalization, and quality of life among patients with hepatitis C infection on hemodialysis.
      however, in the present study, we found that 17% of Swedish patients with CHC infection on hemodialysis have indeed received HCV treatment. Although most studies point to an association between an increase in morbidity and mortality in patients with CHC and CKD, there is very little information about the outcome in HCV treated patients either prior to or during hemodialysis, or after kidney transplantation. With an extended follow-up, we showed that HCV treatment improved survival for patients with CHC infection before and during hemodialysis compared with untreated patients. The main benefit of treating these patients was a significant lower risk of CKD- and ESRD-related deaths after accounting for competing risk. To the best of our knowledge these are novel findings. The study also corroborated findings from a previous study that transplantation confers a significant survival benefit compared with remaining on dialysis in patients infected with HCV.
      • Roth D.
      • Gaynor J.J.
      • Reddy K.R.
      • Ciancio G.
      • Sageshima J.
      • Kupin W.
      • et al.
      Effect of kidney transplantation on outcomes among patients with hepatitis C.
      We also showed that patients treated for HCV had improved survival after transplantation compared with patients who had never been treated. Smaller studies from the IFN-era that focused on long-term evolution after renal transplantation have demonstrated better post-transplant metabolic and hepatic function, as well as significantly lower rates of post-transplant HCV-related de novo glomerulonephritis and chronic allograft nephropathy,
      • Gürsoy M.
      • Güvener N.
      • Köksal R.
      • Karavelioğlu D.
      • Baysal Ç.
      • Özdemir N.
      • et al.
      Impact of HCV infection on development of posttransplantation diabetes mellitus in renal allograft recipients.
      • Mahmoud I.M.
      • Sobh M.A.
      • El-Habashi A.F.
      • Sally S.T.
      • El-Baz M.
      • El-Sawy E.
      • et al.
      Interferon therapy in hemodialysis patients with chronic hepatitis C: study of tolerance, efficacy and post-transplantation course.
      • Cruzado J.M.
      • Casanovas-Taltavull T.
      • Torras J.
      • Baliellas C.
      • Gil-Vernet S.
      • Grinyó J.M.
      Pretransplant interferon prevents hepatitis C virus-associated glomerulonephritis in renal allografts by HCV-RNA clearance.
      but no survival data has to our knowledge been reported.
      In contrast to patients with CHC as a group, where 27% of Swedish patients died because of liver-related causes,
      • Büsch K.
      • Baj R.
      • Kövamees J.
      • Söderholm J.
      PS138 – high mortality in chronic hepatitis C patients in Sweden compared to matched controls – a nationwide population-based register study from 1997 till 2013.
      the rate of liver-related causes of death (CHC, liver cirrhosis and HCC) for patients with CHC/CKD was lower (Table S1). This could be due to a greater number of deaths caused by mainly cardiovascular (Chapter IX [I00-I99] ICD-10) and genitourinary (Chapter XIV [N00-N99] ICD-10) events that occur before the patients with CKD developed liver-related events. This would be in agreement with the increased risk of cardiovascular causes of death previously shown in patients with CKD and CHC.
      • Cacoub P.
      • Desbois A.C.
      • Isnard-Bagnis C.
      • Rocatello D.
      • Ferri C.
      Hepatitis C virus infection and chronic kidney disease: Time for reappraisal.
      The current approach in several countries, especially in the US where there is a long waiting period for a deceased donor, is to prioritize HCV positive organs to HCV positive waitlisted patients.
      • Jadoul M.
      • Martin P.
      Hepatitis C treatment in chronic kidney disease patients: the kidney disease improving global outcomes perspective.
      However, the novel findings in the current study may add to the discussion of timing of antiviral treatment in patients on hemodialysis, especially in patients positive for HCV on hemodialysis, who for medical reasons are not suitable for transplantation. Also, these findings may have implications for patients with CHC on hemodialysis, who are potential living donor transplant recipients as well as patients with CHC waitlisted for kidney transplantation in countries where HCV positive organs are not commonly used.
      Infection with HCV is associated with a number of extrahepatic manifestations, which include metabolic abnormalities such as insulin resistance and hepatic steatosis, as well as promotion of atherogenesis through direct and indirect mechanisms, where underlying chronic inflammation is an important component.
      • Zampino R.
      • Marrone A.
      • Restivo L.
      • Guerrera B.
      • Sellitto A.
      • Rinaldi L.
      • et al.
      Chronic HCV infection and inflammation: Clinical impact on hepatic and extra-hepatic manifestations.
      • Kralj D.
      • Jukić L.V.
      • Stojsavljević S.
      • Duvnjak M.
      • Smolić M.
      • Čurčić I.B.
      Hepatitis C virus, insulin resistance, and steatosis.
      • Voulgaris T.
      • Sevastianos V.A.
      Atherosclerosis as extrahepatic manifestation of chronic infection with hepatitis C virus.
      Patients on hemodialysis are at an increased risk of all-cause mortality and specifically cardiovascular mortality compared with the age-matched general population,
      • Jager K.J.
      • Lindholm B.
      • Goldsmith D.
      • Fliser D.
      • Wiecek A.
      • Suleymanlar G.
      • et al.
      Cardiovascular and non-cardiovascular mortality in dialysis patients: where is the link?.
      and CHC infection in this population further worsens this unfavorable prognosis. A meta-analysis indicated that HCV infection independently predicted a significantly increased relative risk for all-cause mortality (1.35), cardiovascular death (1.26), and liver disease-related death (3.82).
      • Fabrizi F.
      • Dixit V.
      • Messa P.
      Impact of hepatitis C on survival in dialysis patients: a link with cardiovascular mortality?.
      Furthermore, HCV infection was associated with an increase in hospitalization events in a recently updated observational study, mainly from hepatic and cardiovascular causes.
      • Goodkin D.A.
      • Bieber B.
      • Jadoul M.
      • Martin P.
      • Kanda E.
      • Pisoni R.L.
      Mortality, hospitalization, and quality of life among patients with hepatitis C infection on hemodialysis.
      In line with a previous Swedish study, the present study was also able to demonstrate that individuals with CHC infection had a significant risk of presenting with CKD.
      • Hofmann J.N.
      • Törner A.
      • Chow W.-H.
      • Ye W.
      • Purdue M.P.
      • Duberg A.-S.
      Risk of kidney cancer and chronic kidney disease in relation to hepatitis C virus infection: a nationwide register-based cohort study in Sweden.
      Diagnoses of acute kidney failure, kidney cancer, kidney transplantation, cryoglobulinemia, or diabetes were also significantly more common in the CHC patient cohort (Table 2). Additionally, patients with CHC infection are at a greater risk of needing hemodialysis, and mortality in this population is increased compared with the comparator cohort. These risks remained significant after the introduction of the lag period in the sensitivity analysis, suggesting that the increased risk is real among patients with CHC infection.

      Strengths

      Thanks to the registries that are used in Sweden, almost all in-hospital visits for Swedish citizens are captured, as well as all dispensed drugs. This provides an opportunity to analyze patient groups using a large sample size, even with rare conditions such as patients with CHC that require hemodialysis. The introduction of a lag period between CHC diagnosis and CKD diagnosis as a sensitivity analysis reduced the risk of the results being a consequence of observational bias among the CHC patient cohort.

      Limitations

      The register does not capture HCV treatment outcome; thus, in the present study, there is no information on whether patients were cured. This warrants an additional study investigating if treatment outcome further influenced survival in these patients. Furthermore, there is the possibility of a selection bias, in which the patients with CHC infection on hemodialysis that received HCV treatment were patients with less severe liver disease or with fewer comorbidities. Another limitation is that primary care data are missing. However, in Sweden, HCV is exclusively cared for by in-hospital specialists, and all patients with CHC infection requiring hemodialysis will initiate treatment in a Nephrology department. Additionally, it is likely that there was an underreporting of patients with CKD stages 1 and 2, since these patients are not managed by hospital clinics.
      Importantly, since the data are registry-based, there is no information on lifestyle factors, such as smoking, alcohol consumption, or ongoing illicit drug use, in either the CHC or the matched comparison cohorts. Thus, the present study does not allow for adjusting the comparisons for these negative health factors.
      Because the Prescribed Drug Register began in 2005, there may be patients on hemodialysis that received HCV treatment before 2005. The register also does not include drugs provided to patients in clinical trials such as patients with CHC infection and CKD stage 4 or 5. However, apart from the C-Surfer study, which was initiated in 2014, no other clinical treatment trial of this patient population in Sweden has been published in recent years, and the present study ended in 2013.
      • Roth D.
      • Nelson D.R.
      • Bruchfeld A.
      • Liapakis A.
      • Silva M.
      • Monsour Jr, H.
      • 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.
      In addition, just because a pharmacy has dispensed drugs does not automatically mean that the patient has taken all drugs.

      Conclusion

      Patients with CHC infection are at higher risk of developing CKD. Metabolic and cardiovascular factors need to be considered, as well as extrahepatic manifestations affecting the kidneys, in addition to the underlying liver disease. More attention should be paid to the potential benefit of HCV treatment in the CKD population, which may in the long-term reduce the need for dialysis and kidney transplantation. Adverse outcomes in patients with CHC infection on hemodialysis may reflect the cumulative cardiovascular effects of dialysis dependency and HCV infection. If antiviral treatment can consistently confer better outcomes in patients with CHC and a CKD diagnosis, or on maintenance dialysis or after kidney transplantation, as suggested in the present study, providing HCV treatment for these patients should be a priority.

      Financial support

      The design, study conduct, and financial support for the study were provided by AbbVie. AbbVie participated in the study design, data analysis, interpretation of results, review, and approval of the publication. The authors determined the final content. No payments were made to the authors for writing this publication.

      Conflict of interest

      JS, JK, and KB are employees of AbbVie and may hold stocks or stock options. RS received honoraria for lectures from AbbVie, MSD/Merck, Medivir, and BMS. AB received consulting fees from ChemoCentryx and Merck/MSD, and received honoraria for lectures from AbbVie, ChemoCentryx, Merck/MSD, and Sanofi-Genzyme. KL received honoraria for lectures from AbbVie, Merck/MSD, Medivir, Gilead, and BMS. CM has nothing to disclose.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Authors’ contributions

      The study was designed by JS, KB, and AB. JS, KB, and JK performed the data analysis. JS, CM, and AB interpreted the data with support from KB, JK, KL and RS. JS and AB wrote the manuscript with main support from CM. All authors critically revised the manuscript and approved the final version that was submitted.

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