Chronic Hepatitis C Increases the Risk of Chronic Kidney Disease (CKD) while

Effective HCV Treatment Decreases the Incidence of CKD

Haesuk Park1, Chao Chen1, Wei Wang1, Linda Henry1, Robert L. Cook2, David R.
Nelson2

1
Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida,
Gainesville, FL 2Medicine, University of Florida, Gainesville, FL

Authors

Haesuk Park, PhD, hpark@cop.ufl.edu, University of Florida College of Pharmacy

Chao Chen, charl.coverc@ufl.edu, University of Florida College of Pharmacy

Wei Wang, vivianwang@ufl.edu, University of Florida College of Pharmacy

Linda Henry, PhD, lhenry6@cox.net, University of Florida College of Pharmacy

Robert L. Cook, MD, MPH, cookrl@ufl.edu, University of Florida College of Medicine

David R. Nelson, MD, nelsodr@ufl.edu, University of Florida College of Medicine

Key words: HCV, CKD, DAA

Contact information

Haesuk Park, PhD; hpark@cop.ufl.edu

Assistant Professor
Department of Pharmaceutical Outcomes and Policy
University of Florida College of Pharmacy
HPNP Building Room 3325
1225 Center Drive
Gainesville, Florida 32610
Tel: 352.273.6261
Fax: 352.273.6270
Email: hpark@cop.ufl.edu

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as
doi: 10.1002/hep.29505

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 Hepatology Page 2 of 44

List of Abbreviations:

HCV, hepatitis C virus

CKD, chronic kidney disease

GFR, glomerular filtration rate

MPGN, membranoproliferative glomerulonephritis

DAA, direct acting antiviral agents

HR, hazard ratio

CI, confidence interval

EHM, extrahepatic manifestations

ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical

Modification

PS, propensity score

COPD, chronic obstructive pulmonary disease

HIV, human immunodeficiency virus

ACEI, angiotensin-converting-enzyme inhibitors

ARB, angiotensin II receptor blockers

ESRD, end stage renal disease

SVR, sustained virology response

Financial support: Nothing to disclose.

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ABSTRACT

We aimed to assess the risk of chronic kidney disease (CKD) in chronic hepatitis C

virus (HCV) infected patients and the incidence reduction of CKD after receipt of HCV

treatment. We also evaluated the risk of membranoproliferative glomerulonephritis

(MPGN) and cryoglobulinemia in chronic HCV patients. A retrospective cohort

analysis of the Truven Health MarketScan Database (2008-2015) in the United States

was conducted. In a cohort of 56,448 HCV-infected patients and propensity score

(1:3) matched 169,344 non-HCV patients, we examined the association of HCV

infection with the incidence of CKD. Of 55,818 HCV patients, 6.6 % (n=3666), 6.3%

(n=3534), and 8.3% (n=4628) patients received either interferon-based dual, triple, or

all-oral direct acting antiviral agents (DAA) therapy, respectively, whereas 79% of

patients did not receive any HCV treatment. Cox proportional hazards models were

used to compare the risk of developing CKD in HCV patients compared to non-HCV

patients and treated patients compared to non-treated HCV patients. In a

multivariate time-varying Cox regression model, HCV-infected patients had a 27%

increased risk of CKD compared to non-HCV patients (hazard ratio (HR),1.27; 95%

confidence interval (CI),1.18-1.37). Among HCV patients, individuals who received

the minimally effective HCV treatment for dual, triple, or all-oral therapy had a 30%

decreased risk of developing CKD (HR,0.70; 95% CI,0.55-0.88). In addition,

HCV-infected patients experienced a twofold and a nearly 17-fold higher risk of

MPGN (HR,2.23; 95% CI,1.84-2.71) and cryoglobulinemia (HR,16.91; 95%

CI,12.00-23.81), compared to non-HCV patients.

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CONCLUSION: Individuals infected with HCV infection in U.S. are at greater risk of

developing CKD, MPGN, and cryoglobulinemia. Minimally effective treatment of

HCV infection can prevent the development of CKD, although the association was not

significant for all-oral therapy.

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The burden of fatal liver disease is increasing in the estimated 3.2 million United

States (US) adults chronically infected with hepatitis C virus (HCV). (1) Furthermore,

chronic HCV infection is associated with extrahepatic manifestations, reported in up to

74% of patients, and may be present long before advanced liver disease presents

itself and responsible for non-liver related deaths. (2-5)

Chronic kidney disease (CKD) is one of the more common extrahepatic

manifestations present in patients with chronic HCV; however, study reports on the

risk of CKD in the chronically infected HCV population are inconsistent within the US.

(6-10) Two recent studies conducted in US Veteran populations assessed the

association of chronic HCV infection with the development/progression of CKD and

reported divergent results. (6,9,10) Molnar found that chronic HCV was associated

with higher incidence of decreased kidney function whereas Rogal et al. concluded

that chronic HCV was associated with decreased incidence of CKD. (6, 9) Two

meta-analyses determined that patients with HCV had a 23~43% greater risk of

presenting with CKD (11, 12) whereas another meta-analysis found that HCV was not

associated with reduced glomerular filtration rate (GFR). (8)

The most common HCV-related nephropathy is membranoproliferative

glomerulonephritis (MPGN), usually in the context of cryoglobulinemia. (8, 13-15)

Mixed cryoglobulinemia represents 60% to 75% of all cryoglobulinemias (16) leading

to clinical manifestations ranging from the mixed cryoglobulinemia syndrome to more

serious lesions with neurologic and kidney involvement. (17) Recently, two studies

reported the prevalence of MPGN (0.3%) and cryoglobulinemia (0.4~0.9%) in

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chronically HCV-infected patients in the US. (18, 19) However, there is limited

evidence regarding the incidence of these renal manifestations in HCV patients. (20,

21)

Up until late 2013, interferon and ribavirin were the main components of HCV

treatment. Despite the positive effects on slowing the renal disease progression,

supported by recent Taiwanese studies, (22-24) interferon and ribavirin treatment

carries substantial side effects, leading to very poor adherence and relatively low cure

rates. (25-30) In 2014, the FDA approved the first all-oral direct acting antiviral

agents (DAA’s) which have revolutionized the HCV treatment landscape as a result of

excellent adherence and very high cure rates (over 95%) in as little as eight weeks

even for the very difficult to treat patient. (28-30) However, it is unclear whether the

new DAA’s carry an improvement in renal function and or reduce the incidence of

CKD among chronically infected HCV patients residing in the US.

Therefore, the aims of this study were to: 1) determine the incidence of CKD

among chronically HCV-infected beneficiaries enrolled in a large health care plan in

the US; 2) determine the impact of treatment on the CKD incident rate in chronically

HCV- infected patients within the US; and 3) determine the incidence of MPGN and

cryoglobulinemia in chronically HCV-infected patients.

METHODS

Data source

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We conducted a retrospective cohort study using the Truven Health Analytic

MarketScan Commercial and Medicare Supplemental databases (2008 January

-2015 August prior to the implementation of ICD-10 codes). This 8-year nationwide

administrative claims database contains person-level information of diagnoses,

procedures, and prescriptions for over 100 million individuals in the commercial

dataset and 10 million individuals in the Medicare Supplement database. This

database captures healthcare utilization and enrollment records across all settings

including physician outpatient office visits, hospital stays, and pharmacy claims. The

study population consisted of employees, dependents, and retirees with

employer-sponsored or Medicare Supplemental insurance plans. Institutional review

board approval was obtained from the University of Florida.

Study population

Identification of HCV and non-HCV patients (HCV vs. non-HCV cohorts)

Patients with newly diagnosed chronic HCV were identified using the International

Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes:

070.44, 070.54, 070.70, 070.71, V02.62. A patient was determined to be infected

with chronic HCV if they had one inpatient chronic HCV diagnosis or two outpatient

diagnoses of HCV on separate days within one year. The first diagnosis was used

as the index date. To establish a non-HCV control group, we selected 20 non-HCV

patients matching on age, gender and calendar year for each chronic HCV patient.

For non–HCV patients, we randomly selected one of their medical service dates as

the index date. Patients were included if they were 18 years old and continuously

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enrolled in the health plan one-year before and 6-month after the index date.

Patients who had a diagnosis of CKD before the index date were excluded.

Furthermore, for each chronic HCV patient, 3 non-HCV patients were matched using

the propensity score (PS) that was calculated to adjust for the baseline differences in

risk factors for CKD between HCV and non-HCV groups. The PS was estimated

using logistic regression based baseline demographic variables including age and

gender, and medical conditions reported in the literature associated with chronic HCV

and CKD, including diabetes, hypertension, dyslipidemia, chronic obstructive

pulmonary disease (COPD), coronary artery disease, peripheral vascular disease,

cerebrovascular disease, and heart failure identified by ICD-9-CM codes, as well as

disease-modifying medications including angiotensin-converting-enzyme inhibitors

(ACEI) and angiotensin II receptor blockers (ARB).

Identification of HCV treatment groups according to antiviral treatment (treated

vs. non-treated HCV patients)

The chronic HCV patients were further categorized based on the receipt, type, and

duration of HCV treatment using pharmacy claims for HCV treatment. For this

analysis, we excluded patients who had undergone HCV therapy before the index

date. HCV treatments included three classes: 1) Dual therapy - a combination

therapy of interferon and ribavirin (interferon alpha, interferon beta, peg- interferon

alpha-2a or peg- interferon alpha-2b with or without ribavirin); 2) Triple therapy- a

combination of boceprevir, telaprevir, sofosbuvir, or simeprevir plus peg-interferon

and ribavirin; 3) All-oral therapy included ledipasvir/sofosbuvir, sofosbuvir with

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ribavirin and ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin.

(31)

Based on the receipt and duration of treatment received, we classified patients

into three different exposure statuses : a) No treatment patients were not exposed to

any HCV treatments; b) Minimum effectively treated patients received one of three

HCV therapeutic treatment regimens prescribed as at least 16-week of dual therapy

(24), an 8-12 week of triple therapy (28, 29), or an 8-week of all-oral therapy (30); c)

Insufficiently treated defined as the patients who received some treatment but did not

meet the criteria for minimum effectively treated yet.

Study outcomes

The primary outcome was a diagnosis of CKD stages 3-5. The ICD-9-CM codes of

585.3, 585.4 and 585.5 were used to identify CKD cases. (32) CKD was considered

to be diagnosed if there was one inpatient or two separate outpatient claims for CKD

within 1 year. The earliest date of CKD diagnosis was defined as the date of

outcome. Follow-up started from the index date and continued until study outcome,

end of enrollment, or 31 August 2015, whichever came first. The secondary

outcomes were the investigations of the renal conditions of nephrotic syndrome or

MPGN (ICD-9CM: 581.0, 581.1, 581.2, 581.81, 581.89, 581.9 or V13.03) and

cryoglobulinemia (ICD-9CM: 273.2) within the chronically infected HCV adult

population. (18, 19)

Statistical Analysis

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Baseline characteristics were compared between HCV and non-HCV cohorts using

t-test for continuous variables and chi-square tests for categorical variables. After

propensity score matching, the standardized difference was used to check the

balance between two groups and 0.2 was defined as the threshold to determine

statistically significant differences. (33, 34) The number of CKD events and

person-time of observation were determined for each group and subsequently used to

calculate the incidence rates of CKD (number of events/1,000 person-years). We

then stratified CKD by age group, gender, diabetes, and cirrhosis status, as previous

studies have suggested that there was an effect modification on the rate of CKD

among these subpopulations. (35, 36) A Cox proportional hazards regression model

was used to compare the risk of developing CKD, MPGN, and cryoglobulinemia

between HCV and non-HCV cohorts. A Cox proportional hazards regression model

with time-dependent covariates was also employed in a sensitivity analysis (Model 1)

(Table S1). The covariates were adjusted for alcohol/drug abuse disorders, HIV,

hepatitis A virus, hepatitis B virus, cirrhosis, decompensated cirrhosis, and

hepatocellular carcinoma in addition to covariates adjusted in PS matching. We did

not match for presence of liver disease, an effect mediator of HCV rather than a

confounder, and variables that were strongly associated with HCV but weakly

associated with CKD (e.g., alcohol/drug abuse) but adjusted for regression models,

because previous studies found that incorporating these variables can lead to less

successful matching and increased variance. (37-39) However, we performed

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sensitivity analyses with matching/adjustiment for all factors including liver disease

and other covariates.

To assess the association between HCV treatment and the risk of developing

CKD among patients infected with HCV, a time-dependent exposure analysis was

performed. The number of CKD events and person-time of observation were

summarized for each treatment status. Subgroup analyses were performed by type

of HCV treatments including dual, triple, and all-oral therapy. Cox regression models

with time-dependent covariates were used to adjust for all covariates mentioned in the

previous analysis, as well as contraindications to peg-interferon and ribavirin which

included: schizophrenia, depression, seizures, pregnancy, transplant, anemia and

retinopathy (Model 2) (Table S1). All the analyses were performed using SAS 9.4

(SAS Institute Inc., Cary, NC).

RESULTS

Patient characteristics

We identified 56,489 HCV patients and 847,113 non-HCV patients between January

2008 - August 2015 (Figure 1). Table 1 summarizes the baseline demographic

characteristics, comorbid conditions, and medication use between two cohorts before

and after propensity score matching. After propensity score matching, we identified

56,448 HCV patients and 169,344 non-HCV patients. In the propensity

score-matched groups, the patients’ demographic characteristics, including age

(mean age: 55), gender (60% male), and several comorbid conditions (e.g.,

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hypertension, dyslipidemia, diabetes mellitus) were comparable between two groups.

However, heart failure (standardized difference=0.04) and peripheral vascular

disease (standardized difference = 0.04) were slightly more prevalent in the HCV

patients compared to the non- HCV patients, but the differences were still within the

threshold of acceptable imbalance. (40) The presence of liver disease, not included

in PS matching but adjusted in regression models, was more prevalent in HCV

patients compared to non-HCV patients.

Risk of CKD between HCV and non-HCV groups

We identified 1,455 new CKD cases in the HCV group (n= 56,448) and 2,518 new

CKD cases in the non-HCV group (n=169,344). The crude incidence rate of CKD

was 10.36 per 1,000 person-years in HCV and 5.72 per 1,000 person-years in

non-HCV groups. The Cox proportional hazards regression model indicated that

HCV patients had a 57% (hazard ratio (HR), 1.57; 95% confidence interval (CI),

1.47-1.68) increased risk of developing CKD, after adjusting for demographics,

baseline covariates, and the use of ACEI and ARB.

Sensitivity analysis using the Cox regression model with time-dependent

covariates which took the change of comorbidities and medication use during

follow-up into consideration, found that HCV-infected patients had a 27% increased

risk of CKD (HR, 1.27; 95% CI, 1.18-1.37). In a subgroup analysis, when stratified

by different age groups, we found that the association between HCV and CKD was

more significant among young adults (age 18-49; HR, 1.47; 95% CI, 1.13-1.90)

compared to elderly population (age >= 60; HR, 1.19; 95% CI, 1.06-1.33).

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This association appeared to be significant among both males and females

and patients with and without diabetes, but it was not significant among patients

diagnosed with cirrhosis (Table 2). In a sensitivity analysis, when adjusted after PS

matching including all covariates associated with HCV and CKD (52,185 HCV

patients and 156,567 non-HCV patients), we found quantitatively similar results (HR,

1.28; 95% CI, 1.19-1.38) (Table S2-S3).

Risk of CKD among HCV patients who received minimally effective, insufficient

and no treatments

Of 55,818 HCV-infected patients, 43,990 patients (79%) did not receive any HCV

treatment. The remaining 11,809 HCV patients received HCV treatment including

3,666 dual therapy, 3,534 triple therapy, and 4,628 all-oral DAA therapy (Table 3).

Patients who received the all-oral DAA regimens were older and had significantly

more advanced liver disease (i.e., cirrhosis, decompensated cirrhosis) and

comorbidities (e.g, hypertension, diabetes, coronary artery disease, HIV) than the

patients in either the dual or triple therapy groups, respectively. However, though

the patients in the no treatment group had similar advanced liver disease compared to

patients in the all-oral therapy group, they were more likely to have alcohol/drug

abuse and contraindications to peg-interferon and ribavirin such as schizophrenia,

depression, and pregnancy than patients in any of the treatment groups.

Table 4 displays the risk of developing CKD among the HCV patients who

received minimally effective, insufficient, or no treatments. The majority of CKD

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events (90%) occurred in patients who received no HCV treatment carrying a CKD

incidence rate of 10.79 per 1,000 person-years. The CKD incidence rate decreased

among patients who received treatment (10.07 per 1,000 person-years) but

decreased greatly when patients were on a minimally effective dose of treatment

(6.73 per 1,000 person-years). After adjusting for baseline and time-dependent

covariates, overall, we found HCV-infected patients who received the minimum

effective duration of therapy had a 30% decreased risk of developing CKD compared

to those who received no treatment (HR: 0.70; 95% Cl, 0.56-0.88). However, in a

subgroup analysis, these associations were only significant for dual (HR, 0.60; 95%

CI, 0.43-0.85) and triple therapies (HR, 0.59; 95% CI, 0.37-0.94) but not for the new

all-oral therapy (HR, 1.03; 95% CI, 0.68-1.55) (Table 4).

Risk factors related to incidence of CKD in HCV-infected patients

Figure 2 shows risk factors for CKD in HCV-infected patients. Factors associated

with an increased risk of developing CKD included: being older>=60 (HR, 2.12; 95%

CI, 1.74-2.58), having diabetes mellitus (HR, 1.79; 95% CI, 1.60-2.00), congestive

heart failure (HR, 2.14; 95% CI, 1.88-2.45), peripheral vascular disease (HR, 1.20; 95%

CI, 1.05-1.37), cerebrovascular disease (HR, 1.20; 95% CI, 1.04-1.37), hypertension

(HR, 2.43; 95% CI, 2.05-2.88), HIV (HR, 1.93; 95% CI, 1.44-2.57), alcohol abuse (HR,

1.27; 95% CI, 1.10-1.46), decompensated cirrhosis (HR, 1.91; 95% CI, 1.64-2.24),

history of transplant (HR, 3.19; 95% CI, 2.70-3.76), anemia (HR, 2.20; 95% CI,

1.95-2.47), in addition to receipt of ACEI (HR, 7.30; 95% CI, 6.12-8.71) and ARB (HR,

5.57; 95% CI, 4.86-6.39).

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Risk of membranoproliferative glomerulonephritis (MPGN) and

cryoglobulinemia between HCV and non-HCV groups

For this analysis, we further excluded patients with MPGN and cryoglobulinemia

before the index date. Table 5 shows that the association between HCV and the

development of nephrotic syndrome/MPGN and cryoglobulinemia. The crude

incidence rate of MPGN was 0.833 per 1,000 person-years in HCV and 0.221 per

1,000 person-years in non-HCV groups. The crude incidence rate of

cryoglobulinemia was 0.876 per 1,000 person-years in HCV and 0.050 per 1,000

person-years in non-HCV groups. The Cox proportional hazards regression model

indicated that HCV patients had 3.7 times and 17 times higher risks of developing

nephrotic syndrome/MPGN (HR, 3.74; 95% CI,2.84-4.93) and cryoglobulinemia (HR,

17.25; 95% CI, 10.91-27.26). Sensitivity analyses using the Cox regression model

with time-dependent covariates which took the change of comorbidities and

medication use during follow-up into consideration, found that HCV-infected patients

had 2 times and 17 times increased risk of MPGN (HR, 2.23; 95% CI, 1.84-2.71) and

cryoglobulinemia (HR, 16.91; 95% CI, 12.00-23.81). We also found the HCV and

MPGN association was stronger among female patients (HR, 3.78; 95% CI, 2.66-5.36)

compared to male patients (HR, 1.74; 95% CI, 1.37-2.19). In contrast, there were no

significant differences in the development of cryglobulinemia between male and

female HCV patients. However, we did not find any effects of the HCV treatments on

the risk of developing MPGN and cryoglobulin among the HCV patients who received

treatments compared to no treatment. (Table S4-S5)

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DISCUSSION

This retrospective cohort propensity score matched study provides the first US

general population based-evidence to support that HCV infection is linked to an

increased risk of CKD. In fact, the crude incidence rate among our cohort of

chronically infected HCV patients was 10.36 per 1,000 person-years compared to

5.72 per 1,000 person-years in non-HCV groups. This significant finding was further

confirmed in our Cox proportional hazards regression model which indicated that

persons diagnosed with chronic HCV had a 57% increased risk of developing CKD

and in our time-varying Cox regression model chronic HCV-infected patients had a 27%

increased risk of CKD. The decrease in the risk from 57% to 27% was explained as

we controlled for the risk factors known to be associated with the development of CKD

after an HCV diagnosis. Nonetheless, our study demonstrates that HCV is

significantly associated with increasing the risk for CKD among patients with HCV in

the US which corroborates other findings which have associated HCV to the incidence

and progression of CKD. (6, 9, 11, 12, 22-24)

However, a recent study conducted by Rogal et al. using the Electronically

Retrieved Cohort of HCV Infected Veterans Study Group (ERCHIVES) determined

that other factors (older age, female sex, diabetes, hypertension, development of

cirrhosis, and substance abuse) rather than HCV were associated with the incidence

and progression of CKD. (10) They suggested that the reason that HCV was

protective for CKD was probably a result of the amount of time patients were exposed

to HCV as their patient population was not newly diagnosed with HCV unlike our

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population who were newly diagnosed chronic HCV patients. We also suggest that

the differences in our findings may be due to the variables controlled for in our

time-varying multivariate analysis. With the use of time-varying Cox-regression

modeling, we accounted for the dynamic and complex relationship between variables

and time allowing us to identify the top five variables associated with CKD in the

chronically infected HCV patient. Specifically these variables were: ACEI, ARB,

congestive heart failure, hypertension, and transplantation- variables similar to the

variables Rogal found to be predictors of CKD in their population. Since we

accounted for changes that can occur over time, our findings lend more strength of the

association of these variables in the development of CKD within patients with chronic

HCV infection.

A very promising study finding was that exposure to the minimally effective

duration of treatment resulted in chronically HCV-infected patients experiencing a 30%

decreased risk of developing CKD. However, in the subgroup analysis, the

association was only observed with the less tolerated HCV treatment therapies (dual

and triple therapies) and not with the new all-oral regimens. We believe this

discrepancy results from shorter follow-up for patients with the new DAA’s for

treatment (person-years at risk) during the time-period of study. Although sofosbuvir

plus ribavirin regimen was first used in 2013, the FDA approval for the use of the first

all-oral DAA regimen (ledipasvir/sofosbuvir) was not until October 2014, so patients in

our study had less than a year period of time to be exposed to the newer all- oral DAA

regimens (study period ended August of 2015). Nonetheless, we noted a trend

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towards decreasing the risk of CKD in HCV-infected patients treated with the DAA’s- a

trend we suspect will become significant as more research investigates the incidence

and progression of CKD in patients with HCV who are treated with the new DAA’s.

On the other hand, a disturbing study finding was that the majority of HCV

patients (79%) within our study were not treated. Though the no treatment group

had similar advanced liver disease (cirrhosis, decompensated cirrhosis) compared to

the all-oral therapy group, the no treatment group was sicker as noted by the

increased number of patients with alcohol/drug abuse issues as well as the number of

contraindications to peg-interferon and ribavirin based treatment regimens which may

partially explain why they were not treated. This finding is especially noteworthy

since efficacious and safe all-oral pangenotypic therapies are now available and

approved for most people to include patients in whom interferon was contraindicated,

difficult-to-treat patients, HIV co-infection, and cirrhosis. Nonetheless, the majority of

patients not receiving treatment suggests that patients with HCV are still encountering

barriers to treatment even within a group with access to health insurance. Therefore,

identifying and then overcoming the barriers to identification and treatment remains a

very significant issue in eradicating HCV as well as eliminating the clinical and

economic burden of HCV-associated extrahepatic manifestations including CKD. (3,

41)

Another very significant and unique finding of this study was the identification of

the incidence and risk for developing MPGN and cryoglobunemia among chronically

infected HCV patients. To the best of our knowledge, no study has quantified the risk

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of developing these disease in the US chronically infected HCV general population.

The crude incidence rate of MPGN and cryoglobulinemia were 6 times and over 8

times higher compared to non-HCV patients, respectively. In fact, results from our

Cox regression models indicated that chronically infected HCV patients had between 2

to 3 times higher risks for MPGN and 14 to 17 times higher risks of developing

cryoglobulinemia after adjusting for covariates. Our results were similar to those in

studies of extrahepatic manifestations of HCV in US veterans. (20, 21) A hospital

based case-control study, carried out among US male veterans hospitalized

(1992-1999), found there was a greater proportion of MPGN (0.36% vs 0.05%) and

cryoglobulinemia (0.57% vs 0.05%) among patients with HCV infection. (20) In

another cohort study of veterans (1997-2004), investigators reported a fourfold higher

risk of cryoglobulinemia in HCV-infected US veterans, though the association was

notably weaker than our study perhaps due to differences in the study population and

methods. (21)

Interestingly, in our study, female gender HCV patients were at a significantly

higher risk of developing MPGN compared to male gender HCV patients (HR: 3.78 vs

1.74;P>0.05). Several other studies reported a stronger association between female

gender and cryoglobulinemia (42-44) but our study did not find any significant gender

differences in development of cryglobulinemia. Despite the fact that HCV-related

MPGN and cryoglobulinemia are relatively uncommon in the HCV population, these

complications are considered a significant problem as a result of the large number of

people infected with HCV within the US and the potential for serious and

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life-threatening complications to include end stage renal disease. Unfortunately, this

study did not find evidence to support a protective effect of HCV treatment in the

development of these conditions.

There are several strengths to the current study design and the use of a large

claims database. First, this study has methodological strength as it employed

propensity score matching, time-varying Cox proportional hazard models on matched

groups, and adjustment for immortal time bias, analyses which are different from other

previously published studies which may help to indicate a stronger relationship of

HCV and CKD than in other studies (22-24). Second, this study includes the number

of strongly associated CKD covariates which were controlled for in the time- varying

Cox proportional hazard models which included: ACEI, ARB, congestive heart failure,

hypertension, and transplantation; nevertheless, HCV infection was still a positive

predictor for developing CKD. (6, 10) Third, this study is notable for its large sample

size and for it being representative of general populations in the U.S. Lastly, we

conducted numerous sensitivity analyses to assess the robustness of results and

found that none of these analyses produced substantially different results from the

main analysis.

Several study limitations must also be noted. First, this study lacks

laboratory results [e.g., sustained virology response (SVR), GFR] to corroborate ICD

coding. We adjusted for as many confounders as available and known to be

associated with CKD; however, since we were dependent on administrative data,

there may have been some unmeasured confounders that were not reported and thus

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Page 21 of 44 Hepatology

21

unavailable. Selection bias was present between treated and untreated groups.

Detection bias may be introduced by differential screening frequencies for kidney

diseases between HCV and non-HCV individuals. Lastly, our study had a relatively

short follow-up which did not allow us to fully explore the use of DAA’s in this

population.

CONCLUSION

Individuals infected with chronic HCV in the U.S. are at a higher risk of developing

moderate to severe CKD, MPGN and cryoglobulinemia. Antiviral treatment for HCV

is associated with a decreased incidence of CKD, although the association is yet to be

confirmed for the new all-oral DAA therapy. These findings highlight that treating

HCV early helps to change the extrahepatic burden of CKD associated with HCV.

Therefore, research must continue to identify barriers to the identification of

HCV-infected patients and improve access to treatment for all HCV patients. Future

studies should include a longer study period to investigate the effects of the all-oral

DAA treatment on the development and progression of CKD.

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Figure Legends

Figure 1. Flow chart of the cohort creation

(Abbreviations: CCAE, Commercial Claims and Encounters, MDCR Medicare

Supplemental and Coordination of Benefits, HCV hepatitis C virus, CKD chronic

kidney disease)

Figure 2. Adjusted hazard ratios for chronic kidney disease in HCV patients using

time-varying Cox-proportional hazards model

(Abbreviations: CI confidence interval, HR hazard ratio, TX: treatment, COPD chronic

obstructive pulmonary disease, HIV human immunodeficiency virus, ACEI

angiotensin-converting-enzyme inhibitors, ARB angiotensin II receptor blockers)

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Table 1. Baseline characteristics before and after propensity score (PS) matching

Patient Before PS Matching After PS Matching†

Characteristics HCV cohort Non-HCV Standardiz HCV cohort Non-HCV Standardi
(N=56,489) cohort* ed (N=56,448) cohort zed
(N=847,113) difference (N=169,344) difference
(%) ‡ (%) ‡
Median age, years 55 (48, 59) 54 (48, 59) 0.03 55 (48, 59) 54 (48, 59) 0.01
(IQR)
Gender, n(%), male 34,106 (60.37) 499,756 (59.00) 0.03 340,82 (60.38) 103,149 (60.91)
Comorbidities, n (%)
Hypertension 21,141 (37.42) 332,581 (39.26) -0.04 21,122 (37.42) 62,468 (36.89) 0.01
Dyslipidemia 140,46 (24.87) 331,064 (39.08) -0.31 140,34 (24.86) 42,143 (24.89) -0.00
Diabetes mellitus 9,237 (16.35) 147,461 (17.41) -0.03 9,231 (16.35) 27,508 (16.24) 0.00
Propensity COPD 6,891 (12.20) 105,505 (12.45) -0.01 6,881 (12.19) 19,957 (11.78) 0.01
score Heart Failure 1,845 (3.27) 30,010 (3.54) -0.02 1,842 (3.26) 4,412 (2.61) 0.04
adjusted Peripheral vascular 2,431 (4.30) 35,049 (4.14) 0.01 2,430 (4.30) 6,048 (3.57) 0.04
variables disease
Cerebrovascular 2,245 (3.97) 40,506 (4.78) -0.04 2,243 (3.97) 5,681 (3.35) 0.03
disease
Coronary artery 4,097 (7.25) 83,462 (9.85) -0.09 4,092 (7.25) 10,948 (6.46) 0.03
disease
Baseline medication use, n (%)
ACEI 3,003 (5.32) 58,520 (6.91) -0.07 3,001 (5.32) 8,875 (5.24) 0.00
ARB 9,969 (17.65) 155,696 (18.38) -0.02 9,955 (17.64) 29,175 (17.23) 0.01
Propensity Comorbidities, n (%)
score HIV 1,187 (2.10) 2,749 (0.32) 0.16 1,187 (2.10) 552 (0.33) 0.16
unadjusted Hepatitis A 210 (0.37) 187 (0.02) 0.08 210 (0.37) 31 (0.02) 0.08
variables† Hepatitis B 1,193 (2.11) 1,416 (0.17) 0.18 1,190 (2.11) 297 (0.18) 0.18
Cirrhosis 2,509 (4.44) 2,440 (0.29) 0.28 2,505 (4.44) 509 (0.30) 0.27
Decompensated 1,888 (3.34) 6,515 (0.77) 0.18 1,886 (3.34) 1,280 (0.76) 0.18
cirrhosis
Hepatocellular 368 (0.65) 516 (0.06) 0.10 367 (0.65) 119 (0.07) 0.10
carcinoma
Alcohol abuse 3,138 (5.56) 13,288 (1.57) 0.22 3,135 (5.55) 2,578 (1.52) 0.22
Drug abuse 8,260 (14.62) 45,287 (5.35) 0.31 8,257 (14.63) 8,436 (4.98) 0.33

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Abbreviations: PS propensity score, IQR interquartile range, COPD chronic obstructive pulmonary disease, HIV human immunodeficiency virus, ACEI angiotensin-converting-enzyme inhibitors, ARB
angiotensin II receptor blockers.
*Up to 20 controls without HCV infection were matched on age, sex, and index date with each HCV subject.
†Propensity Score matching did not include liver-related comorbidities, alcohol abuse, drug abuse, and medication use; instead these covariates were adjusted as time-dependent covariates in the
Cox regression model.
‡ The standardized difference in % is difference in means or proportions divided by standard error; imbalance defined as absolute value greater than 0.20 (small effect size)

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Table 2. Incidence rate and hazard ratio for chronic kidney disease in the hepatitis C virus cohorts and non-HCV cohort

Study HCV No. of Person- CKD Mean Crude Baseline Baseline and
population Status Patients years events time to Incidence covariates time-varying
CKD of CKD* adjusted HR of covariates
event CKD (95% CI) adjusted HR of
(month) CKD (95% CI)
All patients HCV 56,448 140,468 1,455 20.53 10.36 1.57 (1.47-1.68) 1.27 (1.18-1.37)
Non-HCV 169,344 440,495 2,518 22.37 5.72 Reference Reference

Age
18-49 HCV 15,869 37,643 139 19.53 3.69 1.87 (1.49-2.35) 1.47 (1.13-1.90)
Non-HCV 48,044 122,666 216 22.78 1.76 Reference Reference
50-59 HCV 27,344 72,630 685 21.95 9.43 1.75 (1.58-1.93) 1.32 (1.18-1.47)
Non-HCV 82,304 227,193 1086 22.81 4.78 Reference Reference
>=60 HCV 13,235 30,194 631 19.22 20.90 1.38 (1.25-1.53) 1.19 (1.06-1.33)
Non-HCV 38,996 90,636 1216 21.91 13.42 Reference Reference
Gender
Male HCV 34,082 84,721 956 20.11 11.28 1.59 (1.46-1.73) 1.26 (1.14-1.38)
Non-HCV 103,149 268,076 1,673 22.67 6.24 Reference Reference
Female HCV 22,366 55,747 499 21.34 8.95 1.54 (1.37-1.74) 1.26 (1.10-1.43)
Non-HCV 66,195 172,418 845 21.77 4.90 Reference Reference
Cirrhosis HCV 2,505 5,561 183 20.04 32.90 0.89 (0.63-1.26) 0.91 (0.64-1.29)
Non-HCV 509 1,068 39 15.55 36.52 Reference Reference

Non- HCV 53,945 134,907 1272 22.48 9.43 1.59 (1.48-1.70) 1.29 (1.20-1.39)
cirrhosis Non-HCV 168,835 439,427 2479 20.60 5.64 Reference Reference

Diabetes HCV 9,231 21,655 646 19.36 29.8 1.54 (1.40-1.71) 1.23 (1.10-1.38)
Non-HCV 27,508 69,534 1,218 21.49 17.51 Reference Reference
Non- HCV 47,217 118,813 809 21.47 6.81 1.67 (1.53-1.83) 1.32 (1.19-1.46)
diabetes Non-HCV 141,836 370,961 1,300 23.20 3.50 Reference Reference
Abbreviations: HCV hepatitis C virus, CKD chronic kidney disease, CI confidence interval, HR hazard ratio.
*Per 1,000 person-years

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Table 3. Demographics and clinical characteristics among HCV-infected patients

Patient Characteristics Dual therapy Triple therapy All-oral No treatment p-value

(N=3,666) (N=3,534) therapy (N=43,990)
(N=4,628)
Median age, years (IQR) 52 (47 ,57) 54 (49, 58) 56 (51 ,60) 55 (48 ,59) <0.001
Gender, n(%), male 2,224 (60.67) 2,267 (64.15) 2,934 (63.40) 26,242 (59.65) <0.001
Comorbidities, n (%)
Hypertension 1187 (32.38) 1246 (35.26) 1842 (39.80) 16679 (37.92) <0.001
Dyslipidemia 832 (22.70) 765 (21.65) 1112 (24.03) 11186 (25.43) <0.001
Diabetes 457 (12.47) 514 (14.54) 794 (17.16) 7371 (16.76) <0.001
COPD 363 (9.90) 283 (8.01) 446 (9.64) 5750 (13.07) <0.001
Heart Failure 49 (1.34) 51 (1.44) 95 (2.05) 1640 (3.73) <0.001
Peripheral vascular disease 99 (2.70) 79 (2.24) 190 (4.11) 2045 (4.65) <0.001
Cerebrovascular disease 91 (2.48) 75 (2.12) 147 (3.18) 1914 (4.35) <0.001
Coronary artery disease 185 (5.05) 134 (3.79) 288 (6.22) 3453 (7.85) <0.001
HIV 76 (2.07) 45 (1.27) 106 (2.29) 960 (2.11) 0.006
Hepatitis A 22 (0.60) 19 (0.54) 18 (0.39) 148 (0.34) 0.025
Hepatitis B 46 (1.25) 32 (0.91) 37 (0.80) 1063 (2.42) <0.001
Cirrhosis 106 (2.89) 97 (2.74) 198 (4.28) 2058 (4.68) <0.001
Decompensated cirrhosis 62 (1.69) 52 (1.47) 146 (3.15) 1614 (3.67) <0.001
Hepatocellular carcinoma 5 (0.14) 3 (0.08) 19 (0.41) 337 (0.77) <0.001
Alcohol abuse 173 (4.72) 110 (3.11) 173 (3.74) 2665 (6.06) <0.001
Drug abuse 468 (12.77) 409 (11.57) 522 (11.28) 6797 (15.45) <0.001
Contraindications, n (%)
Schizophrenia 88 (2.40) 68 (1.92) 97 (2.10) 1404 (3.19) <0.001
Depression 455 (12.41) 399 (11.29) 515 (11.13) 6363 (14.46) <0.001
Seizure 30 (0.82) 22 (0.62) 39 (0.84) 432 (0.98) 0.126
Pregnancy 27 (0.74) 20 (0.57) 20 (0.43) 599 (1.36) <0.001
Transplant 22 (0.60) 9 (0.25) 49 (1.06) 514 (1.17) <0.001
Retinopathy 1 (0.03) 0 (0.00) 3 (0.06) 26 (0.06) 0.437
Anemia 228 (6.22) 181 (5.12) 399 (8.62) 4610 (10.48) <0.001
Medication use, n (%)

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ACEI 161 (4.39) 173 (4.90) 271 (5.86) 2365 (5.38) 0.015
ARB 569 (15.52) 593 (16.78) 881 (19.04) 7804 (17.74) 0.002
Abbreviations: COPD chronic obstructive pulmonary disease, HIV human immunodeficiency virus, ACEI angiotensin-converting-enzyme inhibitors, ARB angiotensin II receptor
blockers.

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Table 4. Association of HCV treatments with CKD using time-varying Cox-proportional hazards model

Study population Treatment Status† Person- CKD Crude Adjusted HR of

years events Incidence of CKD (95% CI)
CKD *
All HCV patients Minimum Effective TX 11,737 79 6.73 0.70 (0.55-0.88)
(N=55,818) Insufficient TX 6,854 69 10.07 0.85 (0.66-1.09)
No TX 119,698 1291 10.79 Reference
Subgroup analysis
Dual therapy Minimum Effective TX 6,115 34 5.56 0.60 (0.43-0.85)
(n=3666) Insufficient TX 3,245 34 10.48 0.92 (0.65-1.31)
No TX 108,813 1,190 11.10 Reference
Triple therapy Minimum Effective TX 3,469 19 5.48 0.59 (0.37-0.94)
(n=3534) Insufficient TX 3,023 25 8.27 0.72 (0.48-1.07)
No TX 110,623 1,197 10.82 Reference
All-oral therapy Minimum Effective TX 2,154 26 12.07 1.03 (0.68-1.55)
(n=4628) Insufficient TX 585 10 17.09 0.85 (0.39-1.82)
No TX 114,224 1254 10.98 Reference
Abbreviations: HCV hepatitis C virus, CKD chronic kidney disease, CI confidence interval, HR hazard ratio. TX treatment
†HCV treatment status was coded as time-dependent covariate in the Cox regression model. Therefore, each patient may have different treatment statuses during the study follow-up.
*Per 1000 person-years

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Table 5. Incidence rate and hazard ratio for membranoproliferative glomerulonephritis and cryoglobulinemia in the hepatitis C virus
cohorts and non-HCV cohort, adjusting for baseline characteristics
Secondary outcomes HCV No. of Person- No. of Crude Mean Baseline Baseline and time-
Status Patients years events Incidence* time to covariates varying covariates
event adjusted HR (95% adjusted HR (95%
(month) CI) CI)
Membranoproliferative HCV 55,618 140,408 120 0.833 17.39 3.74 (2.84-4.93) 2.23 (1.84-2.71)
glomerulonephritis Non-HCV 166,854 438,153 97 0.221 19.03 Reference Reference
(MPGN)
Gender
Male HCV 33,395 84,325 83 0.984 18.40 3.50 (2.54-4.84) 1.74 (1.37-2.19)
Non-HCV 101,422 266,423 73 0.274 18.81 Reference Reference
Female HCV 22,223 56,082 37 0.660 15.11 4.40 (2.59-7.47) 3.78 (2.66-5.36)
Non-HCV 65,432 171,730 24 0.140 19.72 Reference Reference

Cryoglobulinemia HCV 55,646 140,435 123 0.876 14.17 17.25 (10.91- 16.91 (12.00-23.81)
Non-HCV 166,938 438,946 22 0.050 24.69 27.26) Reference
Reference
Gender
Male HCV 33,423 84,363 75 0.889 14.96 21.00 (11.10- 20.03 (12.28-32.67)
Non-HCV 100,824 265,142 11 0.041 27.25 39.73) Reference
Female HCV 22,223 56,072 48 0.856 12.95 Reference 14.07 (8.68-22.81)
Non-HCV 66,114 173,804 11 0.063 22.12 13.11 (6.76-25.40) Reference
Reference
Abbreviations: HCV hepatitis C virus, CI confidence interval, HR hazard ratio.
*Per 1000 person-years

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Flow chart of the cohort creation

338x190mm (300 x 300 DPI)

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Adjusted hazard ratios for chronic kidney disease in HCV patients using time-varying Cox-proportional
hazards model

338x190mm (300 x 300 DPI)

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