Download Full GuidanceChronic hepatitis C is independently associated with the development of chronic kidney disease (CKD) (Rogal, 2016); (Fabrizi, 2015). A meta-analysis demonstrated that chronic HCV infection was associated with a 51% increase in the risk of proteinuria and a 43% increase in the incidence of CKD (Fabrizi, 2015). There is also a higher risk of progression to end-stage renal disease (ESRD) in persons with chronic HCV infection and CKD, and an increased risk of all-cause mortality in persons on dialysis (Lee, 2014); (Fabrizi, 2012).
The most frequent form of kidney involvement in chronic hepatitis C is membranoproliferative glomerulonephritis, usually caused by cryoglobulinemic vasculitis. In persons with immune complex glomerulonephritis, antiviral therapy should not be delayed while awaiting kidney biopsy (Awan, 2023). Remission of nephrotic range proteinuria (>3.5 g/d) can occur with antiviral treatment (Pérez de José , 2020). Successful HCV antiviral treatment improves clinical outcomes. Antiviral therapy was associated with a survival benefit among persons on dialysis in a nationwide Swedish registry study (Söderholm, 2018). In a retrospective cohort analysis utilizing the Truven Health MarketScan Database (2008-2015), HCV treatment was associated with a 30% decreased risk of developing CKD (hazard ratio [HR] 0.70; 95% CI 0.55–0.88). Persons with HCV infection experienced a 2-fold and a 17-fold higher risk, respectively, of membranoproliferative glomerulonephritis (HR 2.23; 95% CI 1.84–2.71) and cryoglobulinemia (HR 16.91; 95% CI 12.00–23.81) compared with persons without HCV infection (Park, 2018).
Among persons with diabetes and ESRD receiving care at 4 US health systems, achieving a
sustained virologic response (SVR) reduced the risk of developing extrahepatic
manifestations of HCV disease regardless of cirrhosis status (subdistribution HR 0.46; 95%
CI 0.31–0.67) compared with untreated persons (Li, 2019). In a retrospective observational
cohort study, predictors of estimated glomerular filtration rate (eGFR) improvement after
antiviral therapy included baseline CKD (eGFR <60 mL/min/1.73 m2) and not having
diabetes (Sise, 2019). A prospective cohort study that evaluated outcomes among persons
with eGFR >15 mL/min/1.73 m2 demonstrated a lower risk of ESRD in persons who attain
SVR12 (Liu, 2022).
A systematic review of 106 studies of specific direct acting antiviral (DAA) regimens
conducted among persons with advanced kidney disease (CKD 4 or 5, persons on dialysis,
kidney transplant recipients) concluded that DAAs are eAicacious (SVR12 ≥93%) and safe
in this population (Balk, 2023).
Recommendation for Persons With Chronic Kidney Diseasea |
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| RECOMMENDED | RATING  |
| No dose adjustment in direct-acting antivirals is required when using recommended regimensb | I, A or IIa, Bc |
| a Chronic kidney disease (CKD) stages: 1 = normal (eGFR >90 mL/min); 2 = mild CKD (eGFR 60-89 mL/min); 3 = moderate CKD (eGFR 30-59 mL/min); 4 = severe CKD (eGFR 15-29 mL/min); 5 = end-stage CKD (eGFR <15 mL/min) b A ribavirin dose reduction may be required for patients with CKD stage 3, 4, or 5; see prescribing information for details. c The rating is I, A for patients with CKD stage 1, 2, or 3 and IIa, B for those with CKD stage 4 or 5. |
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Glecaprevir/Pibrentasvir
The EXPEDITION-4 trial evaluated the safety and eAicacy of 12 weeks of daily fixed dose
glecaprevir (300 mg)/pibrentasvir (120mg) for genotype 1, 2, 3, 4, 5, or 6 infection among
persons with severe renal impairment, without cirrhosis or with compensated cirrhosis (Gane, 2017b). This open-label study enrolled treatment-naive and treatment-experienced
adults (previous interferon or peginterferon ± ribavirin, or sofosbuvir and ribavirin ±
peginterferon) with CKD stage 4/5, including those dependent on hemodialysis. Baseline
characteristics of the 104 enrollees were 76% male; 25% Black; 19% compensated
cirrhosis; 40% treatment experienced; and 82% hemodialysis dependent. The genotype
distribution was 22% genotype 1a; 28% genotype 1b; 16% genotype 2; 11% genotype 3;
19% genotype 4; 1% genotype 5; and 1% genotype 6.
The study reported intention-to-treat (ITT) and modified intention-to-treat (mITT) SVR12
rates of 98% and 100%, respectively. There were no virologic failures. Two participants did
not achieve SVR12; 1 person discontinued the study due to diarrhea in the context of
recent gastrointestinal bleeding and the other experienced a cerebral hemorrhage due to
uncontrolled hypertension (had attained SVR4). Adverse events included pruritus (20%),
fatigue (14%), and nausea (12%). There were no serious adverse events related to the study
drugs, and there were no grade 4 laboratory abnormalities reported (Gane, 2017b). The
EXPEDITION-4 trial supports the eAicacy and safety of glecaprevir/pibrentasvir in persons
with CKD including ESRD. The recommended duration of therapy is the same as for
persons without CKD.
EXPEDITION-5 evaluated the eAicacy and safety of daily fixed-dose glecaprevir/pibrentasvir
for chronic HCV infection in adults without cirrhosis or with compensated cirrhosis and
stage 3b, 4, or 5 CKD. Among the 101 study participants, 76% (n=77) were on dialysis and
24% (n=24) had predialysis CKD. Fifty-five percent of participants had genotype 1infection,
27% had genotype 2, 15% had genotype 3, and 4% had genotype 4; no participants had
genotype 5 or 6 infection. Eighty-four participants were treated for 8 weeks, 13 participants
for 12 weeks, and 4 participants for 16 weeks. The overall SVR12 rate was 97% (98/101)
with no reported virologic failures (Lawitz, 2020).
An integrated analysis of the eAicacy and safety of glecaprevir/pibrentasvir in persons with
genotypes 1 through 6 infection and CKD stage 3b, 4, or 5 was performed using data from
the EXPEDITION-4 and EXPEDITION-5 clinical trials. This analysis included 205 adults with
compensated liver disease (with and without cirrhosis) and an eGFR <30 mL/min/1.73 m2
(EXPEDITION-4) or <45 mL/min/1.73 m2 (EXPEDITION-5). The majority of participants were
treatment naive (69%), with genotype 1 infection (54%), and on dialysis (79%). In this
integrated analysis, a 100% SVR12 rate (mITT) was found with glecaprevir/pibrentasvir
therapy in persons with chronic hepatitis C and severe renal impairment regardless of
treatment duration (Lawitz, 2018).
Colchicine-induced rhabdomyolysis due to interaction with glecaprevir/pibrentasvir has
been reported in a person while receiving treatment for gout. Despite a 50% dose reduction
of colchicine before initiation of HCV therapy, the person experienced rhabdomyolysis
(Patel, 2016). This potential interaction with colchicine has the potential for increased risk
for muscle toxicity and should prompt consideration of discontinuation of colchicine
during glecaprevir/pibrentasvir therapy, especially in persons with renal insufficiency (Harrison, 2020).
Sofosbuvir-Based Regimens
In November 2019, the US Food and Drug Administration (FDA) amended the prescribing
information for sofosbuvir-containing regimens to allow use in persons with renal disease,
including those with an eGFR ≤30 mL/min/1.73 m2 and those on dialysis.
A retrospective evaluation of clinical trial participants from 76 clinical trials treated with
sofosbuvir with an eGFR of 30 mL/min/1.73 m2 to 89 mL/min/1.73 m2 in a nationally
representative administrative claims database demonstrated that participants with CKD
did not experience worsening eGFR during sofosbuvir-based treatment. Additionally,
sofosbuvir was not associated with an increased risk of ESRD among people with CKD (Sulkowski, 2022). In a Taiwan real-world HCV registry program of 12,995 persons with a
prospective evaluation of serial eGFR levels during and following treatment, sofosbuvir was
not associated with eGFR change (Huang, 2022).
A prospective multicenter, open-label evaluation of daily ledipasvir (90 mg)/sofosbuvir
(400mg) in adults with HCV infection and ESRD on dialysis demonstrated safety and
eAectiveness with: an 8-week course of therapy for treatment-naive participants with
genotype 1 infection without cirrhosis; a 12-week course of therapy for treatment
experienced persons with genotype 1 infection, and for treatment-naive or treatment
experienced persons with non-genotype 1 infection without cirrhosis; and a 24-week
course of therapy for those with genotypes 1, 2, or 4 infection with compensated cirrhosis.
Ninety-four percent (89/95) of participants achieved SVR12. Six people died during
treatment; no deaths were related to the study drugs (Huang, 2022).
A real-world case series of treatment-naive and treatment-experienced adults
demonstrated that 12 weeks of daily fixed-dose sofosbuvir (400 mg)/velpatasvir (100 mg)
administered to persons on hemodialysis with any HCV genotype infection resulted in an
SVR12 rate of 95% (56/59). There were no treatment-related discontinuations or serious
adverse events. There were 2 virologic relapses; 1 was associated with nonadherence (Borgia, 2019). A retrospective analysis of 31 treatment-naive adults on hemodialysis with
any HCV genotype infection (68% genotype 1) demonstrated that 12 weeks of
sofosbuvir/velpatasvir resulted in an SVR12 rate of 95% (30/31). There was a single virologic
relapse among the 3 persons with cirrhosis (Gaur, 2020). A systematic review and meta
analysis across 21 studies involving 717 adults with CKD stage 4/5 (58.4% on dialysis)
treated with sofosbuvir-based regimens demonstrated a pooled SVR rate of 97% (12/24)
and a serious adverse event rate of 4.8%. Persons with and without cirrhosis attained
comparable SVR12/24 rates (Li, 2019a).
Rare adverse advents have been reported among persons with CKD receiving DAAs.
Colchicine-induced rhabdomyolysis has been reported in an individual with renal dysfunction being treated with ledipasvir/sofosbuvir while continuing atorvastatin (Patel, 2016). Acute interstitial nephritis following DAA treatment has been described in association with sofosbuvir/ledipasvir (n=5), elbasvir/grazoprevir (n=2), and sofosbuvir/simeprevir (n=1) (Duque, 2021).
Elbasvir/Grazoprevir
The C-SURFER trial evaluated the safety and eAicacy of 12 weeks of the daily fixed-dose
combination of elbasvir (50 mg)/grazoprevir (100 mg) versus placebo among 224 adults
with genotype 1 infection and CKD stage 4/5 (eGFR <30 mL/min/1.73 m2). The initial study
randomized eligible participants to immediate or deferred treatment with
elbasvir/grazoprevir. The delayed treatment arm initially received placebo and was later
treated with elbasvir/grazoprevir. Elbasvir and grazoprevir are primarily metabolized in the
liver and undergo minimal renal elimination. The data for the immediate treatment arm
have been published (Roth, 2015). Seventy-five percent (168/224) of the study participants
were on hemodialysis, and 45% were Black. A small number of participants with
compensated cirrhosis were included. ITT and mITT SVR12 rates were 94% and 99%,
respectively. There were no changes in erythropoietin use, hemoglobin, or other adverse
events in the treatment groups compared with placebo. None of the participants with
genotype 1a infection with baseline NS5A resistance-associated substitutions (RASs)
experienced viral relapse. The only reported relapse occurred in a person with genotype 1b
infection. The basis for the lack of impact of NS5A RASs on SVR rates in this population is
unclear but may relate to the moderately increased area under the curve with grazoprevir
and elbasvir observed in persons with stage 4/5 CKD (Zepatier prescribing information, 2019). Among participants assigned to deferred treatment 98% (97/99) achieved SVR12 (Bruchfeld, 2017). Among participants with genotype 1a infection, SVR12 rate was 85%
(11/13) for persons with detectable baseline NS5A RASs and 100% (98/98) among those
without baseline RASs. One serious adverse event (interstitial nephritis) occurred during
the deferred treatment that was considered study drug related. Overall, the eAicacy of
elbasvir/grazoprevir among participants assigned to deferred treatment paralleled the
findings of the immediate treatment group. Overall eAicacy remained high in all study
population subgroups including cirrhosis, diabetes, and hemodialysis. These data support
no modification of elbasvir/grazoprevir dosing for persons on hemodialysis. Of the 3
participants who relapsed in both the immediate and deferred treatment groups, 2 had
genotype 1a infection with baseline NS5AA RASs, underscoring the importance of baseline
NS5A RASs aAecting treatment outcome with elbasvir/grazoprevir (Bruchfeld, 2017).
Based on these data, daily fixed-dose elbasvir/grazoprevir is recommended for persons
with genotype 1 infection and severely compromised renal function. While C-SURFER did
not evaluate persons with genotype 4 infection, it is likely that the high eAicacy of
elbasvir/grazoprevir in genotype 1 and genotype 4 infection in persons with normal renal
function can be extrapolated to persons with genotype 4 and CKD stage 4/5. Treatment
with elbasvir/grazoprevir in persons with CKD has been shown to be cost-eAective in the
United States (Elbasha, 2016).
Several real-world studies demonstrated the eAectiveness of elbasvir/grazoprevir in
persons with genotype 1 or 4 infection. In a retrospective cohort analysis from the TRIO
network, 99% (113/114) of persons with stage 4/5 CKD attained SVR12 (Flamm, 2018). A
nationwide retrospective observational cohort study of persons in the US Veterans Health
Administration system identified 5961 adults (42.5% genotype 1a, 55.0% genotype 1b) who
completed elbasvir/grazoprevir therapy, including 860 persons with stage 3 CKD, 740
persons with stage 4/5 CKD, and 4361 controls (eGFR ≥60 mL/min/1.73 m2). The SVR rates
were 97% overall, 96% for those with an eGFR ≥60 mL/min/1.73 m2, 98% for those with
stage 3 CKD, and 97% for those with stage 4/5 CKD. No statistically significant diAerences
were found in the SVR rates based on dialysis status (utilized or not ) among the persons
with stage 4/5 CKD (adjusted odds ratio 0.91; 95% CI 0.56-1.47 and adjusted OR 1.74; 95%
CI 0.63-4.81, respectively) compared with the controls (eGFR ≥60 mL/min/1.73 m2) (Choi, 2020).
Rare adverse advents have been reported among persons with CKD receiving DAAs. Acute
interstitial nephritis following DAA treatment has been described in association with
sofosbuvir/ledipasvir (n=5), elbasvir/grazoprevir (n=2), and sofosbuvir/simeprevir (n=1)
(Duque, 2021).
Elbasvir, Grazoprevir, and Ledipasvir Metabolism
Elbasvir, grazoprevir, and ledipasvir are primarily metabolized in the liver and undergo minimal renal elimination. While exposures to many of these agents are higher in severe renal impairment—presumably due to the effects of uremic toxins, parathyroid hormone, and/or cytokines on hepatic metabolism—dose adjustments are not required in the setting of renal impairment.