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Treatment of chronic hepatitis C infection in adults with renal impairment
Authors:
Michael D Leise, MD
Lionel Rostaing, MD, PhD
Section Editors:
Adrian M Di Bisceglie, MD
Fernando C Fervenza, MD, PhD
Deputy Editor:
Allyson Bloom, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2018. | This topic last updated: Mar 09, 2018.

INTRODUCTION — There is a strong and likely causal association between chronic hepatitis C virus (HCV) infection and glomerular disease, including mixed cryoglobulinemia, membranoproliferative glomerulonephritis (MPGN), and possibly membranous nephropathy [1]. In addition, the prevalence of anti-HCV antibody is higher among patients on hemodialysis compared with healthy populations, suggesting that dialysis patients may be at higher risk of acquiring HCV infection. In fact, the prevalence of a positive HCV antibody test in the hemodialysis population in the United States is 5 to 10 percent [2]. Antiviral treatment in these patients can be complicated because many of the agents used for anti-HCV therapy can accumulate to toxic levels in the setting of renal impairment. Thus, patients with renal disease and chronic HCV infection represent an important population that warrants specific consideration.

It is anticipated that the management of HCV in adults with significant kidney disease (ie, estimated glomerular filtration rate <30 mL/min per 1.73 m2) will undergo substantial changes over the near future due to the availability of new direct-acting antiviral agents. New HCV medications have allowed for interferon-free, and in some cases, ribavirin-free treatment regimens in patients without renal impairment. However, these agents have to be studied in the patient populations with kidney disease before they can be adopted for widespread use in this historically difficult-to-treat population.

This topic will discuss the approach to antiviral therapy of HCV-infected patients with renal impairment. However, other management issues, such as immunosuppressive therapy as well as treatment of proteinuria and hypertension or other complications of renal disease, may be important in such patients. Discussions of renal disease associated with HCV infection, the epidemiology and prevention of HCV infection among dialysis patients, and HCV infection associated with renal transplantation are found in detail elsewhere:

(See "Overview of renal disease associated with hepatitis C virus infection".)

(See "Clinical manifestations and diagnosis of the mixed cryoglobulinemia syndrome (essential mixed cryoglobulinemia)" and "Treatment of the mixed cryoglobulinemia syndrome".)

(See "Hepatitis C virus infection in patients on maintenance dialysis".)

(See "Hepatitis C virus infection in kidney donors".)

(See "Hepatitis C infection in kidney transplant candidates and recipients".)

RATIONALE FOR ANTIVIRAL TREATMENT — The main reason for antiviral treatment in patients with chronic HCV infection is to prevent liver complications. In the patient with advanced chronic kidney disease who is a potential kidney transplant candidate, an additional reason is to prevent kidney transplant-related complications specific to HCV infection. In the less common scenario of HCV related vasculitis and/or glomerulonephritis (such as mixed cryoglobulinemia), an additional rationale for antiviral treatment is to eradicate the immunologic stimulus (ie, HCV itself) for the vasculitis and/or glomerulonephritis.

The main sequelae of chronic HCV infection usually develop over the span of decades and include cirrhosis and hepatocellular carcinoma. Eradication of HCV prior to the development of decompensated cirrhosis results in decreased all-cause mortality, liver-related death, need for liver transplantation, hepatocellular carcinoma rates, and liver-related complications [3-13]. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Rationale for treatment'.)

Cure of HCV is associated with additional benefits in HCV-infected patients with renal disease. For patients who have renal disease related to HCV, successful antiviral therapy is also associated with an amelioration of the extrahepatic complications of HCV infection. In several studies of patients with membranoproliferative glomerulonephritis and/or mixed cryoglobulinemia, improvements in the cutaneous vasculitis, cryoglobulin titers (figure 1), proteinuria, and in the plasma creatinine concentration were observed in the majority patients who achieved HCV viral suppression on interferon-based treatment [14-28]. In one study of 14 patients, protein excretion fell among viral responders from 6.1 to 1.3 g/day, while there was a lesser, non-statistically significant reduction in protein excretion in nonresponders (6.1 versus 4.2 g/day) [17].

Cessation of interferon therapy resulted in recurrence of viremia and vasculitis in most patients in these studies [14,16,17,19,29]. This observation suggests that the efficacy of interferon is directly related to its antiviral activity [19]. In general, when patients with mixed cryoglobulinemia and HCV are treated for HCV and achieve a sustained virologic response, the mixed cryoglobulinemia and its renal manifestations usually (but not always) resolve [30]. As the treatment paradigm for HCV infection has moved away from interferon-containing regimens in all patients, including those with kidney disease and mixed cryoglobulinemia, case reports and series have emerged demonstrating the efficacy of newer direct-acting antiviral agents in the treatment of HCV and mixed cryoglobulinemia [31-34].

Patients with mixed cryoglobulinemia and glomerulonephritis deserve eventual antiviral treatment. Much less is known about the extrahepatic effects of successful antiviral treatment of HCV associated glomerulonephritides without mixed cryoglobulinemia.

PATIENT SELECTION FOR TREATMENT — The approach to deciding on antiviral treatment for patients with kidney disease is evolving. Prior to the availability of direct-acting antivirals (DAA) agents that could be safely used in patients with kidney disease, including those on dialysis, deciding to treat these patients represented a management challenge. With non-DAA-based regimens (ie, standard or pegylated interferon with or without ribavirin), the efficacy of antiviral therapy was suboptimal, and the potential toxicity of therapy was high, depending on the extent of renal impairment and the comorbid conditions. As new DAAs that can be used safely in patients with kidney disease, including those on dialysis, are being introduced, the decision to treat HCV infection is becoming less challenging. For those in whom a DAA-based regimen is appropriate, we agree with the guidelines from the AASLD and IDSA that recommend treatment for all patients with chronic HCV infection except those with short life expectancies due to comorbidities [35]. The feasibility of a DAA-based regimen and the estimation of life expectancy differs by severity of renal impairment, as below. (See 'Mild or moderate renal impairment' below and 'Severe renal impairment or dialysis' below.)

For patients with renal impairment from HCV-associated vasculitis or glomerulonephritis, another important management consideration is whether immunosuppressive therapy is also indicated. The selection of patients who should also receive immunosuppressive therapy and the suggested immunosuppressive regimens are discussed elsewhere. (See "Treatment of the mixed cryoglobulinemia syndrome", section on 'Immunosuppressive therapy for severe mixed cryoglobulinemia'.)

Patient evaluation and selection for antiviral treatment in general is discussed in detail elsewhere. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection".)

Mild or moderate renal impairment — For the vast majority of patients with mild to moderate renal impairment (ie, estimated glomerular filtration rate [eGFR] ≥30 mL/min per 1.73 m2) who have access to newer generation DAA agents, a highly effective interferon-free regimen with minimal toxicity is available. Thus, we treat such patients who otherwise do not have major limitations to life expectancy. Particular prioritization of antiviral treatment is given to patients with advanced fibrosis or cirrhosis, those with significant HCV-related kidney disease from mixed cryoglobulinemic vasculitis, and those with HCV-related glomerulonephritis. The exact regimen depends on genotype, presence or absence of cirrhosis, and prior treatment history. When ribavirin is required as part of the regimen, dose reductions should be made according to the eGFR. (See 'Regimen selection' below and "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults" and "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults" and "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults".)

Severe renal impairment or dialysis — For patients with severe renal impairment (ie, eGFR <30 mL/min per 1.73 m2) or on dialysis, decisions to provide these patients with HCV treatment should be undertaken on a case-by-case basis. We agree with the Kidney Disease Improving Global Outcomes (KDIGO) guidelines, which state that the anticipated benefits and risk of HCV therapy, life expectancy, comorbidities, and potential for kidney transplant candidacy be taken into account when making the decision to treat HCV [36].

The first step is to assess life expectancy. In many cases, individuals with renal impairment and incidental HCV infection (ie, the renal disease is not associated with HCV) have significant comorbidities, such as diabetes mellitus, hypertension, and cardiovascular disease, which have contributed to the development of or coexist with chronic kidney disease (CKD). In the setting of advanced CKD and with such competing comorbidities, it is difficult to determine whether treatment of chronic HCV infection would actually provide the patient with a survival benefit. Considerations about life expectancy for patients with advanced CKD on hemodialysis who are not kidney transplant candidates should be made individually.

In contrast, patients with HCV-related renal disease are likely to experience improvement in renal function and symptoms related to renal failure with successful treatment, and in the authors' opinion, treatment is warranted even if life expectancy may otherwise be limited due to other comorbidities.

If it is determined that the life expectancy should not preclude antiviral treatment, the next step is to assess whether prompt treatment is indicated. Although DAA-based regimens are feasible for many patients with severe renal impairment, we reserve HCV antiviral therapy to those who are most likely to benefit from it in the short term. These include patients with advanced fibrosis or cirrhosis, patients who are renal transplant candidates, those with significant HCV related kidney disease from mixed cryoglobulinemic vasculitis, and those with HCV-related glomerulonephritis. For patients with vasculitis and/or glomerulonephritis that warrant immunosuppressive therapy, another consideration is the timing of antiviral therapy. (See 'Timing of treatment' below.)

The threshold for treatment also depends on the options for treatment, which in turn depend in part on the genotype. As an example, the threshold is lower for genotypes 1 and 4 infection because of the option of elbasvir-grazoprevir, which has phase III clinical trial evidence for efficacy and safety in renal impairment. The threshold is higher for genotypes 2, 3, 5, and 6 infection, given the uncertainties about safety with sofosbuvir-containing regimens and thus the potential need for interferon-based regimens for treatment of these genotypes. (See 'Regimen selection' below.)

Decisions to treat patients with severe renal impairment and decompensated cirrhosis are more complicated, as most treatment trials of patients with decompensated cirrhosis have excluded those with eGFR <40 mL/min per 1.73 m2 [37]. These patients should be managed by an expert in the care of such patients, preferably at a transplant center. (See 'Decompensated cirrhosis' below.)

TIMING OF TREATMENT — The timing of antiviral therapy is relevant for patients who have HCV-related renal disease as well as for patients with end stage renal disease awaiting transplant.

Patients with HCV-associated renal disease — For patients with severe, acute vasculitic manifestations associated with HCV infection immunosuppressive therapy may be warranted. We initiate immunosuppressive therapy first and delay antiviral therapy for one to four months. This approach is in agreement with the European League Against Rheumatism (EULAR) and the Italian Group for the Study of Cryoglobulinemias (GISC) guidelines [38-40]. Immunosuppressive therapy is discussed in detail elsewhere. (See "Treatment of the mixed cryoglobulinemia syndrome", section on 'Immunosuppressive therapy for severe mixed cryoglobulinemia' and "Overview of renal disease associated with hepatitis C virus infection".)

Although these recommendations were formulated prior to the availability of newer direct-acting antiviral agents, there are still limited data on the efficacy and safety of these agents with concomitant use of potent immunosuppressive therapy. Thus, we continue to favor initiation of immunosuppression for severe vasculitic sequelae and/or HCV related renal disease before starting antiviral medications.

The rationale for delaying antiviral therapy by one to four months in patients who require immunosuppressive therapy is as follows:

Immunosuppressive therapy can rapidly improve inflammation and resolve target organ damage. Clinical improvements due to antiviral therapy are gradual.

High-dose immunosuppressive therapy and antiviral therapy each have side effects. Thus, patients may not be able to tolerate both treatments simultaneously. This rationale will become less important as the field moves towards interferon-free regimens for all genotypes.

Kidney transplant candidates — Patients with HCV infection who are expected to require kidney transplant and are candidates for antiviral therapy could undergo treatment prior to kidney transplantation, if feasible.

However, kidney transplantation should not be prohibited if HCV patients without advanced liver fibrosis have not yet been treated. If willing, such patients may also be able to receive a kidney from a HCV positive donor. Utilizing hepatitis C positive kidney donors could decrease wait time and decrease wait-list mortality if used more uniformly [41]. Interferon-free treatment can be undertaken post-transplant under the guidance of an experienced clinician, although some agents have drug interactions with calcineurin inhibitors. (See 'Kidney transplant' below and "Hepatitis C infection in kidney transplant candidates and recipients".)

ANTIVIRAL EFFICACY AND SAFETY — The large registration trials of agents used for the treatment of chronic HCV infection have generally excluded patients with significant renal impairment, with the exception of glecaprevir-pibrentasvir and elbasvir-grazoprevir. Much of the data on antiviral efficacy in the setting of severe renal impairment is with standard interferon, which, in the general population, is substantially less effective than regimens that are currently standard of care. Additionally, there are no data directly comparing the efficacy of antiviral therapy in patients with and without significant renal impairment. Nevertheless, the available evidence suggests that patients with renal impairment can expect a virologic response rate to a given regimen similar to that observed in the general population, as long as the regimen is tolerated.

In the United States and elsewhere, many new direct-acting antiviral regimens are currently available, and additional agents are expected. Experience with the use of these newer agents in patients with chronic kidney disease is variable and will be reviewed below. Due to the cost of these new agents and the lack of universal availability, especially in resource-limited areas, an evidence-based review of interferon-based regimens will also be covered below.

Regimens with direct-acting antivirals

Efficacy — Emerging data on the use of direct-acting antiviral (DAA) regimens among patients with eGFR <30 mL/min per 1.73 m2 suggest comparably high efficacy as seen in the general population.

The most robust data for a DAA regimen in patients with severe renal impairment are for two NS5A inhibitor and NS3/4A inhibitor combinations.

Glecaprevir-pibrentasvir – In a study (EXPEDITION-4) of 104 patients with genotypes 1 through 6 infection and eGFR <30 mL/min per 1.73 m2, 82 percent of whom were on dialysis, 98 percent achieved sustained virologic response (SVR) with glecaprevir-pibrentasvir for 12 weeks [42]. Twenty percent had compensated cirrhosis.

Elbasvir-grazoprevir – In a study (C-SURFER) that included 122 genotype 1-infected patients with eGFR <30 mL/min per 1.73 m2, three quarters of whom were on dialysis, 94 percent achieved SVR with elbasvir-grazoprevir for 12 weeks [43]. Six percent had cirrhosis. The one documented virologic failure was a genotype 1b-infected patient without cirrhosis who relapsed. Studies in patients with normal renal function have demonstrated that genotype 1a-infected patients who harbor pre-existing NS5A resistance-associated substitutions have a lower likelihood of SVR with the 12 week regimen, but that this may be overcome by extending the duration to 16 weeks and adding weight-based ribavirin. The efficacy of this extended duration with ribavirin will require further study, as initial support was based on experience with six patients. (See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults", section on 'Elbasvir-grazoprevir'.)

Data on the use of other DAA regimens are more limited. The range of findings are illustrated by the following studies, most of which have been presented in abstract form:

In an international cohort study (TARGET) of patients treated with DAA-based regimens in real-world settings, SVR rates were similar, between 80 and 90 percent, among patients across all eGFR spectrums (<30, 31 to 45, 46 to 60, and >60 mL/min per 1.73 m2) [44]. The numbers of individuals with eGFR ≤45 mL/min per 1.73 m2 was rather small, compared to the number with higher eGFR. The regimens included in this study were sofosbuvir plus simeprevir with or without ribavirin, sofosbuvir plus ribavirin, and sofosbuvir plus pegylated interferon and ribavirin.

Another study evaluated the efficacy of sofosbuvir plus simeprevir among 17 genotype 1-infected patients with eGFR <30 mL/min per 1.73 m2, of whom 15 were on dialysis and about 50 percent had cirrhosis [45]. Of the 11 patients who had completed the study, all achieved SVR.

In a study (RUBY-1) of genotype 1-infected patients with eGFR <30 mL/min per 1.73 m2, including those on dialysis and without cirrhosis, a 12-week regimen of ombitasvir-paritaprevir-ritonavir plus dasabuvir (with ribavirin added for subtype 1a infection) resulted in an SVR12 of 90 percent [46]. Ribavirin therapy was suspended in 69 percent (9 of 13) due to anemia, and four of these patients required erythropoietin stimulating agents. Only three patients restarted ribavirin thereafter.

Safety — There is a relative lack of data on the safety of DAAs in patients with moderate to severe renal insufficiency, as the majority of the initial phase III trials excluded patients with advanced kidney disease. In the absence of direct safety data, assumptions about expected safety can also made based on the mechanism of metabolism for the individual agents.

Glecaprevir-pibrentasvir – The safety of this combination regimen has been demonstrated in a fair number of patients with severe renal impairment. In a study of 104 patients with eGFR <30 mL/min per 1.73 m2, 82 percent of whom were on dialysis, glecaprevir-pibrentasvir for 12 weeks was generally well tolerated and none of the severe adverse events were considered drug related [42]. Four percent of patients discontinued the regimen because of adverse events.

Elbasvir-grazoprevir – The safety of the combination regimen of elbasvir-grazoprevir has been demonstrated in a fair number of patients with severe renal impairment. In a study of 122 patients with eGFR <30 mL/min per 1.73 m2, three quarters of whom were on dialysis, elbasvir-grazoprevir for 12 weeks was generally well tolerated and the frequency of adverse events was comparable to that in a placebo control group [43]. None of the participants who received elbasvir-grazoprevir discontinued therapy for adverse effects, although one episode of congestive heart failure was ultimately attributed to the drug.

Ombitasvir-paritaprevir-ritonavir plus dasabuvir – The agents in this regimen are metabolized primarily in the liver, with minimal elimination in the urine. A single-dose pharmacokinetics study evaluating the regimen in patients with eGFR 15-29 mL/min per 1.73 m2 demonstrated increases in area under the curve of 45, 114, 50, and 0 percent for paritaprevir, ritonavir, dasabuvir, and ombitasvir, respectively, none of which were thought to be clinically relevant [47].

Clinical data on the safety of ombitasvir-paritaprevir-ritonavir and dasabuvir in the setting of severe renal impairment are limited. One study included 20 genotype 1 HCV-infected patients with eGFR <30 mL/min per 1.73 m2 (including 13 on hemodialysis) and without cirrhosis [46]. All patients received 12 weeks of ombitasvir-paritaprevir-ritonavir plus dasabuvir, and subtype 1a-infected patients additionally received ribavirin (200 mg/day). Most adverse events were mild or moderate and there were no regimen discontinuations. However, as expected, the genotype 1a-infected patients who received ribavirin had more frequent side effects that were likely directly related to the ribavirin, including anemia, fatigue, nausea, and diarrhea, and 9 of 13 patients interrupted ribavirin during the treatment course. Only three patients restarted ribavirin thereafter, and four patients required erythropoietin-stimulating agents.

Sofosbuvir – The major elimination pathway for sofosbuvir is renal, so exposure to the drug is increased in patients with severe renal impairment. In a clinical pharmacology study of patients who were not HCV infected, levels of the drug and its metabolite among those with eGFR ≥30 mL/min per 1.73 m2 were comparable to those seen in patients with normal renal function [48]. In contrast, drug levels were substantially higher among patients with eGFR <30 mL/min per 1.73 m2 or with end-stage renal disease on hemodialysis. Clinical studies evaluating sofosbuvir dosing in patients with eGFR <30 mL/min per 1.73 m2 are underway.

Clinical data on the safety of this regimen in the setting of severe renal impairment are limited. In an international cohort study (TARGET) of patients treated with a sofosbuvir-containing regimen (including peginterferon and ribavirin-containing regimens), worsening renal function, renal and urinary adverse events, and anemia were more frequently reported among patients with eGFR ≤ 45 mL/min per 1.73 m2 [44]. In small studies of patients on hemodialysis, half-dose (200 mg) sofosbuvir plus either simeprevir or daclatasvir was well tolerated with only minor adverse events and resulted in high SVR rates (91 to 100 percent) [49,50]. Additional small series have suggested that full-dose sofosbuvir may be safe in patients with eGFR <30 mL/min per 1.73 m2, but more data are needed before this can be used routinely [51-53]. In one retrospective study, 11 percent of patients treated with a sofosbuvir-containing regimen experienced acute kidney injury (AKI), defined as ≥0.3 mg/dL or ≥50 percent increase in the baseline creatinine level [54]. However, risk factors for AKI were advanced liver disease and nonsteroidal anti-inflammatory drug (NSAID) use, so the risk of AKI with sofosbuvir remains uncertain.

In the United States, the FDA approval for this drug is for patients with eGFR >30 mL/min per 1.73 m2. European clinical practice guidelines recommend that, sofosbuvir with velpatasvir or daclatasvir can be used if there is an urgent need to treat genotype 2- or 3-infected patients with eGFR <30 mL/min per 1.73 m2 or on hemodialysis (with ribavirin 200mg/day for genotype 3); if used, kidney function should be closely monitored, as it could decline on therapy [55].

Simeprevir – Simeprevir is primarily metabolized by the liver, and renal elimination of simeprevir is negligible [56]. However, the safety of simeprevir has not been studied in patients with severe renal impairment or end-stage renal disease.

Ledipasvir and velpatasvir – The major elimination pathway for ledipasvir and velpatasvir is biliary; only a small fraction (1 percent) of the each drug is eliminated renally. However, ledipasvir and velpatasvir are each available only in a fixed-dose combination with sofosbuvir. Ledipasvir-sofosbuvir and sofosbuvir-velpatasvir have not been well studied in patients with eGFR <30 mL/min per 1.73 m2.

Daclatasvir – Daclatasvir is primarily metabolized by the liver and renal elimination is minor. A pharmacologic analysis did not identify clinically important increases in daclatasvir levels among patients with eGFR ≤30 mL/min per 1.73 m2 or on dialysis [57]. However, daclatasvir is usually given in combination with sofosbuvir, and this combination has not been well studied in patients with eGFR <30 mL/min per 1.73 m2. In locations where daclatasvir plus asunaprevir is an available regimen, preliminary evidence suggests that this regimen is safe in patients undergoing hemodialysis [58].

Preliminary experience with the use of first generation protease inhibitors (eg, telaprevir and boceprevir) in a small number of patients with renal impairment had raised some concern over the possible contribution of these agents to renal insufficiency given a report about the development of eGFR <60 mL/min per 1.73 m2 in about 5 percent of patients who received telaprevir or boceprevir-containing regimens [59]. Regardless, general use telaprevir and boceprevir will be exceedingly rare in favor of newer direct-acting antivirals that are associated with less toxicity.

Peginterferon alfa with ribavirin

Efficacy — The dual combination of peginterferon and ribavirin was previously the standard treatment of chronic HCV but has been replaced by regimens that also contain a direct-acting antiviral and by interferon-free and ribavirin–free regimens. Interferon-free regimens are now the standard of care for all HCV genotypes for the general population, but the cost can be prohibitive, particularly in resource-limited settings. Therefore, peginterferon and ribavirin may be the only option for treatment of patients with HCV infection in some parts of the world until drug prices decline and access improves. Interferon monotherapy (whether with standard interferon or peginterferon) is not recommended for the treatment of chronic HCV infection.

In studies of patients with HCV-associated renal disease or on dialysis, SVR rates are generally low (<50 percent) with varying doses of standard interferon [17,18,60-62] or peginterferon [63-66]. The combination of peginterferon and ribavirin appears to have greater antiviral efficacy than peginterferon alone among hemodialysis patients [65-67]. One open-label randomized trial compared peginterferon-alpha 2a (135 mcg weekly) with similarly dosed peginterferon–alpha 2a plus ribavirin 200 mg daily among 205 treatment-naïve Asian hemodialysis patients with HCV genotype 1 [65]. After 48 weeks of treatment and 24 weeks of additional follow-up, combination therapy resulted in a greater SVR rate (64 versus 33 percent with monotherapy). The proportion of patients who had hemoglobin values <8.5 g/dL was significantly higher in the dual therapy group (72 versus 6 percent in the peginterferon monotherapy arm). Similarly, in another cohort of 26 Asian patients treated with peginterferon alfa-2b 1.0 mcg/kg/week and ribavirin 200 mg three times weekly, the SVR rate was 62 percent, in contrast to 27 percent in a cohort that received only peginterferon [66]. The severe anemia rates, defined as a hemoglobin <8 g/dL, were significantly higher in the dual therapy group (58 versus 27 percent).

Whether these efficacy results can be generalized to non-Asian patients is not clear, as Asian individuals are more likely to respond to interferon-based treatment. Additionally, confidence in these data may be undermined by the open-label design of the trial and the observational nature of the cohort study.

Combination peginterferon and ribavirin has also been evaluated in patients with mixed cryoglobulinemia [68,69]. As an example, a retrospective study compared the outcomes of 32 patients treated with standard interferon (3 million international units three times a week) plus ribavirin with 40 patients treated with peginterferon alfa-2b (1.5 mcg/kg per week) plus ribavirin [68]. Six months after completion of antiviral therapy, treatment with peginterferon and ribavirin was associated with higher rates of SVR (62 versus 53 percent), clinical remission from cryoglobulinemia (68 versus 56 percent), and disappearance of circulating cryoglobulins (58 versus 31 percent). Notably, underlying severe manifestations were more common in the group receiving standard interferon (27 of 32) as compared with peginterferon (15 of 40); severe manifestations were treated with glucocorticoids, cyclophosphamide, and/or plasma exchange.

Safety of peginterferon — Compared with nonuremic patients, patients on hemodialysis demonstrate one-half the clearance, significantly longer half-lives, and markedly larger areas under the concentration curve for interferon [70]. This may contribute to the high rate of serious adverse events reported with daily or high-dose administration of standard interferon among hemodialysis patients [71]. Even with lower doses, associated side effects of interferon may be especially difficult for patients with severe renal impairment to tolerate. Clinical data on the safety of peginterferon in hemodialysis patients (ie, the group deemed most likely to have reduced clearance of the drug) have been mixed, although most have not demonstrated a worrisome excess of adverse effects [63,65,66,72,73]. However, in one trial of 85 patients treated with peginterferon, three deaths were considered possibly related to the peginterferon; these were due to hemorrhagic stroke, pre-existing hypertrophic cardiomyopathy, and complications of pneumonia, sepsis, and multi-organ failure [64].

Among patients with renal disease associated with chronic HCV infection, additional adverse effects of particular concern include induction or exacerbation of glomerulonephritis or vasculitis [74,75]. Of note, in studies of patients treated with standard interferon who subsequently received renal transplantation, there was no associated risk of allograft rejection [76-82].

Safety of ribavirin — The main adverse effect of ribavirin is hemolytic anemia. Ribavirin plasma concentration predicts ribavirin-induced anemia [83]. Elimination of ribavirin is predominately via the kidney and very little ribavirin is removed with hemodialysis. Thus, among patients with renal insufficiency, ribavirin accumulates and can cause severe anemia [84]. Even at lower doses, ribavirin may result in catastrophic anemia in patients with renal impairment.

Ribavirin should therefore be used with caution and dose reduction in patients with mild renal insufficiency [85-87].

The use of ribavirin in moderate to severe renal insufficiency is more controversial. The manufacturer of one brand of ribavirin (Rebetol) has issued warnings for patients with renal dysfunction and contraindicated its use with creatinine clearance <50 mL/min [88,89]. However, a different brand of ribavirin (Copegus) is approved in the United States for patients with end stage renal disease and for those on hemodialysis [90].

We have used ribavirin in patients with moderate to severe renal impairment, including those on hemodialysis, with low starting doses, closer monitoring of the hemoglobin level, aggressive ribavirin dose reductions for anemia, and adjunctive use of erythropoietic growth factors.

This practice is supported by several studies that have reported overall safe use of ribavirin despite anemia in patients with moderate to severe renal insufficiency when such measures are taken [23,91,92]. As an example, in a randomized trial of peginterferon with ribavirin (200 mg daily) versus peginterferon alone in 205 Asian HCV-infected patients on hemodialysis, patients receiving peginterferon and ribavirin were more likely to have significant anemia (defined as hemoglobin <8.5 g/dL) that warranted reduction of ribavirin dose (72 versus 6 percent) and used a higher mean erythropoietin dose (13,946 versus 6449 international units) compared with those who received only peginterferon [65]. Eleven patients who received combination therapy had nadir hemoglobin concentrations <7.5 g/dL, although only one patient in each group required transfusion. The difference in adverse-events related withdrawal rates (seven percent for combination therapy versus four percent for monotherapy) was not statistically significant.

REGIMEN SELECTION — The selection of the antiviral regimen among patients with renal disease depends upon the extent of renal impairment as well as the genotype. In addition, the extent of underlying liver disease as well as any past antiviral treatment history also affects regimen choice. A multidisciplinary approach, with a nephrologist and a hepatologist who have experience treating these complex issues, may improve care for patients with HCV and renal impairment. If HCV-associated cryoglobulinemic vasculitis (such as mixed cryoglobulinemia) is present, the care team may also include a rheumatologist.

Although there is an overall paucity of data on anti-HCV therapy in patients with renal disease, there is growing evidence on the use of various regimens in such patients. An understanding of the pharmacology of the different agents in this populations, as well as data from patients without renal disease, all support the following suggestions for regimen selection, according to estimated glomerular filtration rate (eGFR).

The approach for dosing in the setting of kidney disease below is generally consistent with the AASLD/IDSA joint guidelines on the treatment of HCV, but differs slightly from other published guidelines (see 'Recommendations of others' below), and is based upon personal experience and more recent data from the literature. (See 'Regimens with direct-acting antivirals' above and 'Peginterferon alfa with ribavirin' above.)

The eGFR can be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [93]. This equation is discussed in detail separately. (See "Assessment of kidney function", section on 'CKD-EPI equation'.)

eGFR >50 mL/min per 1.73 m2 — Regimen selection is the same as that for patients without renal impairment. No dose adjustments are warranted. (See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults" and "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults" and "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults".)

eGFR 30 to 50 mL/min per 1.73 m2 — Regimen selection is the same as that for patients without renal impairment. (See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults" and "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults" and "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults".)

Most HCV antiviral agents do not require dose reductions. However, dose adjustments are warranted for peginterferon alfa-2b and ribavirin if they are used:

Peginterferon alfa-2b should be given at a dose of 1mcg/kg/week.

Ribavirin is given orally at alternating doses of 200 and 400 mg every other day.

eGFR <30 mL/min per 1.73 m2 or on dialysis — Data on the safety direct-acting antivirals (DAAs) in the setting of severe renal impairment or dialysis (hemodialysis or peritoneal dialysis) are evolving. Given the significant potential for adverse effects with the combination of peginterferon and ribavirin, we favor utilizing an interferon-free, combination DAA-based regimen in these patients. For all patients with severe renal impairment, we prefer the pangenotypic DAA regimen of glecaprevir-pibrentasvir. It has documented efficacy and safety in this population and, unlike some of the alternatives, can be used for all genotypes without the need for NS5A gene testing or ribavirin.

The duration of glecaprevir-pibrentasvir for patients with renal impairment is the same for those with normal renal function and depends on the presence of cirrhosis and treatment history.

For treatment-naïve patients of any genotype, it is given for 8 weeks for those without cirrhosis and 12 weeks for those with compensated cirrhosis.

For patients with genotypes 1, 2, 4, 5, or 6 infection who have failed prior treatment with peginterferon and/or ribavirin with or without sofosbuvir, it is given for 8 weeks for those without cirrhosis and 12 weeks for those with compensated cirrhosis.

For patients with genotype 3 infection who have failed prior treatment with peginterferon and/or ribavirin with or without sofosbuvir, it is given for 16 weeks, regardless of fibrosis stage.

For patients with genotype 1 infection who have failed prior treatment with a protease inhibitor (but have no NS5A inhibitor exposure), it is given for 12 weeks, regardless of fibrosis stage.

For patients with genotype 1 infection who have failed prior treatment with an NS5A inhibitor (but have no protease inhibitor exposure), it is given for 16 weeks, regardless of fibrosis stage.

Glecaprevir-pibrentasvir is contraindicated in patients with decompensated cirrhosis (Child Pugh class B or C).

If glecaprevir-pibrentasvir is not an option, the alternatives are more limited than in the general population. For patients without renal impairment, many commonly used DAA regimens include sofosbuvir. However, given that sofosbuvir is primarily metabolized renally and that the data on its safety in patients with eGFR <30 mL/min per 1.73 m2 are sparse, this regimen cannot be routinely recommended for patients with severe renal impairment. Administration of a sofosbuvir-containing regimen to a patient with severe renal impairment should only be done in consultation with an expert on HCV management [94].

The non-sofosbuvir-containing alternatives to glecaprevir-pibrentasvir for such patients depends on genotype:

Genotype 1a alternative regimens:

Elbasvir-grazoprevir – Patients with subtype 1a infection should undergo testing for NS5A resistance associated substitutions (RASs) prior to receiving elbasvir-grazoprevir. This regimen is given for 12 weeks to those without RASs. It is given for 16 weeks with ribavirin (if the baseline hemoglobin ≥10g/dL) to those with RASs.

For patients who have failed prior telaprevir- or boceprevir-containing regimens, the manufacturer recommends giving the regimen for 12 weeks with ribavirin without testing for RASs. (See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults", section on 'Prior protease inhibitor failures'.)

Ombitasvir-paritaprevir-ritonavir plus dasabuvir – This regimen is given with ribavirin (if the baseline hemoglobin ≥10g/dL) for 12 weeks to patients without cirrhosis and for 24 weeks to patients with cirrhosis.

Both regimens have a number of drug interactions to consider prior to administration. Additionally, both are contraindicated in the setting of Child Pugh class B and C cirrhosis. For those situations in which ribavirin is warranted, the starting ribavirin dose should be 200 mg thrice weekly with close monitoring of the hemoglobin and hematocrit and implementation of erythropoietin therapy.

Genotype 1b alternative regimens:

Elbasvir-grazoprevir – This regimen is given for 12 weeks for genotype 1b. For patients who had failed prior telaprevir- or boceprevir-containing regimens, it is given with ribavirin (if the baseline hemoglobin ≥10g/dL) for 12 weeks.

Ombitasvir-paritaprevir-ritonavir plus dasabuvir – This regimen is given for 12 weeks for genotype 1b.

Both regimens have a number of drug interactions to consider prior to administration. Additionally, both are contraindicated in the setting of Child Pugh class B and C cirrhosis. For those situations in which ribavirin is warranted, the starting ribavirin dose should be 200 mg thrice weekly with close monitoring of the hemoglobin and hematocrit and implementation of erythropoietin therapy.

Genotype 2 and 3 alternative regimen: If glecaprevir-pibrentasvir or an expert willing to prescribe sofosbuvir are not available, renal transplant is not an option, and there is sound rationale for treatment, dose adjusted pegylated interferon with ribavirin for 24 weeks can be used with caution for genotypes 2 and 3 [94]. However, we only use this regimen if there are no other options.

Peginterferon with or without ribavirin can be safe for patients with severe renal impairment when the patient can be closely monitored and adjunctive therapies are utilized to aggressively manage side effects (in particular, erythropoietin for anemia).

Nevertheless, among patients with eGFR <15 mL/min per 1.73 m2 or on dialysis, the benefit of peginterferon over standard interferon, with or without ribavirin, has not been explicitly studied, and so regimen selection remains controversial for them.

Dose adjustments for both peginterferon and ribavirin are warranted:

For patients with eGFR 15 to 29 mL/min per 1.73 m2:

-Peginterferon alfa 2a is given subcutaneously at a dose of 135 mcg per week.

-Peginterferon alfa 2b is given subcutaneously at a dose of 1 mcg/kg per week.

-Ribavirin is given orally at a dose of 200 mg per day.

For patients with eGFR <15 mL/min per 1.73 m2 or on dialysis:

-Peginterferon alfa 2a is given subcutaneously at a dose of 135 mcg per week.

-Peginterferon alfa 2b is given subcutaneously at a dose of 1 mcg/kg per week.

-Ribavirin is given ribavirin orally at 200 mg weekly with an increase as tolerated to a maximum of every other day. Alternatively, ribavirin can be initiated every other day with close monitoring (eg, weekly hemoglobin levels) and dose adjustments as needed. We generally do not exceed 200 mg every other day.

For patients who have significant baseline anemia, we attempt to correct that prior to initiation of therapy. Because the use of ribavirin can result in catastrophic anemia in patients with renal impairment, it should only be undertaken with extreme caution.

For patients with eGFR <15 mL/min per 1.73 m2 or on dialysis, standard interferon alfa (2a or 2b, 3 million units three times weekly) or weekly peginterferon without ribavirin are alternatives.

Genotype 4 alternative regimens:

Elbasvir-grazoprevir – This regimen is given for 12 weeks for genotype 4-infected patients who are treatment naïve. It is given for 16 weeks with ribavirin (if the baseline hemoglobin ≥10g/dL) to those who have failed prior treatment with peginterferon and ribavirin.

Ombitasvir-paritaprevir-ritonavir – This regimen is given with ribavirin (if the baseline hemoglobin ≥10g/dL) for 12 weeks to patients with or without cirrhosis.

Both regimens have a number of drug interactions to consider prior to administration. Additionally, both are contraindicated in the setting of Child Pugh class B and C cirrhosis. For those situations in which ribavirin is warranted, the starting ribavirin dose should be 200 mg thrice weekly with close monitoring of the hemoglobin and hematocrit and implementation of erythropoietin therapy.

MONITORING OF PATIENTS ON ANTIVIRAL THERAPY — The frequency of monitoring patients on antiviral treatment is dependent upon multiple variables including, but not limited to:

The treatment regimen for HCV

The extent of renal impairment

The presence of HCV-associated renal disease (such as cryoglobulinemia) and its severity

The individual patient and his/her additional comorbidities

Presence of cirrhosis with or without portal hypertension

The tolerance to therapy

Monitoring needs by treatment regimen are discussed in detail elsewhere:

(See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults", section on 'Monitoring during treatment'.)

(See "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults", section on 'Administration of treatment regimens'.)

(See "Management of the side effects of peginterferon and ribavirin used for treatment of chronic hepatitis C virus infection", section on 'Monitoring for side effects'.)

Of note, for patients on hemodialysis receiving pegylated interferon and/or ribavirin, we check a weekly complete blood count throughout the course of therapy because of the greater risk of anemia in such patients.

For patients who have mixed cryoglobulinemia, certain unique aspects of monitoring should be taken into account:

HCV viral particles may be incorporated into the cryoprecipitate and centrifuged during preparation of serum samples or may precipitate from the serum during storage. To prevent falsely low measurements of the viral load, blood specimens may require special handling. To ensure accurate quantitation of the HCV viral load, specimens should be kept at 37 degrees centigrade during serum preparation, and any cryoprecipitate should be dissolved or suspended into the serum before measuring the viral load.

Flares of cryoglobulinemia or other immune-mediated events can rarely be induced by treatment with interferon [95-99]. If an exacerbation of vasculitis occurs in a patient whose disease was previously stable or improving and who does not have serologic evidence of worsening disease (eg, decreasing serum complement), consideration should be given to temporarily lowering the dose of interferon or, if manifestations are severe, temporarily discontinuing therapy.

Similarly, interferon can produce side effects that may mimic some of the manifestations of cryoglobulinemia, such as arthralgias, fever, or rash. In such cases, antiviral therapy may be temporarily discontinued provided a direct-acting antiviral is not part of the regimen. (See "Management of the side effects of peginterferon and ribavirin used for treatment of chronic hepatitis C virus infection".)

RECOMMENDATIONS OF OTHERS — Several guidelines are available that discuss management of chronic HCV infection in patients with kidney disease.

In 2014, guidelines for the diagnosis and management of HCV infection were released jointly by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) [94]. These are continuously updated and can be accessed at www.hcvguidelines.org [94]. These guidelines are the same as those outlined in the regimen selection section.

The Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines for hepatitis C in chronic kidney disease were published in 2008, and updated guidelines are set to be published in 2017 [100,101]. Of note, the 2008 guidelines predate the availability of direct-acting antiviral agents, which are now included in first-line regimens for patients without renal impairment and which may be appropriate for patients with variable degrees of renal insufficiency.

The guidelines suggest adjustments for antiviral regimens that contain interferon or ribavirin, depending upon the estimated glomerular filtration rate (eGFR):

For eGFR >50 mL/min per 1.73 m2, peginterferon and ribavirin

For eGFR 15 to <50 mL/min per 1.73 m2, monotherapy with peginterferon

For eGFR less than 15 mL/min per 1.73 m2 (including patients on hemodialysis); monotherapy with standard interferon that is dose adjusted for a glomerular filtration rate less than 15 mL/min per 1.73 m2

Links to these and other guidelines are found below. (See 'Society guideline links' below.)

SPECIFIC CONSIDERATIONS

Kidney transplant — In general, interferon-based antiviral therapy for HCV infection is contraindicated for patients who have undergone kidney transplantation. The use of interferon is associated with an increased risk of acute rejection of the allograft [36]. An interferon-free regimen is thus preferred in this setting. Any antiviral treatment for HCV infection in renal transplant recipients should only be undertaken by clinicians with experience in caring for such patients. We advise use of the same interferon-free regimens outlined for non-kidney transplant recipients (see 'Regimen selection' above). In most cases, a broader array of HCV treatment options will be available post-kidney transplantation, when the renal function is expected to be better (ie, estimated glomerular filtration rate [eGFR] >30 mL/min per 1.73 m2). While efficacy and safety data are undefined in this population, we believe that data from the post-liver transplant population, among whom three large studies did demonstrate efficacy and safety, are generalizable to post-kidney transplant patients [37,102,103]. Clinical trials are underway for this particular patient group [104], and a randomized open-label trial of 114 kidney transplant recipients demonstrated excellent efficacy (100 percent sustained virologic response [SVR]) and safety of ledipasvir-sofosbuvir [105]. (See "Hepatitis C infection in kidney transplant candidates and recipients".)

Decompensated cirrhosis — Patients with cirrhosis who develop hepatorenal syndrome (I or II) are not candidates for HCV antiviral therapy, and it is not recommended at this time. Patients with either form of hepatorenal syndrome generally have advanced liver disease with portal hypertensive complications and a poor prognosis. While data from trials (SOLAR-1,SOLAR-2, and ASTRAL-4) support the efficacy and safety of ledipasvir-sofosbuvir and velpatasvir-sofosbuvir in patients with child B and C cirrhosis, these trials excluded patients with creatinine clearance <40 mL/min per 1.73 m2 [102,106,107]. Patients who are transplant candidates should have their HCV infection treated post-liver transplantation.

The hepatorenal syndrome is discussed in detail elsewhere. (See "Hepatorenal syndrome".)

Liver transplant — Liver transplant recipients are at risk for declining renal function over time. In the largest study on this topic, 18 percent of liver transplant recipients had renal dysfunction (eGFR <30 mL/min per 1.73 m2) five years after transplantation. Risk factors for post-liver transplant renal disease include pre-transplant renal dysfunction, perioperative renal failure, early allograft dysfunction, infections, and most importantly, calcineurin inhibitors. The management of renal disease in such patients is discussed elsewhere. (See "Liver transplantation in adults: Long-term management of transplant recipients", section on 'Acute and chronic renal disease'.)

Post-liver transplant antiviral treatment should be performed by experienced providers at a transplant center. We agree with the joint guidelines from the American Association for the Study of Liver Disease (AASLD) and the Infectious Diseases Society of America (IDSA) that recommend a direct-acting antiviral-based regimen for liver transplant recipients [94]. The specific regimens depend on HCV genotype and are discussed elsewhere. (See "Recurrence of hepatitis C virus infection following liver transplantation".)

However, dose or regimen modifications are warranted in liver transplant recipients who also have renal impairment.

Those who have eGFR between 30 and 50 mL/min per 1.73 m2 can be treated with the same regimens recommended for the general liver transplant population, although if ribavirin is used, the daily dose should be 200 mg alternating with 400 mg.

For those liver transplant recipients with eGFR <30 mL/min per 1.73 m2, direct data on the safety and efficacy of direct-acting antivirals are not yet available. However, based on indirect data, we prefer glecaprevir-pibrentasvir for this population. In a study of 100 liver or kidney transplant recipients (80 of whom were liver recipients) without cirrhosis, glecaprevir-pibrentasvir for 12 weeks resulted in an SVR rate of 98 percent without serious adverse events leading to drug discontinuation [108]. Although patients with severe renal impairment were not included in this study, the safety of glecaprevir-pibrentasvir in the setting of renal impairment is well documented. (See 'Safety' above.)

Elbasvir-grazoprevir would also be an option for treatment of genotypes 1 or 4 recurrent hepatitis C infection in liver transplant recipients with eGFR <30 mL/min per 1.73 m2. Drug-drug interactions are especially important after liver transplantation. Neither elbasvir-grazoprevir nor glecaprevir-pibrentasvir should be initiated in decompensated allograft cirrhosis.

The alternative, peginterferon with ribavirin, has substantial drawbacks in this population. Pegylated interferon is associated with immune mediated graft dysfunction in up to 7 percent of those treated, eradication rates are very low at approximately 25 percent, and treatment is often poorly tolerated [109]. (See 'Regimen selection' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hepatitis C virus infection".)

SUMMARY AND RECOMMENDATIONS

The main reason for antiviral treatment in patients with chronic HCV infection is to prevent liver-associated morbidity and mortality. For patients with renal impairment, additional reasons are to prevent HCV-associated kidney transplant complications in those who are transplant candidates and to eradicate an immunologic stimulus in those who have HCV-related vasculitis or glomerulonephritis. (See 'Rationale for antiviral treatment' above.)

The decision to treat HCV in patients with renal impairment should be made on a case by case basis. Multiple host factors contribute to this decision, including extent of renal impairment, the extent of liver disease, and the presence of comorbidities that affect the potential toxicity of antiviral therapy. (See 'Patient selection for treatment' above.)

For patients with severe, acute vasculitic manifestations associated with HCV infection, we initiate immunosuppressive therapy first and delay antiviral therapy for one to four months. For patients who are expected to require kidney transplant and are candidates for antiviral therapy, we initiate antiviral therapy so that it is completed prior to kidney transplantation if possible. However, kidney transplantation should not be prohibited in untreated HCV-infected patients without advanced fibrosis, as patients can receive effective interferon-free HCV treatment post transplantation. (See 'Timing of treatment' above.)

Much of the data on antiviral efficacy in the setting of severe renal impairment is with standard interferon, which is substantially less effective than regimens that are currently standard of care for the general HCV-infected population, with sustained virologic response (SVR) rates less than 50 percent. It is unclear if peginterferon provides additional efficacy over standard interferon in the setting of severe renal impairment, but the combination of peginterferon and ribavirin is more effective than peginterferon alone. Limited data on the use of direct-acting antiviral (DAA) regimens among patients with severe renal impairment suggest comparably high efficacy as seen in the general population. (See 'Antiviral efficacy and safety' above.)

Among patients with renal insufficiency, ribavirin accumulates and can cause severe anemia. Ribavirin should therefore be used with caution and dose reduction in patients with mild renal insufficiency. The use of ribavirin in patients with moderate to severe renal impairment is controversial. We use it in such patients only with a low starting dose, close monitoring of the hemoglobin level, aggressive dose reductions for anemia, and adjunctive use of erythropoietic growth factors. (See 'Safety of ribavirin' above.)

Clinical data are limited on the safety of most DAA agents in the setting of severe renal impairment. Most agents are metabolized hepatically. The main concern is with sofosbuvir, which is renally eliminated. (See 'Regimens with direct-acting antivirals' above.)

The selection of the antiviral regimen among patients with renal disease depends upon the extent of renal impairment in addition to the genotype, extent of underlying liver disease, and history of past antiviral treatment. Despite the limited data on DAA-based regimens in severe renal insufficiency, we favor these over interferon-based regimens. (See 'Regimen selection' above.)

For patients with estimated glomerular filtration rate (eGFR) greater than 30 mL/min per 1.73 m2, regimen selection is the same as that for patients without renal impairment. Dose adjustments are warranted with certain agents for eGFR between 30 and 50 mL/min. Specific regimens differ by genotype. (See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults" and "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults" and "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults".)

For patients with eGFR <30 mL/min per 1.73 m2 or on dialysis treatment options are more limited (see 'Regimen selection' above):

-For interferon-free treatment of patients with genotype 1 or 4 infection, we suggest glecaprevir-pibrentasvir (Grade 2B). The duration depends on the treatment history and presence of cirrhosis. Alternatives include elbasvir-grazoprevir with or without ribavirin for genotype 1 or 4 infection and ombitasvir-paritaprevir-ritonavir plus dasabuvir with or without ribavirin for genotype 1 infection or ombitasvir-paritaprevir-ritonavir with ribavirin for genotype 4 infection.

-For interferon-free treatment of patients with genotype 2 or 3 infection, we recommend glecaprevir-pibrentasvir (Grade 1B). The duration depends on the treatment history and presence of cirrhosis. Sofosbuvir has not been well studied in patients with eGFR <30 mL/min per 1.73 m2 and should only be used in consultation with an expert in the treatment of such patients.

Monitoring parameters depend on the treatment regimen. For patients on hemodialysis who receive antiviral therapy that includes interferon or ribavirin, we additionally check a weekly complete blood count during treatment because of the greater risk of anemia. (See 'Monitoring of patients on antiviral therapy' above.)

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