• Elbasvir and Grazoprevir

The combination elbasvir (a NS5A inhibitor) and grazoprevir (a NS3/4 protease inhibitor) is currently 1 of the 2 recommended regimens for patients with CKD stage 4 or 5. The recommended dosage is a daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) and treats patients with HCV genotype 1a, 1b, and 4 infections.

A landmark study highlights the potential of this regimen in patients on dialysis. The C-SURFER (Hepatitis C: Study to Understand Renal Failure’s Effect on Responses) study was a phase 3, randomized study involving 224 patients with CKD stage 4 or 5 with or without dialysis dependence and with HCV genotype 1 infection.23 Seventy-six percent of patients were dialysis-dependent, 81% had CKD stage 5 at baseline, and 80% were naive to treatment. Patients were randomly assigned to receive elbasvir 50 mg and grazoprevir 100 mg (immediate treatment group) or placebo (deferred treatment group) once daily for 12 weeks. The deferred treatment group was used as an internal control for potential safety signals in the immediate treatment group and started active treatment at week 16. The primary outcome was a SVR at 12 weeks, which was achieved by 94% of patients in the intention-to-treat analysis. In the modified full analysis (in which 6 patients were excluded due to reasons other than virologic failure), the SVR rate at 12 weeks was 99% . The most common adverse events were headache, nausea, and fatigue. Elevated lipase was the only drug-related adverse event reported. There was no consistent change in mean eGFR or creatinine.

Another retrospective study further demonstrated that the combination elbasvir/grazoprevir does not worsen kidney function in patients with preexisting renal disease and HCV infection.24 Patients with CKD stage 3 at baseline who were enrolled in elbasvir/grazoprevir phase 2/3 clinical trials with chronic HCV infection with or without ribavirin were included in the study (N=32). Thirty-one patients (97%) achieved SVR at 12 weeks. There was no decline in median eGFR at the end of treatment or at 12 weeks follow-up. In fact, many patients had an improvement in their CKD stage. All 32 patients had a glomerular filtration rate (GFR) of less than 60 mL/min at baseline; however, at the end of treatment, 12 patients had a GFR of at least 60 mL/min. Of note, this improvement was consistent regardless of the presence of cirrhosis, treatment with ribavirin, or HIV coinfection.

• Glecaprevir and Pibrentasvir

The combination glecaprevir (a NS3/4 protease inhibitor) and pibrentasvir (a NS5A inhibitor) has activity against all 6 major HCV genotypes with a recommended fixed daily dose of 300 mg and 120 mg, respectively. In the EXPEDITION-4 (Efficacy and Safety of ABT-493/ABT-530 in Renally Impaired Adults With Chronic Hepatitis C Virus Genotype 1-6 Infection) phase 3 trial, Gane and colleagues assessed the efficacy and safety of the combination regimen in patients with severe renal impairment (stage 4 or 5).25 One hundred and four patients who had chronic HCV genotypes 1 through 6 infections were enrolled and received the combination antiviral therapy for 12 weeks. Fifty-eight percent of patients had no prior treatment history, 81% had compensated cirrhosis, and 82% were on dialysis. The SVR rate at 12 weeks was 98% (102/104; Figure 1). The most common adverse events were pruritus, fatigue, and nausea, and the rates of adverse events between patients on dialysis vs patients not undergoing dialysis were similar (72% vs 68%, respectively). Four patients discontinued treatment due to adverse events; none of the serious adverse events were considered to be drug-related. Of note, 3 of the 4 patients who discontinued the treatment achieved SVR at 12 weeks. Pre- and postdialysis drug levels were similar for both drugs, with only a 3% to 6% difference.

• Ledipasvir and Sofosbuvir

The combination ledipasvir (90 mg) and sofosbuvir (400 mg) is approved for the treatment of HCV genotype 1 or 4 infection in kidney transplant patients. Colombo and colleagues performed a phase 2, open-label study in which 114 patients were given this regimen; 91% of patients had genotype 1 infection, 69% were treatment-naive, 15% had compensated cirrhosis, and the median GFR was 56 mL/min.32 Overall, 100% of patients achieved SVR at 12 weeks. Of note, only 4 patients had a decrease in GFR to less than 30 mL/min during therapy. In 3 of these patients, the GFR increased to more than 30 mL/min at the last visit recorded.

• Glecaprevir and Pibrentasvir

The combination glecaprevir (300 mg) and pibrentasvir (120 mg) is approved for the treatment of HCV genotypes 1 through 6 infections in kidney transplant patients. Reau and colleagues performed a phase 3, open-label, multicenter study in which patients without cirrhosis were treated for at least 3 months after either liver (80%) or kidney (20%) transplant.33 The median GFR was 62.3 mL/min. In total, 100 patients were enrolled and treated with glecaprevir/pibrentasvir for 12 weeks. Of the available data, 89 of 90 patients achieved SVR at 12 weeks; 1 patient experienced virologic failure. Another patient had mild liver transplant rejection but continued with treatment and achieved SVR at 12 weeks.

• Sofosbuvir and Daclatasvir Plus Ribavirin

The combination sofosbuvir (400 mg) and daclatasvir (60 mg) plus a low initial dose of ribavirin (600 mg) has also been approved for kidney transplant patients. In the HCV-TARGET (Hepatitis C Therapeutic Registry and Research Network) study, 443 posttransplant recipients (60 kidney transplant patients, 347 liver transplant patients, and 36 dual liver-kidney transplant patients) were treated with several different regimens, including ledipasvir/sofosbuvir with or without ribavirin (85%), sofosbuvir/daclatasvir with or without ribavirin (9%), and ombitasvir/paritaprevir/ritonavir plus dasabuvir with or without ribavirin (Viekira Pak, AbbVie; 6%).34 Overall, 42% of patients had cirrhosis, and 54% were treatment-experienced, including 28 patients (6%) with prior exposure to the first-generation protease inhibitors telaprevir and boceprevir. The SVR rates at 12 weeks were 96% for liver transplant recipients, 94% for kidney transplant recipients, and 90% for dual transplant recipients. There were 6 episodes of acute rejection. Of note, ribavirin did not affect SVR rates.

Summary

HCV infection in patients with CKD is an important risk factor for morbidity and mortality. Advancements have been made in the treatment of this high-risk patient population with the approval of DAA agents in the treatment of chronic HCV infection. Elbasvir/grazoprevir and glecaprevir/pibrentasvir are the 2 recommended drug regimens for severe renal impairment and have SVR rates greater than 90%, which drastically change the opportunities for HCV eradication in this treatment population. For patients who are candidates for kidney transplantation, treatment after the procedure may be clinically reasonable; there are several regimens approved for such use. By increasing the number of patients treated for chronic HCV infection in both the dialysis and kidney transplant populations, a significant impact in global HCV eradication may be made