In the era of interferon treatment, treatment of HCV infection in patients on hemodialysis is hampered by poor tolerability and low SVR rates. Recently, new paradigms shift of HCV treatment from pegylated interferon-based therapy to DAAs showed high SVR rates, less toxicity, and good tolerability. DAAs have been used successfully in difficult-to-treat HCV patients including those with treatment failure, decompensated cirrhosis, and post-transplantation. We report that DCV and ASV combination therapy is efficacious and safe in patients with genotype 1b HCV infection on hemodialysis.
In this study, 21 patients with HCV genotype 1b infection on hemodialysis received 24 weeks of DCV and ASV. The SVR12 rate was 76.1% with follow-up loss after EOT (n=1), discontinuation due to AEs unrelated to study medications (n=3), and virologic breakthrough (n=1). Indeterminate NS5A polymorphisms at baseline might have played a role in the virologic breakthrough. However, all patients who followed up at 12 weeks after EOT achieved 100% SVR12. Therefore, DCV and ASV combination therapy may be effective in the treatment of genotype 1b infected HCV patients on hemodialysis
The SVR12 rates in this study are not consistent with those reported in genotype 1b HCV patients with normal renal function.12,21 In real-life clinical practice of Korea, the SVR12 rate is 89.5% in all patients and 91.5% in those without baseline NS5A resistance-associated variants (NS5A RAVs) mutations.12 In Japan, the SVR12 rate of patients with HCV genotype 1b and ESRD is reportedly 95.5% to 100%.22,23 This inconsistency of our study can explain as following: First, it is important to clarify and identify the baseline NS5A polymorphism before treating DAAs. Second, it is also an issue to monitor and manage the tolerability and safety in difficult-to-treat patients.
Some naturally occurring HCV polymorphisms that reduce DAA activity in vitro may affect the SVR12 rate, depending on the antiviral drugs used.24 The prevalence of NS5A RAVs in the HCV genotype 1b-infected Korean patients is 10% to 13%.12,21 The presence of baseline NS5A polymorphisms, including L31F/ I/M/V and Y93H, reduced the SVR12 rate in HCV genotype 1b-infected patients treated with DCV and ASV to 35%–40%, compared to 95% in those without such polymorphisms.21 The sole patient who showed treatment failure in our study, this patient was a 62-year-old man without cirrhosis, and indeterminant NS5A mutation status at baseline despite repeated testing. He showed a partial virological response at week 4 (HCV RNA 5,350 IU/mL compared to 143,000 IU/mL at baseline). However, his serum HCV RNA level at week 12 showed a virological breakthrough (a confirmed increase in the HCV RNA more than 1log10 (42,300 IU/mL) from the nadir), although the combination therapy has continued. Therefore, NS5A RAVs should be identified at baseline, and other DAA regimens may be more suitable for patients with indeterminate RAVs.
Tolerability is also an important issue in difficult-to-treat patients. The patients who discontinued the study medication experienced AEs including dizziness, dyspnea, and neutropenia. These AEs were likely not associated with the study medications. However, these patients have relatively more comorbidities (e.g., hypertension and DM) and a high risk of drug-drug interactions between DAAs and medications prescribed for underlying diseases, even if pharmaceutical reactions are considered. Thus, close monitoring of tolerability and safety is need when treating HCV patients on hemodialysis.
Our study had several strengths and limitations. First, this study is the first prospective Korean study of HCV-infected patients on hemodialysis. There are few data to guide dosing and regimens of DAAs in ESRD (Cr <30 ml="" min="" sup="">6,25 This combination regimen may be effective and safe in HCV-infected patients on hemodialysis. However, the number of patients was small, and so a further study is needed. Second, our study highlights that it is important to identify the candidates who can benefit from DCV and ASV combination therapy based on baseline RAVs testing of HCV genotype 1b, to maximize SVR rates and to monitor the tolerability during treatment throughout the difference of SVR12 rate between ITT and PP analysis (76.1% vs 100%, respectively). Third, the limitation of this trial is that DCV-ASV combination in genotype 1b HCV infection is no more recommended regimen, in terms of longer duration of treatment periods, pre-existing and development of resistance associate variants (RAV) of NS5A resulting low achievement of SVR12 compared with recently approved DAA regimens in Korea. Elbasvir+grazoprevir, ombitasvir/paritaprevir/ ritonavir+dasabuvir and glecaprevir+pibrentasvir combinations are better available regimens for Korean patients with genotype 1b, chronic hepatitis C and ESRD.6,25,26
In conclusion, our data demonstrate the efficacy of the DCV-ASV combination in the treatment of genotype 1b infected HCV patients on hemodialysis. To maximize SVR rates, it is important to identify patients who will benefit from DCV and ASV combination therapy by baseline RAVs testing of HCV genotype 1b. Finally, close monitoring of safety and tolerability is necessary during DCV-ASV combination treatment of HCV-infected patients on hemodialysis.