To assess the efficacy and safety of sofosbuvir and daclatasvir regimens for kidney transplantation (KT) patients with hepatitis C virus (HCV) infection.

This study enrolled a prospective cohort of consecutive Chinese KT patients with HCV infection. They were given sofosbuvir combined with daclatasvir, with or without ribavirin. They were monitored regularly during and after the treatment.

Six patients were recruited in our prospective study cohort. All patients were male and naive to direct-acting antiviral treatment. The treatment duration was 12 wk. Most patients (4/6) were infected with HCV genotype 1b. HCV RNA was undetectable at week 4 after treatment and at the end of treatment in all patients. Sustained virological response rate at 12 wk was 100% (6/6). Two patients had to accept a half dose of sofosbuvir due to serum creatinine elevation during treatment. Kidney function in the remaining patients was stable. No serious adverse events (AEs) were observed. No patient discontinued antiviral therapy due to side effects.

Sofosbuvir and daclatasvir for treatment of KT recipients with HCV infection are highly efficient and safe. Patients tolerated the medications well, and no serious AEs were observed. Larger prospective cohort studies are needed to validate these results.

Hepatitis C virus (HCV) infection is common in kidney transplantation (KT) recipients. The worldwide prevalence of HCV infection in patients on hemodialysis is 13.5%, compared with 3% in the general population[1]. The prevalence is significantly higher in patients with KT than in the general population[2]. HCV infection in KT recipients increases the risk of graft loss, liver fibrosis, hepatocellular carcinoma, and death[3,4]. To date, data on the efficacy and safety of direct-acting antivirals (DAAs) in the treatment of KT patients with HCV infection have been limited. New-generation DAAs [e.g., NS5B inhibitor sofosbuvir (SOF) combined with NS5A inhibitor daclatasvir (DCV), with or without ribavirin (RBV)] have been shown to be highly efficient in treating HCV infection in cirrhotic and non-cirrhotic immunocompetent patients[5]. SOF revolutionized the treatment of HCV infection, leading to high rates of sustained virological response (SVR) with few side effects[6]. However, the use of SOF is restricted to patients with an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min per 1.73 m², as it has not been studied in patients with an eGFR < 30 mL/min per 1.73 m². In other words, these limitations are not based on current clinical data. GS331007, the active metabolite of SOF, is eliminated by the kidney. Levels of SOF and GS331007 are substantially higher in patients with severe renal impairment (eGFR < 30 mL/min per 1.73 m²)[7]. Premarket animal testing has raised concerns for cardiovascular and hepatobiliary toxicity at higher levels of SOF dosing, but toxicity of the drug and metabolite levels in humans remains unknown[7]. DCV has been recommend for treatment of patients with severe renal disease, as its components are metabolized mainly by the liver. Currently, few data on the treatment of patients post KT are available so far. The aim of this pilot study was to assess the efficacy and safety of SOF combined with DCV for HCV RNA-positive KT patients.

With a global prevalence rate of approximately 3%, affecting over 170 million individuals, chronic HCV infection is a leading cause of chronic liver disease and hepatocellular carcinoma worldwide[9]. Importantly, for patients with KT, HCV infection is associated with an increased rate of liver fibrosis, graft loss, hepatocellular carcinoma and death[10-12]. To date, treatment recommendations for patients with HCV infection of American Association for the Study of Liver Diseases and European Association for Study of Liver have been modified four times. With these recommendations, new IFN-free DAA therapy may prove to be the treatment of choice.

SOF is an inhibitor of the NS5B polymerase. As a nucleotide analogue, it causes chain termination during the replication of viral genomic RNA. SOF has a pan-genotypic activity and a high resistance barrier. It may only be given to patients with a glomerular filtration rate above 30 mL/min per 1.73 m² due to its renal elimination.

Daclatasvir is an NS5A inhibitor that has high antiviral activity against genotypes 1 to 4 both in vivo and in vitro, and is also active against genotypes 5 and 6. DCV does not require renal dose adjustment and thus provides a promising option for the “difficult-to-treat” cohort.

The combination of SOF + DCV ± RBV has been investigated in treatment-naive patients with genotype 1, 2 and 3 without cirrhosis in several clinical studies. The results showed high SVR rates between 93%-100% regardless of treatment duration and addition of RBV. The ALLY-1 study investigated SOF + DCV + RBV for 12 wk in patients with cirrhosis (n = 60). For genotype 1, patients with cirrhosis achieved an SVR rate of 82%[13]. Initially, only a 24-wk treatment was evaluated in genotypes 2 and 3 patients. The SVR rates were 92% in genotype 2 and 89% in genotype 3[14]. ALLY-3 study genotype 3 patients were treated with SOF + DCV for 12 wk without RBV. Naive patients without cirrhosis achieved a high SVR rate of 97%, while in case of cirrhosis, the SVR rate was lower (only 58%)[15]. However, the efficacy and safety of DAAs, especially the combination of SOF + DCV ± RBV, in patients post KT are rarely reported[16].

In our study, all KT patients with HCV infection who received SOF and DCV regiments achieved RVR, EOT virological response (HCV RNA were undetectable at the EOT) and SVR12. Liver biochemistry parameters ameliorated significantly during antiviral treatment. The RVR rate and SVR12 rate of this group differed from those in several similar studies. For KT patients with HCV infection, Lin et al[17] reported an overall SVR12 rate of 91% (21/23). Patients in their study were given SOF plus simeprevir, with or without RBV, SOF plus ledipasvir, with or without RBV, or SOF plus RBV. Only two patients who relapsed post treatment had traditionally unfavorable treatment profiles. The two patients were African-American, had genotype 1a infection, high pre-treatment HCV viral load, and underlying advanced liver disease/cirrhosis, were previously treatment-experienced with interferon and RBV, and did not achieve RVR[17]. Kamar et al[18] reported an RVR rate of 88% (22/25) in their study, and their SVR12 rate was 100% (25/25). The three patients who did not achieve RVA had an METAVIR fibrosis score of F2. Two of the three patients were infected with HCV genotype 1b and were given SOF + simeprevir + RBV or SOF + ledipasvir without RBV. The third patient was infected with genotype 4 and treated with SOF + ledipasvir. The combination of SOF + DCV ± RBV in our study showed higher RVR and SVR12 rates than other studies. Possible reasons for this include: (1) our patients are all Asian; (2) they were all given SOF combined with DCV with or without RBV; (3) all patients were non-cirrhotic; (4) they were all naive to treatment; (5) they were younger than those in other studies; and (6) they were all compliant.

To date, data regarding efficacy and safety of DAAs in the treatment of KT patients with HCV infection have been limited. Nazario et al[19] reported few AEs with full dose SOF and simeprevir in patients with end-stage renal diseases, although only 11/17 patients completed the 12-wk post-treatment follow-up. Beinhardt et al[20] reported some serious AEs, such as photosensitivity/sunburn, spontaneous bacterial peritonitis, hemolytic anemia, re-listing for transplantation due to graft failure, as well as common AEs, such as headache and myalgia/arthralgia. We did not observe these in our study.

The majority of patients in our study tolerated SOF and DCV regimens well. Some of the more serious AEs may be related to the disease itself. Hemoglobin levels were stable during treatment, consistent with the results of other reports[18]. Notably, 67% (4/6) of our patients tolerated full-dose SOF well. Only two patients, whose baseline serum creatinine levels were higher than normal, received half-dose SOF. Three patients suffered from unstable blood pressure during the first two weeks, as reported in another study[20]. Common AEs including fatigue, diarrhea, tinnitus, discomfort of abdomen and transplanted kidney region, refractory hypertension, and elevation in serum creatinine levels were reported during treatment, just as reported in another study[20].

Dabbous et al[21] reported one recipient death one week following treatment inception, due to unresolved hepatic encephalopathy. Some AEs, such as gastrointestinal bleeding, portal vein thrombosis and Streptococcus bacteremia, sinus bradycardia and first degree A-V block with syncope, shortness of breath, gout flair, headache, dizziness, pain in the lower extremity, photosensitivity, rash, and insomnia, were reported by Lin et al[17].

Anti-HCV assay by enzyme immunoassay (EIA) technique is the most common screening tool for HCV infection due to its simplicity, availability and low cost. The second generation EIA (EIA-2) assay was frequently associated with false negative results in patients with end stage renal diseases on dialysis, with a reported rate of 2.6%-7%[15,20]. In our cohort, two patients were false negative for anti-HCV. Therefore, we recommend that HCV RNA should be determined in patients following KD.

The main limitation of our study is its small sample size. However, in the current clinical environment of increased need for treatment in the “difficult-to-treat” group, we believe that our study results offer proof of concept and feasibility data for future larger studies.

In conclusion, even though HCV patients with KT are considered “difficult-to-treat”, SOF plus daclatasvir is an attractive therapeutic option. The regimens appear to be safe, well-tolerated and efficacious, resulting in high rates of SVR for up to 12 wk following completion of treatment. The optimal dose of SOF should be adjusted according to the creatinine clearance rate and eGFR. With these adjustments, even patients with elevated baseline serum creatinine levels can achieve satisfactory results.