Sofosbuvir-based regimen is safe and effective for hepatitis C infected patients with stage 4–5 chronic kidney disease: a systematic review and meta-analysis

Hepatitis C virus (HCV) infection and chronic kidney disease (CKD) are epidemically correlated and clinically challenging.

It’s estimated that 71 million people were chronically infected with HCV globally, and around 10% of them live with CKD [1, 2]. For patients with CKD, particularly patients receiving hemodialysis, the incidence of HCV is much higher than general population, ranging from 3 to 50% [3]. HCV infection significantly elevates renal disease progression, and clearing HCV has proved to reduce liver related mortality/complications as well as risk of HCV transmission, therefore, HCV cure is of great importance to the patients with dual burden [4‐6].

Sofosbuvir, a nonstructural NS5B polymerase inhibitor, was approved in 2013 and has revolutionized HCV treatment, enhancing the cure bar to above 90% [7‐9]. Sofosbuvir is mainly eliminated through renal pathway, and its use in patients with stage 4 and 5 CKD, defined according to KDIGO guidelines (GFR < 30 mL/min/1.73 m²), is not indicated in label [10, 11]. EASL Recommendations on Treatment of Hepatitis C 2018 suggested that sofosbuvir should be used with caution in patients with an eGFR< 30 ml/min/1. 73m² or with end-stage renal disease, only if alternative treatment is not available [12]. AASLD Guidance: Recommendations for testing, managing and treating hepatitis C mentioned the safe and effective dose of sofosbuvir in persons with an eGFR< 30 ml/min have not been established. However, there is accumulating evidence on use of sofosbuvir-based regimen in those with an eGFR< 30 ml/min [13]. Therefore, we performed a systematic review and meta-analysis to evaluate the safety and effectiveness of SOF-containing therapy for this group of patients.

A total of 496 literatures were identified after preliminary search. Four hundred forty-two were excluded for duplication or irrelevancy. After further judgement by inclusion/exclusion criteria, final 21 studies were included for our review and meta-analysis, and IRB approval information were reported in 12 studies. Figure 1 shows the process of literature review and selection.

Patients living with HCV infection and end-stage renal disease (ESRD) are special population for HCV treatment. Although current guidelines recommend the first-line therapies as elbasvir/grazoprevir, glecaprevir/pibrentasvir, paritaprevir/ ritonavir/ombitasvir/dasabuvir (PrOD) [12, 13], unmet medical needs still exist at some cases (e.g. comorbidity of advanced liver disease, non-GT1 genotype) and when other therapies are not available. In these circumstances, sofosbuvir might be applied after weighing risk and benefit. In vivo, sofosbuvir undergoes intra-hepatic metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which eventually results in ultimate metabolite GS-331007 via dephosphorylation [36]. Sofosbuvir and GS331007 are mainly eliminated through kidney. Compared with subjects of normal renal function, area under the curve (AUC_0-inf) of sofosbuvir and GS-331007 is 171 and 451% higher for patients with eGFR< 30 ml/min (not receiving hemodialysis) [11]. Desnoyer examined plasma concentrations of sofosbuvir (full dose) and GS331007 on hemodialysis patients and concluded they did not accumulate throughout the treatment course and between hemodialysis sessions [32]. Whether sofosbuvir and its metabolite accumulate in ESRD patients who are not on dialysis needs to be answered by further study.

Our meta-analysis included 21 studies, with a total of 717 patients. Pooled SVR12/24 was satisfying (97.1%), similar or higher than that of non-SOF-based therapies [37‐39]. Patients who were on dialysis also achieved a SVR12/24 as high as 95.1%. Although it was lower than that of patients without dialysis, we assume it might not necessarily be the case given limited number of dialysis-free patients in our sub-analysis. Further well-designed RCT are needed to conclude whether effect of sofosbuvir is influenced by dialysis. Aggregated SAE rate was 4.8%, slightly higher than that in HCV infected patients with normal renal function [8, 9], which is reasonable since the patients involved in our meta-analysis had quite a few safety risk factors: old age, severe renal dysfunction, liver/renal transplant recipient, and advanced liver fibrosis. In another meta-analysis, SAE rate was 12.1% for direct-acting antivirals-based antiviral therapies in HCV/Stage 4–5 CKD patients [40]. Common SAEs included renal failure, cirrhosis complications, indicating special attention is needed on renal and liver function during treatment (Table 2).

Treatment strategy of SOF-containing therapy has been under broad discussion. Many physicians explored unconventional dose of sofosbuvir for safety concern, although there is no established pharmacokinetics profile for administration at 200 mg QD, 400 mg/48 h or 400 mg three times a week. Our subgroup analysis suggests that regimen with full and decreased dose of sofosbuvir might be both considerable at acceptable SAE rate (8.8% vs 2.9%) and high SVR12/24 (97.1% vs 96.2%). We assume that sofosbuvir could be alternatively applied at a lower dose as half as normal or at a frequency extended to once every 2 days without compromising its efficacy significantly. While administering three times a week might not be optimal, given that median terminal half-lives of sofosbuvir and its metabolite GS331007 were 0.4 and 27 h (healthy subjects), and possible low SVR12/24 (60% reported in very small sample size) [32]. Ribavirin should be used with caution, considering higher risk of anemia for RBV-containing regimen than RBV-free treatment. Anemia was the most frequently reported AE (6 to 43.7%) in studies of our review, and RBV was included in almost all of these studies (8/9). Manoj reported that 65.4% (17/26) patients in SOF + RBV group developed anemia, and 30% had to discontinue ribavirin [28]. What is worth mentioning is that we found RBV-containing regimen reached lower SVR12/24. One of the reasons is likely to be tolerability issue of ribavirin, another reason might be potent combination drug with sofosbuvir in most RBV-free regimen, 9 studies applied SOF/LDV or SOF + DCV, and 7 achieved 100% SVR12/24.

Kidney function deterioration is a concern for sofosbuvir usage. On one hand, there are few case reports proposed the correlation of nephrotoxicity and SOF-based therapy [41, 42], on the other hand, several large retrospective cohorts conclude SOF-based regimen does not introduce higher acute kidney injury for HCV patients compared to SOF-free treatment [43, 44]. Studies that reported renal function in our review had generally stable eGFR and serum creatinine during treatment. Two SAE cases of AKI and acute renal failure were considered not related to study drug.

There are some limitations to our study. First, we could not perform subgroup analysis according to HCV genotype, CKD stage for lack of enough information. Second, geographical origin of studies enrolled is mainly USA and India, and that limits the representativeness of our analysis. Third, all of the studies were observational studies without control group, and most studies were of medium quality. Heterogeneity was substantial which might attribute to varied sample size and treatment therapy. Furthermore, some newly approved SOF-based therapy (e.g. SOF/VEL) was not included in this analysis for lack of evidence and analysis time frame. The factors above compromise the quality of this review. Prospective and well-controlled studies are expected in near future to provide more robust evidence.

This systematic review and meta-analysis evaluated SOF-based therapy for HCV infected patients with comorbidity of stage 4–5 CKD. Data from this study suggests satisfying sustained virological response and tolerance. For treatment strategy, both full and decreased dose of sofosbuvir could be appropriate. Caution is still needed at clinical practice.