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. 2021 Feb 10;16(2):e0246594. doi: 10.1371/journal.pone.0246594

An updated systematic review and meta-analysis on efficacy of Sofosbuvir in treating hepatitis C-infected patients with advanced chronic kidney disease

Sara Majd Jabbari 1, Khadije Maajani 2, Shahin Merat 3, Hossein Poustchi 3, Sadaf G Sepanlou 1,*
Editor: Chen-Hua Liu4
PMCID: PMC7875415  PMID: 33566846

Abstract

Sofosbuvir seems to be a revolutionary treatment for Hepatitis C-infected patients with advanced chronic kidney disease (CKD) but existing evidence is not quite adequate. The aim of this study was to evaluate the efficacy and safety of Sofosbuvir-based therapy without Ribavirin for all hepatitis C virus genotypes among patients with advanced CKD. We conducted an updated systematic literature search from the beginning of 2013 up to June 2020. Sustained virologic response (SVR) rate at 12 and/or 24 weeks after the end of treatment, and adverse events in HCV-infected patients with advanced CKD were pooled using random effects models. We included 27 published articles in our meta-analyses, totaling 1,464 HCV-infected patients with advanced CKD. We found a substantial heterogeneity based on the I2 index (P = 0.00, I2 = 56.1%). The pooled SVR rates at 12 and 24 weeks after the end of Sofosbuvir-based treatment were 97% (95% Confidence Interval: 95–99) and 95% (89–99) respectively. The pooled SVR12 rates were 98% (96–100) and 94% (90–97) in patients under 60 and over 60 years old respectively. The pooled incidence of severe adverse events was 0.11 (0.04–0.19). The pooled SVR12 rate after completion of the half dose regimen was as high as the full dose treatment but it was associated with less adverse events (0.06 versus 0.14). The pooled SVR12 rate was 98% (91–100) in cirrhotic patients and 100% (98–100) in non-cirrhotic patients. The endorsement of Sofosbuvir-based regimen can improve the treatment of hepatitis C virus infection in patients with advanced CKD.

Introduction

Chronic kidney disease (CKD) is described as the gradual loss of kidney function over time. CKD progresses through five stages [1]. Previous reports reveal that chronic hepatitis C virus (HCV) infection is the most common chronic liver disease in patients with advanced CKD [2]. The prevalence varies worldwide, with a higher proportion of infected patients in developing countries than in developed nations [3, 4]. In Western countries, it has been estimated that almost 6% of patients with advanced CKD, who are on conservative therapy, are infected with HCV [5]. Approximately 4% to 70% of patients on hemodialysis (HD), and between 11% and 49% of kidney transplant (KTx) recipients are infected with HCV [6]. HCV infection is detected as a frequent cause of morbidity, mortality, and graft failure among patients on HD and kidney transplant (KTx) recipients [7–10].

In earlier studies, PEGylated interferon (Peg-IFN) monotherapy showed higher SVR rates (approximately 40%) compared to conventional interferon therapy (approximately 30%) in HCV-infected CKD patients [11]. The addition of ribavirin (RBV) did not result in higher SVR rates compared to regimens restricted to peg-IFN. Antiviral therapy with peg-IFN with or without RBV was not quite effective and was associated with several side effects, which raised concerns about its safety [12]. Interferon and RBV are associated with significant toxicity including anemia, depression, anxiety, and other psychiatric side effects [13–15]. As a result, the main limitation of interferon-based regimens is their high withdrawal rates due to side effects (26.9%) [12].

Sofosbuvir is classified as a superior direct-acting nucleotide polymerase inhibitor that inhibits HCV replication through inhibition of NS5B RNA polymerase, which regulates the chronic HCV infection. This drug is metabolized in vivo into its active intracellular metabolite GS-461203 and the pharmacologically inactive form GS-331007. This active triphosphate of Sofosbuvir, GS-461203, targets the vastly conserved active site of the HCV-specific NS5B polymerase and acts as a nonobligatory chain terminator, an effect that is independent of the viral genotype [16]. The use of Sofosbuvir (400 mg/day) leads to drastically increased level of inactive metabolite GS331007 in patients with e-GFR < 30 mL/min/1.73 m2, which raises concerns about the accumulation of GS331007 in patients with advanced CKD, possibly leading to toxicity as GS331007 is mostly eliminated by kidneys [17, 18]. The effective and safe dose of Sofosbuvir in advanced CKD patients is thus not established. Still, existing evidence on usage of Sofosbuvir in patients with e-GFR< 30 ml/min/1.73 m2 is accumulating [19].

In a recent systematic review, the safety and efficacy of Sofosbuvir was explored among patients on HD [20] and results are quite similar to the results of the current study. However, there is a very important difference between the two studies. In our study, we included patients with eGFR<30 ml/min/1.73 m2 and our search was not confined to patients on HD. This difference is quite important as the risk of toxic metabolite accumulation in patients with advanced CKD and not necessarily on HD may be even higher than patients on HD. We also excluded studies on acute HCV and studies on patients with HBV and HIV co-infection and we conducted subgroup and sensitivity analyses. Thus, in this updated systematic review and meta-analysis we used the currently available evidence to evaluate the antiviral efficacy of SOF-based therapy in combination with other direct acting antivirals (DAA) in advanced CKD patients infected chronically with HCV.

Materials and methods

We performed this systematic review to identify studies on Sofosbuvir-based antiviral therapy among HCV-infected patients with advanced CKD. This study was conducted in accordance with preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines [21].

Search strategy

For systematic literature search, we used several international databases including PubMed/Medline, Web of sciences, Scopus and CENTERAL on the Cochrane library from January 1st, 2013 (the year Sofosbuvir was approved for medical use) up to June 26th, 2020. The search strategy was based on a combination of key words from medical subject headings (Mesh) and free texts including "(dialysis OR hemodialysis OR end stage renal disease OR chronic kidney failure OR chronic kidney disease OR severe renal impairment) AND (Sofosbuvir OR N5B polymerase OR direct-acting antiviral). The details of our search strategy are presented in the S1 Appendix in S1 File. Finally, to avoid missing any relevant evidence, we reviewed the reference list of all included studies.

Study selection

After literature search by two independent reviewers (Kh M and S M), results of the initial search were incorporated into the reference manager software, duplicates were removed, and the two reviewers screened the studies by title, abstract, and full text independently and included or excluded them based on defined eligibility criteria.

Eligibility criteria

All studies would be eligible if they were published in full English and reported the efficacy and safety profiles of Sofosbuvir-based regimen for treatment-naive chronic HCV-infected patients (aged ≥ 18 years) with advanced CKD, defined as e-GFR ≤ 30 ml/min per 1.73 m2 or being on dialysis. Studies on all HCV genotypes were included. Outcomes of interest were SVR rates at 12 or 24 weeks after the end of treatment. Studies were excluded if there was no sufficient data to calculate SVR12 or SVR24 rate and if HCV-infected patients were co-infected with other viral infections such as hepatitis B and HIV/AIDS.

Quality assessment

To assess the quality of included studies we used Newcastle—Ottawa quality assessment scale for cohort studies, which comprised three sections as follow: 1. Selection, 2. Comparability, and 3. Outcome [22]. Therefore, studies with cumulative score equal to 7 or more were classified as high quality studies (n = 6) and studies with cumulative scores between 4 and 6 were defined as fair quality studies (n = 21). Two reviewers (Kh M and S M) independently assessed the quality of each study. In order to explore the agreement between the two reviewers, we used Kappa statistics (Weighted kappa = 87%). Disagreements between the reviewers were resolved through discussions, or the final decision was made based on the opinion of the third reviewer (SM).

Data extraction

To extract the relevant data, two reviewers (Kh M and S M) independently used a pre-specified data extraction sheet in Microsoft Excel, which consisted of the following variables: name of the first author, year of publication, time of the study, country, study design, number of patients, mean age, sex distribution, baseline HCV RNA level, cirrhosis diagnosis, treatment strategy, doses of drugs and duration of treatment, the rate of SVR12 and/or SVR24, side effects, and mortality rate.

Statistical analysis

To investigate the between study heterogeneity we used I2 index and chi-squared test at the 5% significance level (p <0.05). A random effects model was used to pool the SVR12 rate. We used metaprop command to estimate the exact binomial and score-test-based confidence intervals for proportions near boundaries (i.e., near 100% or zero) [23]. We also conducted subgroup analysis and meta-regression by treatment strategy, dose of Sofosbuvir, diagnosis of cirrhosis, country of origin, and age. In this study, publication bias was not assessed, as the SVR rate is a proportion, is always a positive number, and the asymmetry in the funnel plot is not due to publication bias. This meta-analysis was performed in Stata 11 (StataCorp, College Station, TX, USA).

Results

Study characteristics

Our final systematic search yielded 27 relevant articles based on the eligibility criteria and we included these studies in our systematic review and meta-analyses (Fig 1). These studies were conducted in 10 countries, comprising 6 studies in the USA, 10 in India, 2 in France, 2 in Pakistan and single studies in Austria, Czech Republic, Iran, Korea, Egypt, and Brazil (Table 1). Detailed study characteristics are demonstrated in S1 Table in S1 File. The included studies contained extractable data on 1464 patients, among whom 809 were males and 655 were females. The mean age of all enrolled patients was 48.6±11 year. We included all articles that used Sofosbuvir-based therapies, and the enrollment period of these patients ranged from 2013 to 2020. All patients in 22 studies received full dose Sofosbuvir (400 mg) daily, while patients in 5 studies received half dose (200mg) Sofosbuvir daily. In all of the studies, Sofosbuvir was used in combination with other direct-acting antivirals (DAAs). Among all patients enrolled in the included studies, only 274 patients were cirrhotic. Characteristics of included studies are demonstrated in Table 1.

Fig 1. PRISMA flowchart showing different phases of selecting relevant publications.

Fig 1

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Table 1. Study characteristics included in meta-analysis of SVR12 rate among HCV-infected patient with advanced chronic kidney disease.

First author/year Country No. of patients Recruitment period Mean Age (SD) Cirrhosis N(%) No. of patient on dialysis/Total patient SVR12 SVR24 NOS score
Taneja 2018 [24] India 65 2016 49 (13) 21 (32.3%) (54/65) 100 _ 6
Surendra 2018 [25] India 19 2016 44 0 (19/19) 100 _ 6
Manoj 2018 [26] India 71 2015–2017 42 17 (23.9%) (11/71) 100 98.5 6
Akhil 2018 [16] India 22 2015–2016 49.8 0 (22/22) 100 _ 6
Sperl 2017 [27] Czech Republic 6 2015–2016 39 2 (33.3%) (6/6) 100 _ 5
Dumortier 2017 [28] France 50 2013–2015 60.5 (7.5) 0 (35/50) 86 _ 6
Cox-North 2017 [29] USA 29 2014–2016 _ 13 (44.8%) (0/29) 97 _ 6
Choudhary 2017 [30] India 16 2015–2016 45 (12) 2 (12.5%) (16/16) 80 _ 6
Aggarwal 2017 [31] USA 14 _ 61 (4.9) 12 (85.7%) (14/14) 92.8 _ 6
Agarwal 2017 [32] India 62 2015–2016 33.8 (10.2) 3 (4.8%) (62/62) 95.2 _ 6
Singh 2016 [33] USA 8 2014–2015 56.8 (20) 3 (37%) (8/8) 100 _ 6
Saxena 2016 [34] USA 18 _ ≥65 - - 88 _ 8
Nazario 2016 [35] USA 17 _ 57 8 (47%) (17/17) 100 _ 6
Desnoyer 2016 [36] France 12 2014–2015 52 10 (83.4%) (12/12) 83.3 100 6
Beinhardt 2016 [37] Austria 10 _ 50.6 (10.9) 4 (40%) (10/10) 96 96 8
Hundemer 2015 [38] USA 6 2014 60 (14) 3 (50%) (6/6) 64 _ 6
Goel 2018 [39] India 41 2015–2017 41 5 (12%) (41/41) 90.2 _ 6
Gupta 2018 [40] India 7 2015–2016 48.8 ± 14.5 2 (28.6%) (7/7) 100 _ 6
Mehta 2018 [41] India 38 2016 49.5 _ (26/26) 100 _ 6
92.3
Borgia 2019 [42] Canada, the United Kingdom, Spain, Israel, New Zealand, and Australia 59 2017–2018 60 17 (29%) (59/59) 95 _ 6
Poustchi 2020 [43] Iran 103 2017–2018 50.3±13.5 39 (37.9%) (75/103) 100 _ 6
Eletreby 2020 [44] Egypt 579 2014–2018 52 107 (11%) 10/579 96.7 _ 8
Debnath 2020 [45] India 18 2017–2018 39.4 ± 8.3 0 18/18 100 _ 6
Michels 2020 [46] Brazil 34 2016–2017 60.7±10.4 0 34/34 99.3 97.1 8
Cheema 2019 [47] Pakistan 18 2017–2018 47.2±14.1 4 (22.2%) 18/18 83.3 83.3 8
Mandhwani 2020 [48] Pakistan 133 2016–2018 31.9 ± 9.8 0 133/133 96.9 _ 8
Seo 2020 [49] Korea 9 2017–2018 59.9 2 (22.2%) 9/9 100 _ 6
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Heterogeneity

The between study heterogeneity based on I2 index (P = 0.00, I2 = 56.1%) was substantial.

Pooled SVR rate

Based on the random effects model, the pooled SVR12 and 24 rates were 97% (95% CI: 95–99) and 95% (89–99) respectively in our meta-analysis (Fig 2 and S1 Fig in S1 File).

Fig 2. Forest plot of the pooled SVR12 rate in HCV-infected patients with advanced chronic kidney disease.

Fig 2

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Subgroup analysis

According to the results of subgroup analysis in Table 2, the pooled SVR12 rates were 98% (96–100) and 94% (90–97) in patients under 60 and over 60 years old respectively (S2 Fig in S1 File). The pooled SVR12 rate was 98% (91–100) in patients with cirrhosis and 100% (98–100) in non-cirrhotic patients (Fig 3). In subgroup analysis based on Sofosbuvir dose, the pooled SVR12 rate was 97% (94–99) in studies using full dose regimen (400 mg), and 99% (91–100) in studies using half dose (200mg) regimen (Fig 4). Results sub-grouped by region of study are presented in S3 Fig in S1 File showing lower SVR12 rates in Europe [95% (89–100)]. Fig 5 demonstrates the pooled SVR12 rate sub-grouped based on being treated only with Sofobuvir [99% (98–100)] or its combination with RBV [99% (95–100)]. We additionally defined subgroups by treatment strategy such as the result of the pooled SVR12 rate in 19 studies in which Sofosbuvir was used in combination with Daclatasvir [97% (94–99)], Simeprevir [99% (94–100)], and Ledipasvir [100% (100–100)]. Detailed results are reported in Fig 6. Table 2 demonstrates the summary of all sub-group analyses.

Table 2. Results of subgroup analysis for estimating the pooled SVR12 rate in HCV-infected patients with advanced CKD.

Title Subgroup Number of included studies SVR12 95%CI I2 (P)
1 Treatment strategy SOF+DCV 19 97% (94–99) 53.6% (P = 0.00)
SOF+SMV 9 99% (94–100) 0.00 (P = 0.83)
SOF+LDV 6 100% (100–100) 0.00 (P = 0.99)
SOF+RBV 8 97% (83–100) 57.6% (P = 0.02)
SOF+DCV +RBV 3 97% (95–99) 0.00 (P = 0)
SOF+PEG+RBV 3 96% (79–100) 0.00 (P = 0)
2 Type of combination Only SOF-based 27 99% (98–100) 29.5% (P = 0.06)
SOF-based + RBV 11 99% (95–100) 51.8% (P = 0.01)
3 Dose of treatment Full dose (400 mg) 22 97% (94–99) 58.4% (P = 0.00)
Half dose (200 mg) 5 99% (91–100) 53.7% (P = 0.07)
3 Diagnosis of cirrhosis Cirrhotic 12 98% (91–100) 54.7% (P = 0.01)
Non-Cirrhotic 19 100% (98–100) 38.7% (P = 0.04)
4 Age group <60 year 19 98% (96–100) 60.1% (P = 0.00)
>60 year 8 94% (90–97) 0.00 (P = 0.57)
5 Region America 7 96% (91–100) 16.1% (P = 0.31)
Asia 15 98% (94–100) 68.7% (P = 0.00)
Europe 4 95% (89–100) 0.00 (0.5)
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†SVR = Sustained viralogic response. RBV = Ribavirin. SOF = Sofosbuvir. DCV = Daclatasvir. LDV = Ledipasvir. SMV = Simeprevir.

Fig 3. Forest plot of the pooled SVR12 rate in HCV-infected patients with advanced CKD sub-grouped based on diagnosis of cirrhosis.

Fig 3

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Fig 4. Forest plot of the pooled SVR12 rate in HCV-infected patient with advanced CKD sub-grouped by SOF-based regimen dose.

Fig 4

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Fig 5. Forest plot of the pooled SVR12 rate in HCV-infected patients with advanced CKD sub-grouped based on the use of SOF-based regimen with or without RBV.

Fig 5

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(1): SOF+DCV; (2): SOF+LDV; (3): SOF+SMV; (4): SOF+RBV; (5): SOF+DCV+RBV; (6): SOF+PEG+RBV.DCV = Daclatasvir. LDV = Ledipasvir. SMV = Simeprevir. RBV = Ribavirin.

Fig 6. Forest plot of the pooled SVR12 rate in HCV-infected patients with advanced CKD by treatment strategy.

Fig 6

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DCV = Daclatasvir. LDV = Ledipasvir. SMV = Simeprevir. RBV = Ribavirin.

Safety

Severe adverse events (SAE) were reported in 6 studies (S4 Fig in S1 File). The pooled incidence of SAE was 0.11 (0.04–0.19), and the incidence of SAE in patients who received full dose SOF compared to half dose were 0.14 (0.04–0.28) vs. 0.06 (0.01–0.15). Mortality was reported in 11 studies, and none of them were due to treatment (S5 Fig in S1 File). Therefore, the estimated pooled mortality rate was 0.04 (0.01–0.09). In eight studies the discontinuation rate was reported and the pooled rate was 0.04 (0.00–0.11). (S6 Fig and S2 Table in S1 File)

Meta-regression analysis

The results of meta-regression analysis are shown in Table 3. There was a significant association between age (P = 0.03, β = 13.4) and country (P = 0.02, β = -18.1) and the pooled SVR12 rate in the univariable model, which disappeared in the multivariable model. None of the variables of cirrhosis diagnosis, treatment strategy, and dose of treatment had significant association with the pooled SVR12 rate, neither in the univariable model nor in the multivariable meta-regression model.

Table 3. Meta-regression analysis for the effect of suspected variables on the pooled SVR12 rate in HCV-infected patients with advanced chronic kidney disease.

Variable Univariable Model Multivariable Model
β SE P Value β SE P Value
Age 18.1 7.4 0.02 10.1 9.7 0.30
Country -19.3 7.5 0.01 -12.6 9.9 0.21
Cirrhosis diagnosis 6.1 6.4 0.34 3.2 5.3 0.55
treatment strategy -4.2 9.5 0.65 -3.1 10.1 0.75
dose of drugs 4.4 9.7 0.64 3.4 10.3 0.74
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Sensitivity analysis

To assess the effect of all studies on the pooled SVR12 rate, we used sensitivity analyses. In each step, we excluded one of the total of 27 studies and calculated the pooled SVR12 rate across the remaining 26 studies. Thus, we performed 27 sensitivity analyses and we made 27 different estimates of SVR12 upon exclusion of each study in each step. The highest and lowest estimates after excluding the studies by Dumortier [28] and Poustchi [43] were 98.9% (90.8–100) and 95.3% (91.1–100) respectively. So the pooled SVR12 rate was stable across studies. Our results are actually robust and don’t depend on the choice of included studies.

Discussion

HCV-infected patients with advanced CKD form a susceptible population that can be treated with a combination of Sofosbuvir-based regimen and antiviral therapy. We included 27 relevant studies, comprising 1464 patients in our meta-analysis. The pooled SVR12 rate was 97%, which was an acceptable outcome.

The endorsement of Sofosbuvir-based regimen was a major advance in treatment of HCV-infected patients with stage 4–5 of CKD. Efficacy and safety profile concurs with high rates of SVR12-24 with few side effects.

In the systematic review conducted by Li M et al in 2019, the pooled SVR12/24 rate (97.1%) achieved by the SOF-based regimen was compatible with the results of our meta-analysis [50]. Also in the study conducted in 2016 by Li T et al [51], the reported SVR12 rate of DAAs-based regimens was 93.2%, which was lower compared to the result of our study as we focused only on Sofosbuvir-based regimen. In comparison with studies that included non-SOF-based therapies, our study revealed higher SVR12 rates and better tolerability following SOF-based therapy in HCV-infected patients with advanced CKD.

To assess the safety of SOF-based therapy, we computed the pooled discontinuation rate due to adverse events, which was just 4%. The low estimate reveals the satisfactory outcome of SOF-based therapy. The discontinuation rate due to adverse events in the meta-analysis conducted by Li T [51] was 2.2%, which is compatible with our findings.

The pooled incidence of SAE due to SOF-based regimen in our study was 11%, which was similar to the study by Li T et al, in which the pooled SAE rate for DAA-based antiviral therapies in HCV/Stage 4–5 CKD patients was 12.1% [51]. Shehadeh et al also reported a 10% incidence for SAE, which is quite similar to our results [20].

Out of the 15 studies that reported anemia as an adverse event, RBV was used in combination with SOF-based therapy in 11 studies. Also in the meta-analysis conducted by Li T et al in 2016 [51], the most frequent adverse event was anemia, and in the systematic review by Li, M et al in 2019 [50], anemia was the most frequently reported adverse event and RBV was included in almost all of these studies. Shehadeh et al reported fatigue as the most frequent adverse event, followed by anemia. They consistently reported more prevalent anemia in treatment regimens containing RBV. Therefore, regimens containing RBV should be used with caution compared to RBV-free regimens due to high risk of anemia. In the study conducted by Manoj et al, 65.4% of patients who used SOF with RBV developed anemia [26].

Our subgroup analysis suggests that half dose SOF-based regimens are as effective as full dose regimens. The SVR12 rates are similar between half dose (99%) and full dose (97%) regimens. Furthermore, the SAE of half dose regimen (6%) is lower than the full dose treatment (14%). Similarly, Li M et al. (2019) found that both half dose and full dose regimens had considerably high SVR rate (97.1% vs. 96.2%). Li M et al (2019) also suggested lower dose of SOF as routine or usage of half dose once every 2 days with the same efficacy [50]. Shehadeh et al also showed higher efficacy with low-dose treatment [20].

The result of our meta-analysis also showed that the rate of SVR12 in patients who received Sofosbuvir-based treatment without RBV was 99%, which was similar to patients who received SOF with RBV (99%). As we mentioned previously, use of SOF-based treatment in combination with RBV should be used with caution since in addition to increasing the risk of anemia, it increases the discontinuation rate.

Additionally, in cirrhotic patients, the SVR12 rate was slightly lower than non-cirrhotic patients (98% vs. 100%). This finding of our study was similar to the results reported by Rezaee`i-Zavare et al. [52] They recommended that cirrhotic patients be treated with SOF-based regimen in combination with RBV for 12 weeks or without RBV for 24 weeks. Similar to the result of our study, they found that treatment of non-cirrhotic patient with SOF-based regimen without RBV for 12 weeks had acceptable outcomes [52].

Our study is a comprehensive systematic review and meta-analysis on efficacy of SOF-based therapies. We conducted subgroup analysis by combinations of Sofosbuvir with other DAAs regimens and we found out that this regimen is effective and safe in HCV-infected patients with advanced CKD. In addition, these combinations of SOF-based therapies with DAA regimens reduced the incidence of anemia caused by RBV [51].

Our study has certain limitations as well. Firstly, we observed a substantial heterogeneity that might be due to different sampling frames and sample size or different treatment strategies used in a variety of contexts. All included studies were observational without proper control groups. Additionally, almost all studies were conducted in the USA and India. Therefore, the findings of our study cannot be generalized to all populations.

Conclusions

The results of this study showed satisfactory and novel findings regarding the usage of half dose SOF-based regimen in HCV-infected patients with advanced CKD. We demonstrated that the use of SOF-based therapy in full or low dose has considerable efficacy in cirrhotic and non-cirrhotic patients. The results of our study have important policy implications as well. The massive production of Sofosbuvir can be a cost-effective strategy to eliminate chronic HCV or at least prevent premature death in advanced CKD patients infected with hepatitis C virus.

Supporting information

S1 Checklist. PRISMA 2009 checklist.

(DOC)

Click here for additional data file. (119KB, doc)
S1 File

(PDF)

Click here for additional data file. (1MB, pdf)

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

The authors received no specific funding for this work.

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Decision Letter 0

Chen-Hua Liu

3 Nov 2020

PONE-D-20-30679

An updated systematic review and meta-analysis on effectiveness of Sofosbuvir in treating hepatitis C infected patients with end‑stage renal disease

PLOS ONE

Dear Dr. Sepanlou,

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Reviewer #2: Yes

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Reviewer #2: I Don't Know

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Reviewer #1: Dear Dr. Sepanlou,

Thank you for your effort on the field about effectiveness and safety of sofosbuvir-based regimen in ESRD patients. Several questions should be clarified.

1. Based on our knowledge, ESRD is defined as patient's eGFR less than 15 ml/min or receiving renal replacement therapy. However, in this study, ESRD was defined as eGFR less than 30 ml/min. You may revise the title and manuscript to "advanced CKD stage" rather than ESRD alone.

2. Line 142, the total patient number is 1571 less than the sum of male and female patients. There would be a mistake in recording patient numbers.

3. Table 1. reference number [26] and [27], the patients were acute infected by HCV virus and the treatment duration was different. Dose these two studies be suitable for enrollment ?

4. Table 1. reference number [30], the eGFR of these 73 renal-impaired patients was less than 45 ml/min. Dose these patient met the inclusion criteria ?

5. Table 1. reference number [31], the SVR of patients with renal impairment is 96.7% but the SVR of patients with ESRD is 80%. However, the SVR of ESRD patients seems not be enrolled in this meta-analysis

6. Table 1, reference number [34], the patient numbers and percentage of cirrhosis were not compatible with original

study, please confirm the accuracy of data extraction

7.please reconfirm the accuracy of patient numbers, SVR rate, the definition of CKD in all the enrolled studies.

Reviewer #2: The authors did an updated systemic review and meta-analysis on the effectiveness of sofosbuvir (SOF)-based regimens in treating hepatitis C virus (HCV)-infected patients with end-stage renal disease (ESRD) from 29 published articles including 1571 subjects. They found that the pooled sustained virologic response (SVR) rates were 97% and 98% 12 and 24 weeks after cessation of antiviral therapies, respectively. Age, cirrhosis, and dose-reduction of SOF did not affect the treatment efficacy while adding on ribavirin (RBV) was associated with a higher incidence of treatment discontinuation and adverse events especially anemia. Though not a novel study, this manuscript has its scientific value in providing healthcare provider guidance in treating chronic HCV-infected patients who have end-stage renal disease. However, several issues deserve clarification or amendment in its current version.

1. Give necessary references to the following sentence “In earlier studies, PEGylated interferon (Peg-IFN) monotherapy…in HCV-infected ESRD patients.” in the second paragraph of the introduction.

2. Change ribavirin abbreviation to “RBV” instead of “rib” in the context.

3. Did HBV co-infection exclude from the enrolled studies?

4. Explain why the number of included studies was greater than 29 in the subgroup analysis table 2?

5. Polish the language for the context such as correct “Sustained viralogical response” to “Sustained virologic response” in Table 2 footnote, and remove unnecessary capital to medication names.

6. In ‘Sensitivity analysis’ please explain why references 30 and 31 were excluded for SVR calculation. The 2nd & 3rd sentences under this subject “The highest and lowest SVR12…respectively. So the pooled SVR12 rate was stable across studies.” were poorly understood.

7. Address the causes of the high incidence of SAE in SOF-based regimen to HCV-infected ESRD patients since the potential harm of its inactive metabolite GS-331007 to these subjects is the most concern issue by healthcare providers.

8. Give proper author names and published year in Figure 2.

**********

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Reviewer #1: No

Reviewer #2: No

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PLoS One. 2021 Feb 10;16(2):e0246594. doi: 10.1371/journal.pone.0246594.r002

Author response to Decision Letter 0

14 Dec 2020

Dear Dr. Chen-Hua Liu,

Thank you very much indeed for considering our manuscript for publication in PLOS One and your detailed comments. We entirely repeated the analyses based on the comments of respected reviewers. Please find our point-by-point response to your comments and the comments of the respected reviewers.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Response: We modified our manuscript according to the requirements of the journal.

2. Please include the following publication in your introduction and discuss what your research contributes in light of this recent published work: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459301/

Response: Thanks for this very valuable comment. We included this publication and added the following paragraph to the introduction section of the manuscript:

“In a recent systematic review, the safety and efficacy of Sofosbuvir has been explored among patients on HD.[20] The results are quite similar to the results of the current study. However, there is a very important difference between the two studies. In our study, we included patients with eGFR<30 ml/min/1.73 m2 and our search was not confined to patients on HD. This difference is quite important as the risk of accumulation of toxic metabolites in advanced CKD may be even higher than patients on HD. We also excluded studies on acute HCV and studies on patients with HBV and HIV co-infection. We have also conducted subgroup and sensitivity analyses”.

3. In the Methods, please state the justification the restriction of the timeline to January 2013 onwards.

Response: We mentioned in the methods section that we restricted the timeline to January 2013 as Sofosbuvir was approved for medical use in that year.

Reviewer comments:

Reviewer #1: Dear Dr. Sepanlou,

Thank you for your effort on the field about effectiveness and safety of sofosbuvir-based regimen in ESRD patients. Several questions should be clarified.

1. Based on our knowledge, ESRD is defined as patient's eGFR less than 15 ml/min or receiving renal replacement therapy. However, in this study, ESRD was defined as eGFR less than 30 ml/min. You may revise the title and manuscript to "advanced CKD stage" rather than ESRD alone.

Response: Thanks for this valuable comment. We replaced ESRD with “advanced CKD” in the title and throughout the manuscript.

2. Line 142, the total patient number is 1571 less than the sum of male and female patients. There would be a mistake in recording patient numbers.

Response: We repeated all analyses based on your valuable comments. We corrected the numbers: “The total sample size of 27 included articles amounted to 1464 patients, among whom 809 were males and 655 were females.”

3. Table 1. reference number [26] and [27], the patients were acute infected by HCV virus and the treatment duration was different. Dose these two studies be suitable for enrollment?

Response: Thanks for this valuable comment. We dropped these two studies on acute HCV patients and repeated all analyses.

4. Table 1. reference number [30] Saxena, the eGFR of these 73 renal-impaired patients was less than 45 ml/min. Dose these patient met the inclusion criteria?

Response: Thanks for this very valuable comment. You are quite right and we are sorry for this mistake. The study by Saxena et al is mainly conducted on 73 patients with GFR <45 ml/min. But in their subgroup analyses, they have reported the SVR among 17 patients with GFR < 30 ml/min as well. But details about these 17 patients are not reported. Therefore, we used this study only in estimating the overall SVR 12 reported for 17 patients but we dropped it from all other sub-group analyses.

5. Table 1. reference number [31] Eletreby, the SVR of patients with renal impairment is 96.7% but the SVR of patients with ESRD is 80%. However, the SVR of ESRD patients seems not be enrolled in this meta-analysis 80% is patients on dialysis.

Response: We used the SVR of 96.7% among patients with GFR <30 ml/min in our meta-analysis. We haven’t done a meta-analysis exclusively on patients on hemodialysis.

6. Table 1, reference number [34] Manoj, the patient numbers and percentage of cirrhosis were not compatible with original study, please confirm the accuracy of data extraction.

Response: Thanks very much indeed for this really valuable comment. We corrected the entire table 1.

7. Please reconfirm the accuracy of patient numbers, SVR rate, the definition of CKD in all the enrolled studies.

Response: We reviewed and revised the entire table 1.

Reviewer #2: The authors did an updated systemic review and meta-analysis on the effectiveness of sofosbuvir (SOF)-based regimens in treating hepatitis C virus (HCV)-infected patients with end-stage renal disease (ESRD) from 29 published articles including 1571 subjects. They found that the pooled sustained virologic response (SVR) rates were 97% and 98% 12 and 24 weeks after cessation of antiviral therapies, respectively. Age, cirrhosis, and dose-reduction of SOF did not affect the treatment efficacy while adding on ribavirin (RBV) was associated with a higher incidence of treatment discontinuation and adverse events especially anemia. Though not a novel study, this manuscript has its scientific value in providing healthcare provider guidance in treating chronic HCV-infected patients who have end-stage renal disease. However, several issues deserve clarification or amendment in its current version.

1. Give necessary references to the following sentence “In earlier studies, PEGylated interferon (Peg-IFN) monotherapy…in HCV-infected ESRD patients.” in the second paragraph of the introduction.

Response: Thanks indeed for this valuable comment. We added the following reference:

“KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease. Kidney international Supplement. 2008;(109):S1-99. Epub 2008/05/03. doi: 10.1038/ki.2008.81. PubMed PMID: 18382440.”

2. Change ribavirin abbreviation to “RBV” instead of “rib” in the context.

Response: We used “RBV” throughout the manuscript as you kindly mentioned.

3. Did HBV co-infection exclude from the enrolled studies?

Response: Yes, we excluded studies on patients with HBV or HIV co-infection and we mentioned it in introduction and methods sections.

4. Explain why the number of included studies was greater than 29 in the subgroup analysis table 2?

Response: The number of included studies was greater than 29 (currently 27 studies as we dropped two studies on patients with acute HCV) in subgroups because in some studies, more than one subgroup analysis has been reported. For example, in the study by Desnoyer et al, the SVR for treatment strategies SOF+DCV, SOF+LDV, SOF+RBV, and SOF+SMV have been separately reported. So the results of the study have been reported in all subgroups. Another example is the SVR reported based on whether the treatment was only SOF based or was combined with RBV. In a number of studies, both of these two regimens have been separately reported.

5. Polish the language for the context such as correct “Sustained viralogical response” to “Sustained virologic response” in Table 2 footnote, and remove unnecessary capital to medication names.

Response: Thanks indeed for this comment. We changed the “Sustained viralogical response” to “Sustained virologic response” throughout the manuscript.

6. In ‘Sensitivity analysis’ please explain why references 30 and 31 were excluded for SVR calculation. The 2nd & 3rd sentences under this subject “The highest and lowest SVR12…respectively. So the pooled SVR12 rate was stable across studies.” were poorly understood.

Response: As we dropped two studies on acute HCV patients based on the comments of reviewer #1, there are 27 studies in this meta-analysis. In the sensitivity analysis we excluded studies one by one to estimate the effect of their exclusion on the pooled analysis on the remaining 26 studies. When we excluded the study of Durmontier et al (in the revised version of this manuscript), the pooled SVR on the remaining 26 studies was highest (98.9%) and when we excluded the study by Poustchi et al, the pooled SVR on the remaining 26 studies was lowest (95.3%). When we excluded other studies one by one, the SVR on remaining 26 studies lied between 95.3% and 98.9%. We hope this explanation is adequate.

7. Address the causes of the high incidence of SAE in SOF-based regimen to HCV-infected ESRD patients since the potential harm of its inactive metabolite GS-331007 to these subjects is the most concern issue by healthcare providers.

Response: Thanks for this comment. The main message of this study is the low SAE in SOF-based regimens which confirms the utility, the safety, and the effectiveness of this treatment strategy and can’t be a concern for healthcare providers. This point is mentioned in the manuscript.

8. Give proper author names and published year in Figure 2.

Response: Thanks for this comment. All figures were re-drawn and corrected.

Attachment

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Decision Letter 1

Chen-Hua Liu

31 Dec 2020

PONE-D-20-30679R1

An updated systematic review and meta-analysis on effectiveness of Sofosbuvir in treating hepatitis C infected patients with advanced chronic kidney disease

PLOS ONE

Dear Dr. Sepanlou,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.​

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We look forward to receiving your revised manuscript.

Kind regards,

Chen-Hua Liu

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Dear Dr. Sepanlou,

Thank you for revised the manuscript. Several issues should be clarified.

1. Line 101 ~ 107: Please revise English. Please do not use "Inclusion criteria :" For example : "All studies published in full English reporting the effectiveness and safety profiles of sofosbuvir-based regimen for treatment-naive chronic HCV-infected patients with advanced chronic kidney disease would be eligible." This would be more fluent and easy to be understood.

2.Line 168~171, Please well clarify the result of your subgroup analysis rather than using the Fig demonstrates ....

3.Line 197~200, Please clarify what you want to tell us. You want to illustrate age and country were associated with SVR12 rate in univariate analysis and none were found to be associated with SVR12 in multi-variate analysis ?

4.Sensitivity analysis : I still could not understand what this mean. Is there any statistical evidence that sensitivity test is done by excluding the lowest and highest extreme values of enrolled studies. The result of pooled SVR12 rate remain around 90~98% after excluding the extreme value didn't mean the meta-analysis is more reliable.

5. English editing of this manuscript would be necessary and helpful.

Reviewer #2: The authors revised the manuscript according to my comments point-by-point, I have no further comments.

**********

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Reviewer #1: No

Reviewer #2: No

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PLoS One. 2021 Feb 10;16(2):e0246594. doi: 10.1371/journal.pone.0246594.r004

Author response to Decision Letter 1

7 Jan 2021

Dear Dr. Chen-Hua Liu,

Thank you very much indeed for considering our manuscript for publication in PLOS One and your detailed comments. Please find our point-by-point response to the comments of the respected reviewers.

Reviewer #1: Dear Dr. Sepanlou,

Thank you for revised the manuscript. Several issues should be clarified.

1. Line 101 ~ 107: Please revise English. Please do not use "Inclusion criteria :" For example : "All studies published in full English reporting the effectiveness and safety profiles of sofosbuvir-based regimen for treatment-naive chronic HCV-infected patients with advanced chronic kidney disease would be eligible." This would be more fluent and easy to be understood.

Response: Thanks indeed for this comment. We modified the text accordingly and used the sentence that you kindly suggested, though the sentence is rather long.

2.Line 168~171, Please well clarify the result of your subgroup analysis rather than using the Fig demonstrates ...

Response: The following sections were added:

“Results sub-grouped by region of study are presented in S3 Fig showing lower SVR12 rates in Europe [95% (89-100)]. Fig 5 demonstrates the pooled SVR12 rate sub-grouped based on being treated only by Sofobuvir [99% (98-100)] or by its combination with RBV [99% (95-100)]. We additionally defined subgroups by treatment strategy such as the result of pooled SVR12 rate in 19 studies in which Sofosbuvir was used in combination with Daclatasvir [97% (94-99)], Simeprevir [99% (94-100)], and Ledipasvir [100% (100-100)], which are reported in Fig 6. Table 2 demonstrates the summary of all sub-group analyses.”

3.Line 197~200, Please clarify what you want to tell us. You want to illustrate age and country were associated with SVR12 rate in univariate analysis and none were found to be associated with SVR12 in multi-variate analysis?

Response: Yes, we want to say the exact points you mention here. We corrected the sentence accordingly:

“There was a significant association between age (P=0.03, β=13.4) and country (P=0.02, β=-18.1) and the pooled SVR12 rate in the univariable model, which disappeared in the multivariable model. None of the variables of cirrhosis diagnosis, treatment strategy, and dose of treatment had significant association with the pooled SVR12 rate, neither in the univariable model nor in the multivariable meta-regression model.”

4.Sensitivity analysis: I still could not understand what this mean. Is there any statistical evidence that sensitivity test is done by excluding the lowest and highest extreme values of enrolled studies. The result of pooled SVR12 rate remain around 90~98% after excluding the extreme value didn't mean the meta-analysis is more reliable.

Response: Sensitivity analyses are integral components of meta-analysis. Sensitivity analysis may explore the impact of excluding or including studies in meta-analysis based on sample size or variance (and not extreme values). If results remain consistent across different analyses, the results can be considered robust as even with different decisions to include or exclude the studies, they remain the same / similar. If the results differ across sensitivity analyses, this is an indication that the result may need to be interpreted with caution. It is very important to note that we haven’t excluded the extreme values. You can notice that Dumortier and Poustchi have not reported extreme values. We excluded each one of the studies out of the entire 27 studies in each step and performed the analyses on the remaining 26 studies. So we repeated 27 sensitivity analyses and we made 27 different estimates of SVR12 upon exclusion of each study from the list. The highest and the lowest estimates across these 27 analyses were reported in the text upon exclusion of studies by Dumortier and Poustchi respectively. Here, the analyses show that the results of these 27 sensitivity analyses are consistent and within the range of the overall SVR12 across all 27 studies. Therefore, our results are actually robust and don’t depend on the choice of included studies. We hope these explanations are adequate.

We added the following section to the manuscript:

“To assess the effect of all studies on the pooled SVR12 rate, we used sensitivity analyses. In each step, we excluded one of the total of 27 studies and calculated the pooled SVR12 rate across the remaining 26 studies. Thus, we performed 27 sensitivity analyses and we made 27 different estimates of SVR12 upon exclusion of each study in each step. The highest and lowest estimates after excluding the studies by Dumortier [28] and Poustchi [43] were 98.9% (90.8-100) and 95.3% (91.1-100) respectively. So the pooled SVR12 rate was stable across studies. Our results are actually robust and don’t depend on the choice of included studies.”

5. English editing of this manuscript would be necessary and helpful.

Response: Thanks for this very important comment. We edited the entire manuscript. We made a major change and used the term “efficacy” instead of “effectiveness” in the title and throughout the entire text of the manuscript.

Reviewer #2: The authors revised the manuscript according to my comments point-by-point, I have no further comments.

Response: Thanks indeed for your positive feedback.

Attachment

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Decision Letter 2

Chen-Hua Liu

22 Jan 2021

An updated systematic review and meta-analysis on efficacy of Sofosbuvir in treating hepatitis C-infected patients with advanced chronic kidney disease

PONE-D-20-30679R2

Dear Dr. Sepanlou,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Chen-Hua Liu

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Dear Dr. Sepanlou,

Thank you to revised the manuscript according to my comment point-to-point and made English editing. I do not have further comment on this study.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Acceptance letter

Chen-Hua Liu

28 Jan 2021

PONE-D-20-30679R2

An updated systematic review and meta-analysis on efficacy of Sofosbuvir in treating hepatitis C-infected patients with advanced chronic kidney disease

Dear Dr. Sepanlou:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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Kind regards,

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on behalf of

Dr. Chen-Hua Liu

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PLOS ONE

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