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Table of Contents
REVIEW ARTICLE (SYSTEMATIC REVIEW AND META.ANALYSIS)
Year : 2022  |  Volume : 16  |  Issue : 3  |  Page : 243-266

Adjuvant use of ribavirin with treatment of hepatitis C virus in kidney transplant recipients: A systematic review and meta-analysis of real-world data


1 Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar Mohali, Punjab, India
2 Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Date of Submission13-Jan-2022
Date of Acceptance14-May-2022
Date of Web Publication30-Sep-2022

Correspondence Address:
Dr. Pramil Tiwari
Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Mohali - 160 062, Punjab
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_10_22

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  Abstract 


Hepatitis C virus infection among kidney transplant recipients (KTRs) is an important public health concern worldwide. Evidence on available treatments given shows a greater variability for safety and efficacy, thus we performed this large analysis to present the pooled findings. PubMed/Medline, ScienceDirect, and Google Scholar were searched to identify observational studies of both interferon-based conventional treatment (CT) and recently approved direct-acting antivirals (DAAs), published before November 2020. Meta-analysis of effectiveness outcome (sustained virological response [SVR12]) and safety data (adverse events and discontinuation rate) was performed using a random-effect model. Subgroup analysis based on ± ribavirin with both treatments was performed to assess its relevance in clinical practice. Chi-square and I2 tests were used to assess heterogeneity between the studies. Twenty-five and 9 observational records reporting on treatment with DAAs (n = 943) and CT (n = 125), respectively, are analyzed. The overall pooled estimate of SVR12 rate was found as 95.3%, (range: 92.6%–97%) with DAAs in comparison to 46.4% (range: 33.7%–59.6%) with CT. The pooled prevalence of adverse drug reactions (ADRs) in CT was higher as 47.8% than in DAAs as 23.8%, consequently showing a high discontinuation rate of 31.7% in CT as compared to 6.5% with DAAs. Subgroup analyses of both DAAs and interferon-based treatment ± ribavirin showed decreased effectiveness and increased ADR rates on adding ribavirin. The effectiveness of DDAs was found significantly higher than CT with a better safety profile in KTRs. Ribavirin did not provide any additional benefits while given in combination with either of the treatments available.

Keywords: Direct-acting antivirals, hepatitis C virus, kidney transplantation, pegylated interferon, systematic review


How to cite this article:
Bashir A, Verma A, Duseja A, De A, Tiwari P. Adjuvant use of ribavirin with treatment of hepatitis C virus in kidney transplant recipients: A systematic review and meta-analysis of real-world data. Indian J Transplant 2022;16:243-66

How to cite this URL:
Bashir A, Verma A, Duseja A, De A, Tiwari P. Adjuvant use of ribavirin with treatment of hepatitis C virus in kidney transplant recipients: A systematic review and meta-analysis of real-world data. Indian J Transplant [serial online] 2022 [cited 2022 Nov 27];16:243-66. Available from: https://www.ijtonline.in/text.asp?2022/16/3/243/357600




  Introduction Top


The prevalence of hepatitis C virus (HCV) infection among end-stage renal disease (ESRD) with or without renal transplant is higher than observed in general population. The reported prevalence varies from 1% (range; 0.8–1.1) in general population to 10%–65% in kidney transplant recipients (KTRs) and consequently keeping them at an increased risk of liver abnormalities, glomerular disease, loss of renal graft, acute graft rejection, and death.[1],[2] Therefore, an early infection management is required to prevent the further complications. In addition, while using immune suppressants after transplantation, patients remain at a high risk of viral replication which further cause's recurrence of the HCV infection and implicate the liver disease progression.[3]

Until 2013, the conventional treatment (CT) with interferon/pegylated interferon (PEG-Interferon) with or without ribavirin was the only treatment option available, however, after the approval of direct-acting antivirals (DAAs), the treatment has dramatically improved in terms of safe and effective infection management.[4],[5] Interferon-based treatment has a high non-compliance due to its adverse effects thereby giving a high discontinuation rate with partial effectiveness of only 20%–30%.[6] In contrast, the novel DAAs which target three important proteins as NS3/4A protease, NS5A protein, and RNA polymerase NS5B protein; necessary to complete the life cycle of HCV, are seen to provide a higher rate of sustained virological response (SVR12).[7],[8]

Evidence over the use of these both treatment options for HCV in KTRs in clinical practice is reported through different individual studies however the results show a greater variability on their effectiveness and safe use. In addition, how using ribavirin in combination with available treatment is affecting the infection management is not reported. Thus, we performed this systematic review and meta-analysis to evaluate the clinical outcomes of both available treatment options when used with and without ribavirin. To the best of our knowledge, this is the first report to provide pooled effect sizes from all observational studies and at the same time giving a real-world comparison between the two treatments.


  Materials and Methods Top


Literature search strategy

This systematic review was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA).[9] The review was registered with the PROSPERO database prospectively (CRD42021229494). PubMed/Medline, Science Direct, and Google Scholar were searched to identify observational records published in English language up to the end of November 2020. Further, the potentially relevant studies were searched manually from the reference lists of searched studies to prevent missing records from the initial search results. A search strategy was applied using a combination of relevant medical subject heading terms (MeSH) and keywords for both main subjects as DAAs or conventional therapy with renal transplant and hepatitis C separately. Results from both search combinations were downloaded into the EndNote library for further evaluation. The detailed search strategy is given in [Appendix S1A] and [Appendix S1B].

Inclusion and exclusion criteria

Two reviewers (AB and AV) screened and identified studies independently that met the predefined inclusion and exclusion criteria. The observational studies that evaluated the efficacy and safety of DAAs or CT for the treatment of hepatitis C infection in KTRs were included. Recipients of either gender having any HCV genotype with 18 years or older age were eligible. Observational records that have reported at least one of the included primary outcomes as rate of SVR12 (SVR24 in CT), rate of adverse drug reactions (ADRs), and rate of treatment discontinuation due to ADRs for both the therapeutic options were included. The studies were excluded if they had included patients with concurrent co-infection with hepatitis-B virus or human immunodeficiency virus (HIV). All clinical trial studies, conference abstracts, letters, historical articles, editorials, review articles, or non-English language articles were excluded.

Study selection

Both reviewers (AB, AV) independently screened the titles and abstracts after excluding the duplicate and irrelevant studies. Both prospective and retrospective observational cohorts were included. After checking eligibility and relevance against inclusion criteria, the reviewers evaluated the full-text articles for data extraction. Other independent reviewers (PT, AD, and AD) were consulted to resolve any discrepancies. The literature selection process for both individual therapies used in renal transplant recipients positive for HCV is presented in [Figure 1].
Figure 1: Flowchart of study selection process (n = n1/n2, n1 for DAAs and n2 for CT). DAAs: Direct-acting antivirals, CT: Conventional treatment

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Data extraction and quality assessment

Data extraction was independently performed by two reviewers (AB and AV) with the help of a standardized data extraction form using Microsoft Excel. Any discrepancies were resolved by a group discussion and/or consulting the other reviewers (PT, AD, and AD). The following data were extracted; publication characteristics (first author, year of publication, study country), population characteristics (age, fibrosis/cirrhosis status, HCV genotype, serum creatinine/estimated glomerular filtration rate [eGFR], alanine aminotransferase [ALT], aspartate aminotransferase [AST]), methodological quality (sample size, study design), treatment regimens and duration, efficacy (SVR12, follow-up duration), and safety outcomes (distribution and rate of ADRs, dose modifications, rate of discontinuation, change in renal function).

The included studies were assessed for their quality using Newcastle–Ottawa Scale (NOS).[10] The NOS tool uses a scoring system to judge the quality of study on the basis of selected populations, the comparability of the groups, and the exposure/outcome of interest. The scale comprises eight questions with nine possible points and a study with NOS ≥6 was assigned as of good quality while NOS 3–5 was assigned to be of a fair quality.

Data synthesis and analysis

This work presents a comprehensive qualitative and quantitative synthesis of results from the included studies. Meta-analysis of effectiveness outcome (SVR12) and safety data (proportion of patients reporting adverse events [AEs] or discontinuation) was performed to calculate the rates reported in the observational cohorts. Owing to the high likelihood of variance between the observational studies, random-effect model was preferred over fixed-effect model to obtain the pooled effect size presented as event rates with lower and upper limits of 95% confidence interval (CI). Subgroup meta-analyses were also performed for different outcomes of interest such as rate of SVR12, ADRs, and discontinuation with different therapeutic regimens: DAAs with or without ribavirin and PEG-Interferon with or without ribavirin.

Chi-square and I2 tests were used to assess heterogeneity between the studies. Statistical significance was counted at P < 0.05 and I2 >50%. In the presence of statistical heterogeneity, sensitivity analyses were performed by sequentially removing individual studies and re-estimating the pooled effect size for remaining studies to assess the impact of each individual study. Overall as well as subgroup analyses were conducted using Comprehensive Meta-Analysis v. 2 (Biostat, Englewood, NJ, USA).


  Results Top


Study selection

Initial systematic search from PubMed identified 622 and 225 records for DAAs and CT, respectively, while 51 and 11 extra records were identified through other sources. After the removal of duplicate records (21/6), 652 and 230 records were screened for the titles and abstracts in both the treatment categories. Of these, 564 and 194 were not relevant from both the treatment options and were excluded, respectively. Among the remaining 88 and 36 records from two therapeutic options screened for eligibility in full-text version, 63 and 27 were excluded based on inclusion and exclusion criteria. From the DAA treatment, 48 articles were excluded because they did not report the outcome of interest while 15 articles were excluded because they were not observational studies. However, from CT option, 21 articles were excluded because they did not report the outcome of interest and 7 articles were excluded because they were not observational. Twenty-five[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35] studies for DAA and 9[36],[37],[38],[39],[40],[41],[42],[43] studies for CT finally qualified for qualitative and quantitative synthesis. The PRISMA flow diagram of the detailed literature selection process is illustrated in [Figure 1].

Study characteristics

Characteristics of studies for direct-acting antivirals

This set of studies comprised a total of 25 observational records which reported the effectiveness and safety of different regimens of DAAs in renal transplant recipients who were infected with HCV. A total of 943 recipients with mean age ± standard deviation (SD) of 50.50 ± 10.88 years, treated with DAAs were included in these studies. All the included studies were with observational cohort design and the sample size ranged from 6 to 114. The patients were mainly found with HCV genotype 1 and were mostly treated for 12 to 24 weeks with DAAs. The detailed study characteristics of the included studies are presented in [Table 1].
Table 1: Baseline study characteristics of studies with sustained virological response 12 rate for hepatitis C virus treatment with direct-acting antivirals in kidney transplant reciepients

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Characteristics of studies for conventional treatment

From the CT, a total of 9 observational cohort studies reported the treatment outcomes of PEG-interferon or ribavirin in renal transplant recipients who were infected with HCV. In total, 125 recipients with mean age ± SD of 43.76 ± 12.88 years were included in this study. The sample size varied from 4 to 39. Here too, the patients were mainly seen with HCV genotype 1 and were mostly treated up to 48 weeks. The detailed study characteristics of the included studies are presented in [Table 2].
Table 2: Baseline study characteristics of studies with sustained virological response rate for hepatitis C virus treatment with conventional treatment in kidney transplant recipients

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Quality assessment and publication bias

None of the studies were excluded on the basis of quality assessment results. Only one study in each treatment categories, i.e., DAA and CT scored NOS = 5 as the lowest score, however, 25 studies scored NOS between 6 and 7 (20 in DAA and 5 in CT group) and further 7 studies (4 in DAA and 3 in CT) had scored NOS between 8 and 9. The NOS scores of the risk of bias assessment are presented in a forest plot [Figure 2] and [Figure 3].
Figure 2: Forest plot of SVR12 rate with DAAs used in treatment of HCV-infected KTRs. Overall (I2 = 43.82, P = 0.011). SVR: Sustained virological response, DAAs: Direct-acting antivirals, HCV: Hepatitis C virus, KTR: Kidney transplant recipient

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Figure 3: Forest plot of SVR rate with CT used in treatment of HCV-infected KTRs. Overall (I2 = 42.946%, P = 0.081). SVR: Sustained virological response, CT: Conventional treatment, HCV: Hepatitis C virus, KTR: Kidney transplant recipient

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The funnel plots of pooled SVR12 rate, ADR, and discontinuation rate were constructed for each group (DAA and CT). In the funnel plot, the vertical axis used the precision to estimate the sample size of the studies. In DAAs group, the funnel plot indicated asymmetry and showed a small study effect [Figure 4] and [Appendix Figure S4A] and [Appendix Figure S4B]. Egger's test also suggested an evidence of asymmetry in SVR12 and discontinuation rate as P < 0.001 (SVR12), P < 0.001 (discontinuation rate) and while a symmetry was suggested in ADRs (P = 0.4054) [Appendix Figure S4A]. However, in CT group, the plots were symmetrical and showed no small study effect for the pooled outcomes [Figure 5] and [Appendix Figure S4C] and [Appendix Figure S4D]. In addition, Egger's test was also performed to confirm the funnel plots. The test results indicated no evidence of asymmetry as P = 0.674 (SVR 12), P = 0.4054 (ADR) and P = 0.23 (discontinuation rate) were observed.
Figure 4: The funnel plots of pooled SVR12 rate with DAAs. Egger's test – (Intercept = 1.966, P = 0.0000). SVR: Sustained virological response, DAAs: Direct-acting antivirals

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Figure 5: The funnel plots of pooled SVR rate with CT. Egger's test – (Intercept = –0.597, P = 0.6746). SVR: Sustained virological response, CT: Conventional treatment

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Sensitivity analysis

A significant heterogeneity (P < 0.05) was present in all outcomes in the both treatment groups with an exception of SVR24 and discontinuation rate for CT group, as respective P values found were P = 0.081 and P = 0.407 [Figure 3] and [Appendix Figure S3D]. I2 value for SVR12, discontinuation rate of DAA group, and SVR12 and ADR of CT group are found between 40% and 60%, indicating the presence of moderate heterogeneity [Figure 2], [Figure 3], [Figure 6] and [Appendix Figure S3A]. I2 value for ADR of DAA group is 79.5% representing substantial heterogeneity [Figure 7] and I2 value for discontinuation rate of CT group is 2.46% indicating the absence of heterogeneity [Appendix Figure S3D]. After removing one study, sensitivity analysis was performed for all the outcome arms to check the impact of heterogeneity; however, we did not find a significant alteration in pooled estimates.
Figure 6: Forest plot of ADR rate with CT used in treatment of HCV-infected KTRs. Overall (I2 = 53.838%, P = 0.043). ADR: Adverse drug reaction, CT: Conventional treatment, HCV: Hepatitis C virus, KTR: Kidney transplant recipient

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Figure 7: Forest plot of ADR rate with DAAs used in treatment of HCV-infected KTRs. Overall (I2 = 79.59%, P = 0.000). ADR: Adverse drug reaction, DAAs: Direct-acting antivirals, HCV: Hepatitis C virus

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Furthermore, subgroup analyses were performed to remove the heterogeneity for SVR12 and ADR rate in DAA group and for SVR24 rate in CT group. I2 value for SVR12 rate for DAA in combination with RBV reduced from 43.82% to 11.18% [Appendix Figure S3C] and for DAA without RBV from 43.82% to 0% respectively [Appendix Figure S3B]. Further, for ADR rate, I2 value reduced to 60.43% for DAA without RBV [Figure 8] and 72.58% for DAA with RBV from 79.59% [Figure 9]. In the final subset of subgroup analysis of SVR12 rate in CT group, I2 reduced from 42.91% to 0% for PEG-Interferon without RBV [Figure 10], however, I2 value increased from 42.91% to 50.90% [Figure 11] for PEG-Interferon when used in combination with RBV.
Figure 8: Forest plot of ADR rate of DAAs without ribavirin used in treatment of HCV-infected KTRs. Overall (I2 = 60.43%, P = 0.002). ADR: Adverse drug reaction, DAAs: Direct-acting antivirals, HCV: Hepatitis C virus, KTR: Kidney transplant recipient

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Figure 9: Forest plot of ADR rate of DAAs with ribavirin used in treatment of HCV-infected KTRs. Overall (I2 = 72.58%, P = 0.000). ADR: Adverse drug reaction, DAAs: Direct-acting antivirals, HCV: Hepatitis C virus, KTR: Kidney transplant recipient

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Figure 10: Forest plot of SVR rate of PEG-interferon without ribavirin used in treatment of HCV-infected KTRs. Overall (I2 = 0.000%, P = 0.805). SVR: Sustained virological response, PEG: Pegylated interferon, HCV: Hepatitis C virus, KTR: Kidney transplant recipient

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Figure 11: Forest plot of SVR rate of PEG-interferon with ribavirin used in treatment of HCV-infected KTRs. Overall (I2 = 50.90%, P = 0.057). SVR: Sustained virological response, PEG: Pegylated interferon, HCV: Hepatitis C virus, KTR: Kidney transplant recipient

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Clinical outcomes

Sustained virological response

All the included studies which evaluated the two treatment options (25 for DAAs and 9 for CT), used to treat HCV infection in renal transplant recipients were included in the final quantitative analysis to assess the effectiveness. All the important details related to sample size, age, genotype, treatment regimens, duration of treatment, and SVR12 are presented in [Table 1] and [Table 2]. The estimated overall SVR12 rate with DAAs treatment among included population (n = 943) was 95.3% (95% CI: 92.6%–97%; I2 = 43.2%) [Appendix S2A], in comparison to 46.4% (95% CI: 33.7%–59.6%; I2 = 42.91%) as achieved with the use of CT with PEG-interferon and ribavirin in 125 recipients [Figure 2] and [Figure 3], [Appendix S2B]. In DAAs, the minimum SVR12 rate achieved was reported by Gentil et al., as 81.4% (95% CI: 73.2%–87.6%); however, from CT, it was 21.4% (95% CI: 7.10%–49.4%) shown by Sharma et al.[34],[42]



While extending the analysis on the basis of subgroups, the SVR12 rates were estimated for DAAs with or without ribavirin and similarly for CT, for PEG-interferon with or without ribavirin. Patients treated with different regimens of DAAs in 21 included studies (n = 508), SVR12 rate was found to be 95% (95% CI: 92.2%–96.8%; I2 = 0.0%) while DAAs when used in combination with Ribavirin have shown SVR12 rate of 93% (95% CI: 88%–96%; I2 = 11.8%) in 321 patients reported in 18 studies [Appendix Figure S3B] and [Appendix Figure S3C]. Similarly in CT subgroups, SVR12 rate with PEG-interferon alone was 52.4% (95% CI: 36.6%–67.7%; I2 = 0.0%); however, when used in combination with ribavirin, SVR12 rate was found to be 47% (95% CI: 29.5%–65.2%; I2 = 50.90%) as presented in [Figure 10] and [Figure 11].

Adverse drug reactions and discontinuation

From all the included studies, 21 from DAAs and 7 from CT, that reported data on AEs, were subjected to meta-analysis to assess the safety profile. Reported drug-related AE rate and distribution, eGFR, serum creatinine, ALT/AST ratio, change in renal function, follow-up period, dose modification, and treatment discontinuation of each included study are provided in [Table 3] and [Table 4].
Table 3: Reported adverse drug reactions, kidney/liver impact and discontinuation rate with direct-acting antiviral treatment in hepatitis C virus positive kidney transplant recipients

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Table 4: Reported adverse drug reactions, kidney/liver impact and discontinuation rate with conventional treatment in hepatitis C virus positive kidney transplant reciepients

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The most common reported AEs with the use of DAAs were anemia (8 studies), headache (4 studies), impaired renal function (9 studies), dizziness or fatigue (6 studies), and diarrhea (3 studies) with an overall pooled prevalence of 23.8% (95% CI; 16.9–32.4%) [Figure 7]. However, studies of CT have reported anemia (5 studies), renal allograft rejection (5 studies), and altered hematological parameters (5 studies) as the main AEs with a pooled prevalence of 47.8% (95% CI; 32.5–63.5%) [Figure 6]. Further analyzing the ADR rates between the subgroups shows that when using DAAs alone, the ADR rate was 21.9% (95% CI; 13.8%–32.8%) in comparison to when used in combination with ribavirin as 39% (95% CI; 26.2%–53.5%) [Figure 8] and [Figure 9].

From the both therapeutic options, 22 studies in DAA and 7 studies in CT have reported treatment discontinuation due to some serious AEs. The estimated rate of discontinuation was found as 6.5% (95% CI; 4.3%–9.8%) in DAAs and 31.7% (95% CI; 22.7%–42.4%) in CT, respectively [Appendix Figure S3A] and [Appendix Figure S3D].


  Discussion Top


This report provides a cumulative evidence of globally conducted observational studies evaluating the effectiveness and safety of DAAs and conventional interferon-based treatment for HCV infection in renal transplant recipients with special emphasis on the adjuvant use of ribavirin. After the introduction of multiple DAA regimens in the last decade, the HCV treatment has substantially improved.[45],[46] Conventional interferon-based treatment was gradually replaced with DAAs to achieve a higher level of efficacy and safety in treating patients having chronic HCV.

In general practice, an NS5A and NS5B inhibitor or an NS5A or NS5B inhibitor together with a protease inhibitor are used.

The pooled data in the current study show that the predominant HCV genotype in the KTRs treated with DAAs was genotype 1 in 628 (66.5%) patients, followed by genotype 4 in 141 (14.9%) patients, 3 in 81 (8.58%) patients, and 2 in 34 (3.6%) patient while in patients treated with CT the genotype 1 was found in 62 (68.8%) followed by 2 in 8 (8.8%) and 3 in 6 (6.6%). Available evidence from earlier studies has reported that the prevalence and distribution of genotype vary with several geographic regions reporting the most common genotype as G1, i.e., in line with our results.[1] Among the DAA regimens, daclatasvir (27.35%), ledipasvir (25.66%), ribavirin (13.4%), ribavirin + ledipasvir (12.6%), and ribavirin + daclatasvir (5.9%) were used in combination with sofosbuvir predominantly [Table 1]. Moreover, in patients treated with conventional agents, interferon with ribavirin was used in 56.6% of patients followed by interferon in 21.6% and ribavirin alone in 7.54% of patients [Table 2].

We found an excellent overall pooled estimate of effectiveness as 95.3% (range: 92.6%–97%) with DAAs in comparison to 46.4% (range: 33.7%–59.6%) with CT, based on SVR12 rate. Earlier, a meta-analysis of 24 studies (both observational and RCTs) by Cheungpasitporn et al., in 2017, has evaluated the efficacy and safety of DAAs treatment for HCV in 892 KTRs.[46] The authors have reported a pooled SVR12 rate as 97% (95% CI: 95%–99%; I2 = 22%) with 2% treatment discontinuation rate. In another study by Chen et al., in 2017, 6 studies (case–control and cohort) with 360 KT patients were meta-analyzed and have reported SVR12 rate of 98.3% with serious AEs in only four patients.[47] Similarly, for CT, a meta-analysis of 287 ESRD patients (on dialysis) was performed by Fabrizi et al., in 2014, who included patients treated with interferon and ribavirin.[48] They have reported SVR rate of 60% (95% CI: 47%–71%) with 18% (95% CI: 8%–35%) discontinuation due to AEs. The results with CT were used as evidence at that time to assume this combination as a standard of care for treating ESRD patients with HCV infection.

The present analysis has further confirmed these findings with more number of studies as well as patients from real world by indicating that the DAAs are highly effective to provide a higher virological response rate with a better safety profile. In addition, our study has compared the effectiveness and safety between the two available therapeutic options by presenting the real-world clinical experiences obtained from observational studies.

Among the studies that reported ADRs, anemia was the most common AE with a pooled prevalence of 12.3% followed by headache and fatigue in 7% of patients and renal impairment in 6.88% of patients. Anemia was significantly seen in patients who were treated with a regimen containing ribavirin. Further with use of CT, the most commonly found AEs were anemia (25%), allograft rejection (9%), leukopenia, or flu-like symptoms (8%). With HCV infection in KTRs, there are always high chances of allograft rejection simultaneously associated accelerated hepatic fibrosis or cirrhosis, new-onset diabetes, cardiovascular disease, sepsis, and recurrent glomerular issues. With the CT, SVR is poor accompanied with side effects leading to frequent dose reduction and treatment discontinuation. However, after DAAs, more favorable outcomes are seen. In the present study, due to a higher pooled prevalence of ADRs in CT (47.8%) than DAAs (23.8%), the patients were seen with a high discontinuation rate of 31.7% in comparison to 6.5% with DAAs.

While performing subgroup analysis for both the treatment options, to use them in combination with ribavirin, we found that the SVR12 rate decreases to 93% (88%–96%) from 95% (92.2%–96.8%) when DAAs were combined with ribavirin. Furthermore, SVR12 rate was seen reducing to 47% (29.5%–65.2%) from 52.4% (36.6%–67.7%) when ribavirin was combined with PEG-interferon. These results predict that the novel interferon-free DAAs are highly effective in treating HCV infection than the conventional way of treatment and even these are more effective when used without ribavirin. In addition, analyzing the ADRs at the subgroup level, using DAAs alone are seen with a better safety profile (ADR rate 21.9%) than using with ribavirin (ADR rate 39%).

Enough evidence is available to state that ESRD or kidney transplant patients are highly prone to get anemic when treated with ribavirin which in turn further worsens the patient's condition.[49] Therefore, a genuinely evaluated clinical decision is needed on whether to include ribavirin or not. Our findings suggest that without using ribavirin, the effectiveness of DAAs is higher additionally with a better safety profile. This fact might be helpful to clinicians to understand risks and benefits while prescribing ribavirin in KTRs. Furthermore, with higher efficacy, better safety, and short duration of treatment, DAAs are currently highly recommended to use in clinical practice for treating HCV in all the populations including KTRs. However, special emphasis is always needed to prevent possible drug–drug interactions in between DAAs or with other used immunosuppressants after transplantation.[50]

Limitations

Our study has some known limitations which deserve a mention. First, this analysis is based on results from observational reports and comparisons may be confounded due to patient- and regimen-based differences. Also in CT group, few studies have reported virological response at different time intervals than SVR12 rates as efficacy outcome which might add some bias. Second, the number of patients in the two arms of comparison is not balanced. Third, since all the included studies were observational in nature, the random effect model was used instead of fixed model due to the presence of higher heterogeneity. Finally, it was not feasible to evaluate effectiveness and safety based on genotype and different regimens of DAAs due to the unavailability of data on included outcomes separately. Hence, genotype or regimen-specific effectiveness and safety are recommended with future studies.


  Conclusion Top


Virological response to DAAs was significantly better than CT with a better safety profile in KTRs. Ribavirin did not offer any additional benefits when given in combination with either DAAs or CT. However, it was associated with more AEs. This summarized evidence from real-time clinical studies supports the use of DAAs instead of conventional interferon-based treatment for HCV infection in KTRs. Future research assessing genotype- or regimen-specific effectiveness and safety of available treatment options is needed to advance the management of this important patient population.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.


  Appendix Top


S1A: “Direct-acting antivirals” (tiab) OR “Antiviral agents” (Mesh) OR “therapeutic use” (tiab) OR “Antiviral treatment” (tiab) OR “DAAs” (tiab) OR “DAA therapy” (tiab) OR “NS3/4A protease inhibitors” (tiab) OR “NS5A protein inhibitors” (tiab) OR “NS5A protein inhibitors” (tiab) OR “Ribavirin” (MeSH Terms) OR “velpatasvir” (tiab) OR “Sofosbuvir” (MeSH Terms) OR “Dasabuvir” (tiab) OR “Grazoprevir” (tiab) OR “Paritaprevir” (tiab) OR “glecaprevir” (tiab) OR “ombitasvir/paritaprevir/ritonavir/ribavirin” (tiab) OR “glecaprevir and pibrentasvir” (tiab) OR “sofosbuvir, velpatasvir, and voxilaprevir” (tiab) AND “hepatitis c, chronic” (MeSH Terms) OR “Flaviviridae Infections” (MeSH Terms) OR “Hepacivirus” (MeSH Terms) OR “Viral hepatitis” (tiab) OR “Hep C” (tiab) AND “Renal replacement therapy” (Mesh) OR “Renal transplant*” (tiab) OR “Renal dialysis” (Mesh) OR “Hemodiafiltration” (Mesh) OR “Haemodialysis” (tiab) OR “Peritoneal dialysis” (Mesh) OR “Kidney Grafting” (tiab).

S1B: “Standard of care” (Mesh) OR “Ribavirin” (Mesh) OR “Pegylated interferon” (tiab) OR “Pegylated interferon and ribavirin” (tiab) OR “Pegylated-interferon” (tiab) OR “pegylated interferon–ribavirin” (tiab) OR “conventional therapy” (tiab) OR “conventional treatment” (tiab) AND “hepatitis c, chronic” (MeSH Terms) OR “Flaviviridae Infections” (MeSH Terms) OR “Hepacivirus” (MeSH Terms) OR “Viral hepatitis” (tiab) OR “Hep C” (tiab) AND “Renal replacement therapy” (Mesh) OR “Renal transplant*” (tiab) OR “Renal dialysis” (Mesh) OR “Hemodiafiltration” (Mesh) OR “Haemodialysis” (tiab) OR “Peritoneal dialysis” (Mesh) OR “Kidney Grafting” (tiab).





 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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