Efficacy and safety of direct-acting antivirals for treatment of hepatitis C infected kidney transplant recipients ; a meta-analysis

Introduction Hepatitis C virus (HCV) infection universally affects greater than 200 million people worldwide (1). Transmission of HCV occurs essentially via blood transfusion. Consequently, the prevalences of HCV infection in end-state kidney disease on hemodialysis (2.6%-22.9% in Western countries) and in kidney transplant recipients (1.8%-8% in developed countries) are higher than in the general population (~1% in the United States) (2-5). Most kidney transplant patients have received HCV infection while on dialysis. Transmission from organ transplantation is a scarcity in this current era due to decent donor screening (6). In the current years, remarkable advancement has been made in the development of oral anti-HCV agents that undeviatingly inhibit and target multiple HCV viral proteins with interferon (IFN) free direct-acting antiviral (DAA) therapies with excellent reported sustained Wisit Cheungpasitporn1*, Charat Thongprayoon2, Karn Wijarnpreecha2, Ankit Sakhuja3, Wonngarm Kittanamongkolchai1, Jackrapong Bruminhent4


Introduction
Hepatitis C virus (HCV) infection universally affects greater than 200 million people worldwide (1).Transmission of HCV occurs essentially via blood transfusion.Consequently, the prevalences of HCV infection in end-state kidney disease on hemodialysis (2.6%-22.9% in Western countries) and in kidney transplant recipients (1.8%-8% in developed countries) are higher than in the general population (~1% in the United States) (2)(3)(4)(5).Most kidney transplant patients have received HCV infection while on dialysis.Transmission from organ transplantation is a scarcity in this current era due to decent donor screening (6).In the current years, remarkable advancement has been made in the development of oral anti-HCV agents that undeviatingly inhibit and target multiple HCV viral proteins with interferon (IFN) free direct-acting antiviral (DAA) therapies with excellent reported sustained Cheungpasitporn W et al virologic response (SVR) at 12 weeks with smaller side effects (1,7,8).Since DAAs do not stimulate the host immune system, which is a main concern of IFN therapy, studies have implied that DAAs can be utilized for the eradication of HCV infection following renal transplantation (1,(9)(10)(11).However, its efficacy and tolerability in kidney transplant recipients are unclear.Thus, we conducted a meta-analysis to assess the efficacy (SVR 12) and safety of DAA therapy for HCV infection in kidney transplant recipients.

Search strategy
This systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines (12).The study protocol is registered with PROSPERO (International Prospective Register of Systematic Reviews; no.CRD42017054575).W.C. and C.T. (two investigators) independently searched published articles and conference abstracts listed in MEDLINE, EMBASE and the Cochrane databases from inception through January 2017 using the following words: " direct-acting antiviral" AND "transplantation" AND "kidney" or "renal" (Item S1 in online supplementary data).A manual search for additional relevant studies using references from retrieved articles was also performed.Differing decisions were resolved by mutual consensus.

Inclusion criteria and outcomes
The inclusion criteria were 1) observational studies or randomized controlled trials (RCTs) published as original studies or conference abstracts that evaluated the efficacy and safety of DAAs for treatment of HCV infection in kidney transplant populations and 2) crude number of kidney transplant patients who achieved SVR or developed adverse effects with DAA therapy were provided.Our outcomes of interest in this study included the efficacy of DAA treatment representing by pooled rate of SVR and serious adverse side effects requiring DAA discontinuation representing by pooled rate of DAA discontinuation.

Data extraction
A structured data collection report utilized to derive the data from included studies consisted of the first author, country where studies were conducted, type of study, year of publication, total number of kidney transplant patients, HCV genotype, baseline estimated glomerular filtration rate (eGFR) (mL/min/BSA), DAA regimens, time between transplant to DAA treatment, duration of DAA treatment, SVR12, reported adverse events and drug-related serious adverse events, adverse event details, change in renal function with DAA treatment, changes in immunosuppression (dose changes during DAA treatment), rate of treatment discontinuation due to serious adverse events.

Statistical analysis
MetaXL software (EpiGear International Pty Ltd) (13) was used for meta-analysis of efficacy and safety of DAA treatment.A random-effect model was employed rather than a fixed-effect model, given the high likelihood of between-study variances.Statistical heterogeneity was appraised using Cochran's Q test.This statistic was complemented with the I 2 statistic, which quantifies the proportion of the total variation crossed studies that is due to heterogeneity rather than chance.An I 2 of 0%-25% renders insignificant heterogeneity, 26%-50% low heterogeneity, 51%-75% moderate heterogeneity and >75% high heterogeneity (14).The likelihood of publication bias was evaluated by funnel plots of the logarithm of odds ratios vs. their standard errors (15).

Results
The search strategy yielded 643 potentially relevant articles: 540 were excluded based on the title and abstract which apparently showed that they did not fulfill inclusion criteria regarding study design, article type, population, or outcome of interest (Figure 1).The remaining 103 articles underwent full-length review, with 79 excluded because they were not observational studies or RCTs (n = 10) or did not report outcomes of interest (n = 69).Twentyfour studies (1,10,11, with 892 kidney transplant recipients were included in the meta-analysis.

Kirushnan et al (25)
The drugs were well tolerated in the majority.1 patient required erythropoietin temporarily after RBV therapy.
There were no new onset graft dysfunctions indicating no major drug interactions between SOF and immunosuppressants predisposing either to rejection or calcineurin toxicity.
There was no change in the baseline creatinine 2 weeks and 1 month after initiation of therapy.
N/A 0% N/A The treatment was well tolerated, with no episodes of adverse events while on therapy or relevant adverse events.

No episodes of AR while on therapy
There were no differences between baseline and EOT (20 The other cases showed no severe adverse events in liver or renal function.
The tacrolimus concentration was maintained and no substantial dose adjustment was required.

Efficacy of DAAs for treatment of HCV-infected kidney transplant recipients
Of 24 studies, 22 were included in the analysis to assess the effectiveness of DAA treatment for HCV infection among kidney transplant recipients as shown in Table 1.Details regarding HCV genotype, baseline eGFR, DAA regimens, time between transplants to DAA treatment, duration of DAA treatment of each included study were provided in Table 1.The estimated SVR12 rate with DAAs treatment for HCV among kidney transplant patients was 97% (95% CI: 95%-99%; I 2 = 22%), as demonstrated in Figure 2.

Safety of DAAs for treatment of HCV-infected kidney transplant recipients
Of 24 studies, 23 were included in the analysis to assess the safety of DAA treatment for HCV infection among kidney transplant recipients as shown in Table 2. Reported adverse events and drug-related serious adverse events, adverse event details, change in renal function with DAA treatment, changes in immunosuppression, rate of treatment discontinuation due to serious adverse events of each included study were provided in Table 2. Reported treatment-related serious adverse events included bradycardia with syncope especially co-administration of sofosbuvir (SOF) with amiodarone (1,10), pulmonary embolism (10), gastrointestinal bleeding (1), portal vein thrombosis (1), bacteremia (1), anemia especially with regimens including RBV, and uncommonly increased serum creatinine (10,18).The estimated rate of discontinuation of DAAs treatment for HCV among kidney transplant patients was 2% (95%CI: 1%-3%; I 2 = 0%), as demonstrated in Figure 3.

Evaluation for publication bias
Funnel plots to appraise publication bias regarding the efficacy and safety of DAA treatment in recipients with DAA treatment for HCV infection are presented in Figure S1-S2.Overall, the publication bias was insignificant.

Discussion
In this meta-analysis of 892 kidney transplant recipients, we showed an excellent efficacy of DAA therapy for treatment of HCV infection among kidney transplant recipients with overall estimated SVR12 rate of HCV after DAA therapy in kidney transplant recipients of 97%.Besides, DAA therapy in kidney transplant recipients is well-tolerated with an overall estimated discontinuation rate of 2%.Before the development of DAA therapy, the use of IFNbased treatment for HCV infection has been restricted to pretransplant administration due to concerns related to acute allograft injury, immune stimulation related allograft rejection, allograft loss, and poor tolerability (1,9).Also, IFN-based regimens have unfortunately been limited in efficacy and poorly tolerated in the end stage renal disease patients (9).Recently, Studies have demonstrated that novel DAA-based antiviral therapies are efficient for HCV patients with stage 4-5 chronic kidney disease with SVR as high as 89% to 94.3% (8,42,43).In this current study, we demonstrated an excellent efficacy of the use of DAAs in post-kidney transplantation setting with pooled estimated SVR12 of 97%.Despite favorable safety and tolerability profile of DAAs treatment for HCV among kidney transplant patients with only 2% rate of discontinuation of treatment, there are several cautions of DAA therapy and drug-drug interactions bear mention.One of the major reported serious adverse effects was bradycardia with syncope (1, 10).Amiodarone is a known inhibitor of P-GP transport, and SOF is partially cleared via the P-GP system (44).
A decreased in P-GP activity means patients taking amiodarone could be exposed to higher levels of SOF, which is thought to be the cause of bradycardia.Thus, excellent communication between patients and physicians with transplant center are very important to avoid potential drug-drug interactions (10).In addition, drugdrug interactions between DAA and immunosuppression need to be carefully considered.Calcineurin inhibitor (CNI) levels have been shown to fluctuate during and even after DAA treatment is completed (1,10,11,.

Conclusion
In summary, our meta-analysis shows excellent efficacy and tolerability profiles of DAA therapy for HCV-infected kidney transplant recipients.HCV infection should no longer be a major concern among kidney transplant recipients.

Limitations of the study
There are several limitations of our meta-analysis.First, almost all included studies were observational studies with various DAA regimens.

Figure 2 .
Figure 2. Forest plot of SVR12 rate of DAAs for treatment of HCV among kidney transplant patients.

Table 2 .
Reported adverse effects, renal safety and discontinuation rate of HCV treatment with DAAs in kidney transplant recipients