Objectives: Direct-acting antiviral agents have recently been recommended in renal transplant recipients. Considering our previous encouraging responses with combined sofosbuvir and ribavirin in renal transplant recipients and the availability of daclatasvir, we aimed to evaluate the effectiveness and safety of sofosbuvir-based direct-acting antiviral agents in our population.
Materials and Methods: All renal transplant recipients who received sofosbuvir-based direct-acting antivirals from August 2015 to March 2018 were included in our study. Patients were treated with sofosbuvir and ribavirin for 24 weeks or with combined sofosuvir, daclatasvir, and ribavirin for 12 weeks. Patient demo-graphics and baseline laboratory parameters were collected. Rapid virologic response, end of treatment response, and sustained virologic response at 12 weeks were analyzed. Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 20.0, IBM Corporation, Armonk, NY, USA).
Results: In our study group of 79 patients, mean age was 36.5 ± 10.2 years and 60 were men (78.5%). Fifty-six patients (70.9%) were treatment naive; of the remaining patients, 20 received interferon before transplant and 3 were treated with sofosbuvir and ribavirin after renal transplant. Genotype 1 was observed in 42 patients (53.2%), whereas mixed genotype (1 and 3) was shown in 10 patients (12.6%). Sixty-two patients (78.5%) received sofosbuvir and ribavirin, and 17 patients (21.5%) received sofosbuvir, daclatasvir, and ribavirin. End of treatment response was achieved in 78 recipients (98.1%). Anemia was observed in 13 patients (16.4%).
Conclusions: Hepatitis C virus was successfully eradicated in renal transplant recipients who received a combination of sofosbuvir plus ribavirin or sofosbuvir, daclatasvir, and ribavirin. These combinations were effective and well tolerated in our study population, even in those with mixed genotype, with no major adverse events.
Key words : Direct-acting antiviral agents, Genotype, Kidney transplant, Ribavarin
The reported prevalence of hepatitis C virus (HCV) in renal transplant recipients (RTRs) ranges from 1.8% to 8.0%.1 Hepatitis C virus infection in post-transplant patients infers higher risks of decreased graft and recipient survival.2 Direct-acting antiviral agents (DAAs) have recently been recommended for HCV eradication in transplant patients.3 These agents target nonstructural viral proteins such as NS3A, NS4A, NS4B, NS5A, and NS5B and are more effective than interferon owing to less adverse effects and shorter treatment duration.4
Various studies and case reports have reported promising results of HCV eradication in RTRs by these novel agents.5-10 Kamar and associates6 and Xue and associates7 reported 100% sustained virologic res-ponse at 12 weeks (SVR12) with sofosbuvir plus ribavirin combination and also sofosbuvir, daclatasvir, and ribavirin combination. However, allograft rejec-tion, renal dysfunction, and requirement of immuno-sup-pression dose modification have also been reported.5,10
We previously reported an SVR12 of 100% in 37 RTRs, with 24-week treatment, with combined sofosbuvir and ribavirin.11 With the availability of daclatasvir, we aimed to evaluate the effectiveness and safety of a sofosbuvir-based DAAs treatment, considering the nonavailability of other novel agents in our region.
Materials and Methods
All RTRs with HCV infection who visited the outpatient Department of Hepatogastroenterology and Transplantation of Sindh Institute of Urology and Transplantation (Karachi, Pakistan) and who received DAAs from August 2015 to March 2018 were included in the study. Our institute’s ethical committee approved the treatment protocol.
Laboratory parameters were recorded at the start of treatment and then after 4 weeks and at end of treatment. Hepatitis C virus polymerase chain reaction (PCR) and genotype testing were performed in all RTRs at the start of treatment (Roche Cobas TaqMan and Abbott RealTime HCV, Karachi, Pakistan). Patients were given 400 mg of generic sofosbuvir and a glomerular filtration rate-based dose of ribavirin for 24 weeks. After daclatasvir became available, RTRs were prescribed combined sofosbuvir, daclatasvir, and ribavirin for 12 weeks. During treatment, HCV PCR was checked at 4 and 24 weeks to document rapid virologic response and end of treatment response (ETR).
After treatment ended, HCV PCR was checked at weeks 12 and 24 (at end of treatment) to document SVR (ie, SVR12 and SVR24). All renal donors were negative for hepatitis B virus surface antigen, anti-HCV and anti-human immunodeficiency virus antibodies, and HCV RNA based on PCR.
Data were analyzed using SPSS Statistics software (SPSS: An IBM Company, version 20.0, IBM Corporation, Armonk, NY, USA). Continuous variables were analyzed using t tests or the Wilcoxon signed-rank test. Categorical variables were analyzed using the chi-square test or the Fisher exact test. A comparison of quantitative variables with repeated measurements was analyzed using the paired t test. End of treatment was considered as the final outcome. P < .05 was considered statistically significant.
Of the 93 RTRs, 79 completed the treatment course, 7 were lost to follow-up, 4 were undertreated, and 3 died due to underlying sepsis. In total, 79 RTRs were analyzed. The mean age of our study population was 36.5 ± 10.2 years, and most were men (n = 62; 78.5%). Fifty-six patients (70.9%) were treatment naive; of the remaining 23 patients, 20 received interferon before transplant and 3 were treated with sofosbuvir and ribavirin after transplant.
In the 20 RTRs who had received interferon, 16 were responders, 3 were nonresponders, and 1 had relapse after treatment. Genotype 1 was found in most patients (n = 42; 53.2%), whereas only 1 patient had genotype 4. Table 1 shows the clinical and demographic characteristics of our study population.
Sixty-two RTRs (78.5%) received sofosbuvir and ribavirin for 24 weeks, whereas 17 RTRs (21.5%) were prescribed combined sofosbuvir, daclatasvir, and ribavirin. We found that rapid virologic response was achieved in 73 RTRs (92.4%). Treatment was extended to 9 months in the remaining 6 patients (7.5%).
End of treatment response was not achieved in 3 patients on sofosbuvir regimen; 2 patients responded to the combined sofosbuvir, daclatasvir, and ribavirin regimen, and 1 patient had a new genotype. Thus, ETR was achieved in 78 RTRs (98.7%). Until the time of data collection, 23 patients had achieved SVR24. One patient did not achieve SVR12 on both sofosbuvir and the combined sofosbuvir, daclatasvir, and ribavirin regimen.
Table 2 shows the significant decline in serum hemoglobin and alanine aminotransferase levels, with increased serum platelet count. Although creatinine showed improved levels from nadir value, the difference was not significant. Anemia was observed in 13 RTRs (16.4%). Ribavirin was stopped in 6 patients, whereas dose modification was performed in the remaining RTRs.
Treatment was not discontinued in our study population. Three patients (3.22%) died during treatment due to underlying sepsis, but these patients were not included in our analyses.
Because of low efficacy and associated risk of allograft rejection with interferon treatment in RTRs, recently approved DAAs have revolutionized the treatment of HCV.12 In a retrospective study by Goetsch and associates,13 DAAs improved graft survival in patients with HCV as demonstrated by significantly decreased protein-to-creatinine ratio in RTRs. The American Association for the Study of Liver Diseases3 recently published guidelines recom-mending glecaprevir/ pibrentasvir combination and ledipasvir (90 mg) and sofosbuvir combination, depending on treatment experience and HCV genotype. However, alternative recommended regimens include daclatasvir plus sofosbuvir com-bination along with low doses of ribavirin for 12 weeks.
Various studies and case reports have revealed effective and safe HCV eradication with sofosbuvir-based regimens.5-10 Kamar and associates6 docu-mented 100% SVR12 in 25 RTRs; 3 patients received sofosbuvir with ribavirin, whereas 3 were prescribed sofosbuvir with daclatasvir combination. Similarly, Xue and associates7 documented 100% SVR12 in 6 RTRs treated for 12 weeks with sofosbuvir and daclatasvir combination. Hussein and associates8 reported the successful treatment of HCV genotype 4 in 3 renal transplant patients using the combination of sofosbuvir and ribavirin. In our study, we used sofosbuvir, an NS5B inhibitor, along with ribavirin for 24 weeks in 62 patients and sofosbuvir along with daclatasvir, an NS5A inhibitor, for 12 weeks in 17 patients because this was the only DAAs licensed in Pakistan.
The initial hindrance in utilization of sofosbuvir-based regimens in RTRs was risk of drug-related interactions with immunosuppressive agents and accumulation of sofosbuvir and its metabolites, leading to renal injury. Recent guidelines3 have not established any drug-related interactions between sofosbuvir and commonly used immunosuppressive drugs. Although Sawinski and associates5 docu-mented 100% SVR in 20 RTRs treated with a sofosbuvir-based regimen with stable renal function, 45% of the study population required calcineurin inhibitor dose reduction. Similar to Kamar and associates6 and Kwo and Badshah,14 none of our study population required immuno-suppressive dose modification.
Fernández and associates10 analyzed 103 RTRs patients from a Spanish registry and found that 98% SVR was reached, with 57% of patients given sofosbuvir plus ledipasvir and 17% of patients given sofosbuvir plus daclatasvir. The group documented allograft rejection in 3, renal dysfunction in 17, and immunosuppression adjustment in 57 RTRs. Various studies and case reports in RTRs have demonstrated effective HCV eradiation with no allograft rejection with a sofosbuvir-based regimen.6-9 This fact was shown in our study population, as none of the RTRs had allograft rejection.
Pakistan has a high incidence of HCV infection, in 4.9% of the general population, with the major genotype reported as genotype 3.15 Because of multiple exposures to dialysis, patients are more prone to mixed genotype infections. More often, its detection is missed due to less sensitive techniques.16 We have demonstrated the efficacy of sofosbuvir plus ribavirin and the combination of sofosbuvir, daclatasvir, and ribavirin in 79 treatment-naive and treatment-experienced RTRs with HCV infection. In our study population, most patients had HCV genotype 1, followed by genotype 3, and we also reported the effectiveness of this regimen in patients with mixed HCV genotype 1 and 3 (n = 10). We observed a significant decline in transaminases in our study population, which is consistent with our previous study result and other studies.5,6,11,17
Limitations of our study include the small study population and nonavailability of multiple newer DAAs. However, the achievement of a 98.7% ETR is quite encouraging. We were also not able to demonstrate the effectiveness of a sofosbuvir-based regimen in treating extrahepatic HCV-related complications.
Hepatitis C virus was successfully eradicated in RTRs using a combination of sofosbuvir plus ribavirin and with combined sofosbuvir, daclatasvir, and ribavirin. These combinations were effective and well tolerated in our study population, even in those with mixed genotype (1 and 3), with no major adverse events.
Volume : 17
Issue : 1
Pages : 198 - 201
DOI : 10.6002/ect.MESOT2018.P64
From the Department of 1Hepatogastroenterology and 2Transplantation, Sindh
Institute of Urology and Transplantation, Karachi, Pakistan
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Farina Muhammad Hanif, 48/2, Lane 15, Khayaban-e-Badban, DHA phase VII, Karachi, Pakistan
Phone: +92 3002171785
Table 1. Clinical Characteristics of Study Population (N = 79)
Table 2. Laboratory Parameters of Renal Transplant Recipients