Objectives: Chronic hepatitis C infection incidence and prevalence are high in Egypt and represent a major health burden. Hepatitis C virus infection can affect graft outcomes in kidney transplant recipients. Treatment of hepatitis C virus infection among this special group was difficult during the interferon era; however, with advances in direct-acting antivirals, treatment outcomes have become more promising.
Materials and Methods: This is a pilot, observational, single-center, one arm study that included 50 kidney transplant recipients seen at the Mansoura (Egypt) Urology and Nephrology Center. Patients were consen-ted to receive a sofosbuvir-based regimen as all had creatinine clearance of greater than 30 mL/min/1.73 m2.
Results: All patients achieved rapid virologic responses 4 weeks after starting treatment. Forty-nine of 50 patients achieved 12-week and 24-week sustained viral responses. Six patients had increased serum creatinine levels. Four graft biopsies were performed. Anemia was the most common adverse effect among the patients who were maintained on ribavirin.
Conclusions: Treatment of chronic hepatitis C infection has become easier and safe with the advance of new direct-acting antivirals.
Key words : Direct-acting antiviral agents, Drug interactions, Kidney transplantation
Hepatitis C virus (HCV) infection can increase morbidity and mortality.1 Cirrhosis, hepatocellular carcinoma, liver transplantation, and liver-related deaths worldwide are complications of HCV.2 Hepatitis C virus represents a great health and economic burden due to its hepatic and extrahepatic manifestations.3
Egypt has the highest incidence of HCV in the world. The incidence of HCV antibodies and HCV RNA in individuals from 15 to 59 years old was estimated by the Egyptian Demographic Health Survey to be 14.7% and 9.8%, respectively, in 2008. Based on the 2008 population census and the Egyptian Demographic Health Survey, it was found that more than 6.8 million individuals aged 15 to 59 years had HCV antibodies, of which more than 4.5 million individuals had active HCV infection.4
Chronic HCV infection is highly represented with a risk of renal impairment.5 The incidence of HCV is higher among patients with chronic kidney disease, particularly stage 5 diseases, than among the general population.6 As a result, chronic HCV infection is common among kidney transplant recipients (KTRs) and is a significant reason for comorbid conditions. Substantial evidence has indicated that chronic HCV infection in renal allograft cases is associated with a higher risk of renal impairment and graft loss and with higher mortality rates.7
Chronic HCV infection is a systemic disease with important extrahepatic manifestations. This disease has been implicated in the pathogenesis of glo-merular diseases and in the development of new-onset diabetes after transplant in KTRs, which may cause cardiovascular disease and malignancy.8
Before the appearance of direct-acting antivirals (DAAs) in 2015, the guidelines recommended a combination treatment with pegylated interferon injections and oral ribavirin. Today, DAAs are the standard treatment for HCV, especially in those with normal kidney function. The DAA-based regimens are advantageous because they have an oral route of administration, few side effects, and a much higher efficacy.9
After kidney transplant, treating HCV infection with the goal of eliminating the risk of complications has been difficult.10 Interferon regimens have been associated with poor tolerability, with these regimens having only modest efficacy in viral eradication.11 In addition, interferon therapy is associated with increased risk of rejection due to its immuno-stimulatory effect, and ribavirin alone cannot affect the HCV viral load.12
Since the advent of DAAs, several studies have been done among recipients of liver and other solid-organ transplants with HCV infection. In these groups, DAA-based therapy has been found to be safe and effective, and its use is recommended.13 However, the experience with these drugs in KTRs is limited.
Materials and Methods
In this pilot study, 394 KTRs of 2700 who were shown to be HCV antibody positive after screening using the chemiluminescent microparticle immunoassay technique, ARCHITECT set (Abbott, Abbott Park, IL, USA), were considered for inclusion. All of these patients were seen at the Mansoura Urology and Nephrology Center until December 2015. Quantitative HCV RNA polymerase chain reactions (PCRs) were performed for HCV antibody-positive KTRs using the HCV RNA TaqMan real-time PCR test, Ampiprep/COBAS TaqMan 48 set (Roche, Indianapolis, IN, USA), which considered viral loads below 15 IU/L as negative. The results were positive for 114 patients. Fifty patients were enrolled in this study, and they were consented to receive the DAAs.
Before start of treatment, all patients were investigated for serum creatinine levels and creatinine clearance, liver function tests, serum albumin, lipid profile, complete blood counts, urine analysis, drug levels, antinuclear antibodies, and alpha-fetoprotein. In addition, pelvic-abdominal and liver ultrasonography scans were done for all patients.
The plan for treatment was determined by the hepatology consultants. Before treatment, hepatic decompensation and creatinine clearance results were considered as recommended by the 2015 European Association for the Study of the Liver Guidelines14 and the Protocol of Insurance Institute Egyptian Ministry of Health. All patients received a sofosbuvir-based regimen (dual DAA) because all patients had stable graft function with creatinine clearance of more than 30 mL/min/1.73 m2. A triple DAA regimen that included ribavirin was prescribed to 5 patients who experienced relapse on or after interferon therapy. Duration of treatment was 6 months. The dose of ribavirin was calculated with regard to creatinine clearance for each patient (those with level > 50 mL/min received 1200 mg, and those with levels of 30-49 mL/min received alternating doses of 200 and 400 mg every other day). No discontinuation of any drug occurred except for ribavirin, which was modified or stopped due to drop of hemoglobin levels.
During the treatment period, liver function and renal function were monitored monthly. Drug trough levels were assessed every 2 weeks during month 1 and then monthly. A baseline quantitative HCV PCR was done for all patients and then at 1 month after start of treatment and at 3 and 6 months after end of treatment.
Thirty-three patients received tacrolimus, 15 patients received cyclosporine, and 10 patients received sirolimus for immunosuppression. Thirty-five patients were maintained on mycophenolate mofetil and 10 patients on azathioprine. Induction therapies utilized included basiliximab (29 patients) and thymoglobulin (7 patients).
Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 17.0, IBM Corporation, Armonk, NY, USA). Descriptive measures were used for demographic and pre-treatment data. The repeated-measures analysis of variance test for parametric data and the Freidman test for nonparametric data were used to compare the laboratory findings before, during, and after treatment. P ≤ .05 was considered significant.
Baseline demographic characteristics
Fifty KTRs were included in this study. Mean age was 41.4 ± 11.6 years, and 41 patients were males. Mean body mass index was 23.1 ± 3.9 kg/m2. Five patients were treated with interferon before transplant; however, the interferon course was not completed due to recurrent infections and bone marrow suppression, and HCV was not cleared. Hepatitis B virus coinfection was reported in 2 patients, and both received lamivudine, with hepatitis B virus PCR becoming below detection limits before start of DAA therapy. One patient was diagnosed with hepatocellular carcinoma, and he was treated with chemoembolization.
Baseline kidney transplant data
Mean duration after kidney transplant was 13.5 ± 5.4 years. Regarding graft function, baseline serum creatinine level was 1.3 ± 0.6 mg/dL, and estimated glomerular filtration rate was 69.3 ± 33.24 mL/min/1.73 m2. Glomerular filtration rate was estimated using the Modification of Diet in Renal Disease equation. In our patient group, 54% had previous acute rejection episodes and 38% had chronic changes at their last biopsy (Table 1).
Child-Pugh score assessment showed that 94% of patients were Child-Pugh class A. A noninvasive assessment for liver fibrosis (FibroScan, Echosens, Paris, France) was performed for all patients (Table 2): ~90% had no fibrosis (F0) or portal fibrosis (F1), and the remainder had portal fibrosis with septae (F2) or bridging fibrosis (F3). Mean viral load (quantitative HCV PCR) before start of treatment was 285 796 ± 52 364 IU/mL. Forty-five patients were genotype 4, and 5 patients were genotype 1 (genotype 2). Antinuclear antibodies and alfa-fetoprotein levels were within normal ranges.
Efficacy of treatment
All patients achieved a rapid virological response (RVR) within 4 weeks of starting DAAs. A sustained viral response (SVR) at 12 weeks and 24 weeks was successfully reached in 49 patients (98%). The relapse occurred in the sofosbuvir and ribavirin group 3 months after completion of treatment. A significant improve-ment in liver enzyme levels was shown (P < .001) with no significant hematologic effects (Table 3).
Direct-acting antivirals were tolerable for patients, and there were few adverse effects. Seven patients on ribavirin had anemia, with 1 patient needing blood transfusion. Ribavirin dose was reduced to 30% in 5 patients and discontinued for 2 patients. This corrected anemia in the patients; therefore, no significant differences were shown regarding hemoglobin levels before, during, and after treatment (Table 3). The patient with relapse showed severe decompensation 3 months after the end of treatment, with increased liver enzymes and low albumin levels; he was then treated with liver supportive drugs, including ursodeoxycholic acid and intravenous albumin and diuretics, and received regular upper gastrointestinal endoscopy with ligation of any varices. Unfortunately, 1 case of malignancy was found: this was non-Hodgkin lymphoma and not hepatocellular carcinoma.
Regarding graft function, serum creatinine levels increased in 6 patients, and graft biopsies were done for 4 patients. Biopsies revealed acute cellular rejection grade 1A in 1 patient, acute cellular rejection grade 1B in 1 patient, chronic transplant glomerulopathy in 1 patient, and acute tubular injury in 1 patient (Table 4).
We observed no significant differences in serum creatinine levels, creatinine clearance, and tacrolimus, cyclosporine, and sirolimus trough levels before, during, and after treatment (Table 5).
To the best of our knowledge, this is the first study to assess the safety and efficacy of sofosbuvir-based DAAs in HCV-positive KTRs (genotype 4) in Egypt. Type and duration of the different DAAs were chosen according to guidelines for the treatment of HCV in renal transplant patients.14
In our work, all patients achieved RVR 4 weeks after start of treatment. In a French population, Kamar and associates reported that RVR was achieved in only 80% of patients.15 They also observed no difference between cirrhotic and noncirrhotic patients. These results differ from those observed by Lin and colleagues,16 in which noncirrhotic patients achieved an undetectable viral load sooner than cirrhotic patients. However, not all of the patients reached RVR within 4 weeks. This may be due to differences in race/ethnicity and/or genotype in which about 80% of their cases were genotype 1.16
An SVR represents the standard measure for successful treatment. As reported in the 2015 European Association for the Study of the Liver Guidelines, SVR is defined as undetectable HCV RNA at 12 weeks after completion of DAA treatment.14 In our cohort, 98% achieved SVRs at 12 and 24 weeks. In the study from Kamar and colleagues,15 SVR at week 12 was 100% but SVR at week 24 was only reached in 8 of 25 patients (32%) (only 25 patients had available data at this point of follow-up). In a US study from Sawinski and associates, 100% of patients achieved SVR at week 12, but their study included a small number of cases (25 patients) and only included a sofosbuvir-based regimen.17 Goel and associates reported that an RVR and an SVR of 100%, but their sample size included only 6 KTRs.9
In our study, liver enzyme levels, serum bilirubin, and serum albumin were assessed before, during, and after treatment. The overall significant improve-ment that we observed is similar to that reported in an Austrian study by Beinhardt and colleagues.18
Anemia was only reported in recipients who received ribavirin (7 patients). Dose modifications were needed, and erythropoietin-stimulating agents were added until hemoglobin levels improved. Therefore, there were no significance differences in hemoglobin levels before, during, and after treatment. Bhamidimarri and associates had advised to not use ribavirin.19 Apart from ribavirin, the other DAAs were well tolerated and did not cause any significant adverse effects, which is similar to the findings reported by the PRISMA-compliant study from Chen and associates (meta-analysis of 6 studies that including 360 kidney transplant patients).20
Regarding graft function, 6 patients (12%) had increased serum creatinine levels in our patient cohort. At the end of treatment, serum creatinine had improved in 4 of 6 patients. Four graft biopsies were performed, with 1 revealing transplant glomeru-lopathy, 2 with acute graft rejection, and 1 showing acute tubular injury. Bhamidimarri and associates reported increased serum creatinine in 4 of 25 patients with biopsy-proven antibody-mediated rejection and no improvement at the end of treatment.19 No graft rejection episodes were reported by Lin and associates.16 In the study from Sawinski and associates, 4 of 20 KTRs showed increased serum creatinine levels, which had resolved after stopping losartan.17
Calcineurin inhibitors and sirolimus trough levels were not affected by drug interactions with the sofosbuvir regimens, and there were no changes in these doses during treatment in our study patients. This result was also reported in liver transplant recipients maintained on tacrolimus with sofosbuvir and ribavirin.21
Dose adjustments, mainly increases, were required for 13 of 25 patients in the study from Bhamidimarri and associates, especially after clearance of viral load and improvement in liver function tests.19 Kamar and colleagues15 also reported a significant reduction in tacrolimus trough levels during and after treatment, but, in contrast to our study, no change in dose was required. Our results may be attributed to recipients having worse liver conditions or a longer period of HCV infection.
Our study has some limitations. First, it was observational and lacked the rigor of a randomized controlled trial. We were also unable to assess the effects of DAAs on proteinuria posttransplant. In addition, the safety of sofosbuvir in those with low creatinine clearance was not tested. No protocol biopsies were performed during DAA treatment to detect any subclinical rejections. This study included a large number of Egyptian kidney transplant patients who were maintained on various types of immunosuppressive drugs.
We conclude that the DAAs effectively treated HCV in our cohort of Egyptian KTRs, who had prevalence of genotype 4 and of which some were cirrhotic, regardless of the immunosuppressive regimen used and time since transplant. Few adverse events affected the transplanted kidney, and changes in immunosuppressive drug trough levels were minimal.
Volume : 17
Issue : 1
Pages : 62 - 67
DOI : 10.6002/ect.MESOT2018.L57
From the 1Urology and Nephrology Center, Mansoura University; the
Medicine Department, Zagazig University; and the 3Egyptian Liver Research
Institute and Hospital, Mansoura, Egypt
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare. The HCV Working Group includes the Urology and Nephrology Team of Mohamed Adel Bakr, Mohamed Ashraf Foda, Ayman Refaie, Ahmed Donia, Samir Sully, Hussein Sheashaa, Khaled Eldahshan, Salwa Elwasif, Ahmed Kamal, Hanzada El Maghrabi, Mohamed Zahab, Mohamed Hamed, Mohamed Saftawy, Mohamed Mashaly, Yasser Matter, Ahmed Elmowafy, Mohamed Taher, Mohamed Hosny, Eman Refaie, Ahmed Naguib, and Hazem Saleh; and the Egyptian Liver Research Institute and Hospital Team of Gamal Elsayed Shiha, Reham Elsayed Soliman, and Mohamed Adel Elbassiony. We thank the Egyptian Medical Insurance System for affording the direct-acting antivirals.
Corresponding author: Mohamed Adel Bakr, Urology and Nephrology Center, Mansoura University, El gomhoria Street, PO Box 35516, Mansoura, Egypt
Phone: +20 502202222
Table 1. Demographic Data and Associated Medical Disorders in Kidney Transplant Recipients (N = 50)
Table 2. Clinical Conditions Associated With Hepatic Disease in Kidney Transplant Recipients (N = 50)
Table 3. Laboratory Investigations
Table 4. Treatment Details and Complications in Kidney Transplant Recipients (N = 50)
Table 5. Graft Function and Immunosuppressive Drugs