Objectives: Although direct-acting antiviral agents have revolutionized hepatitis C virus treatment, these novel agents are not widely available in the developing world. Further, no treatment recommendation for renal transplant recipients includes these agents. We aimed to evaluate the effectiveness of sofosbuvir and ribavirin, the only direct-acting antiviral agents available in Pakistan, in renal transplant recipients.
Materials and Methods: All renal transplant recipients receiving sofosbuvir and ribavirin from August 2015 to March 2016 were enrolled in the study. Patients’ demographics and baseline laboratory parameters were collected. Rapid virologic response, early virologic response, end-of-treatment response, and sustained virologic response at 12 and 24 weeks were analyzed. Statistical analyses were performed using IBM SPSS Statistics software, version 20.0.
Results: Of the 37 renal transplant recipients, the mean age was 37.2 ± 10.7 years and the majority (33 [89.2%]) were men. Twenty-five patients were treatment naive; of the remaining 12 patients, 10 were responders, 2 were nonresponders, and 5 were relapsers to pretransplant hepatitis C treatment. The genotype most commonly seen posttransplant was genotype 1 (56.8%). Rapid virologic response was achieved in 33 patients (89.2%). Early virologic response, end-of-treatment response, and sustained virologic response at 12 weeks were achieved in all 37 patients (100%). Until the time of data collection, 14 patients had achieved a sustained virologic response at 24 weeks. No complications were noted during therapy. In 2 of 4 patients who developed decompensated cirrhosis, treatment led to the resolution of ascites.
Conclusions: Sofosbuvir and ribavirin are well tolerated and effective in renal transplant recipients for eradicating hepatitis C virus. Their effectiveness is not limited to renal transplant recipients with genotypes 1, 2, 3, and 4 but also extends to those with mixed genotype (in this study, genotypes 1 and 3).
Key words : Direct-acting antiviral agents, Genotype, Hepatitis
Hemodialysis is a risk factor for hepatitis C virus (HCV) infection.1 The prevalence of HCV in hemodialysis patients in Pakistan ranges from 16.4% to 68.0%.2 Anti-HCV seropositive renal transplant recipients (RTRs) have better survival outcomes compared with patients receiving hemodialysis. Hence, renal transplant is not contraindicated on the basis of HCV infection.3
With the advent of interferon-free direct-acting antiviral agents (DAAs), the treatment of HCV has been reformed. Considering their low treatment efficacy and high risk of adverse effects, interferon-based therapies in RTRs are now limited only to life-threatening conditions.4,5 However, although DAAs are considered safe in most HCV-infected patients after renal transplant, there is no official recommendation of their use in hemodialysis patients or RTRs.6
Recently, a few studies (including case reports) have documented the effective eradication of HCV infection after renal transplant with DAAs.4,5,7,8 Sawinski and associates4 and Kamar and associates7 documented a 100% sustained virologic response (SVR) in RTRs they studied. Both studies reported neither adverse effects nor allograft rejection with sofosbuvir-based therapy.
Sofosbuvir is the only DAA currently available in Pakistan, and its use in renal and liver transplant patients has been documented as showing an encouraging response. Therefore, we aimed to document the effectiveness of sofosbuvir and ribavirin combination therapy for the eradication of HCV infection in RTRs.
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, and received sofosbuvir and ribavirin from August 2015 to March 2016, were included in the study. All of the protocols conformed to the ethical guidelines of the 1975 Helsinki Declaration. Written informed consent was obtained from all participants.
All recipients’ laboratory parameters were recorded at the start of treatment and then after 4, 12, and 24 weeks of therapy. In all patients, glomerular filtration rate (GFR) was calculated using the Modification of Diet in Renal Disease formula. Hepatitis C virus polymerase chain reaction (PCR) and genotype (GN) testing were performed in all recipients at the start of treatment (Roche Cobas TaqMan and Abbott RealTime HCV). All patients were given 400 mg generic sofosbuvir and a GFR-based dose of ribavirin for 24 weeks.9
During treatment, HCV PCR was checked at 4, 12, and 24 weeks to document rapid virologic response (RVR), early virologic response, and end-of-treatment response. After the treatment period ended, HCV PCR was checked at posttreatment weeks 12 and 24 to document SVR (ie, SVR 12 and SVR 24). All renal donors were negative for hepatitis B virus surface antigen, anti-HCV and anti-HIV 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 the paired t test or the Wilcoxon signed-rank test, as indicated. Categorical variables were analyzed using the chi-squared test or the Fisher exact test. A comparison of quantitative variables with repeated measurements was analyzed using the Friedman test. A value of P < .05 was considered statistically significant.
In our study population, the male-to-female ratio was 33:4, with mean age of 37.2 ± 10.7 years. The clinical characteristics of patients are shown in Table 1.
Of a total of 37 patients, 12 were treated for HCV before transplant. Most of the patients (7 [58.3%]) had GN 1. All patients received interferon-based treatment. In these 12 patients, 2 were nonresponders, and both had GN 1. Among the remaining 10 responders, 5 patients relapsed with HCV after transplant. Of the total study population, the majority had GN 1 (n = 21). None of our patients had GN 5 or GN 6. Four patients had mixed GN HCV (ie, 1 and 3).
Rapid virologic response was defined as undetected HCV PCR at 4 weeks after starting therapy and was observed in 33 RTRs (89.2%). For all patients, early virologic response, end-of-treatment response, and SVR 12 were achieved by the end of the study—a 100% response. Twenty-four weeks after sofosbuvir and ribavirin therapy ended, data were available for only 14 patients; of these, 100% achieved SVR 24.
In our study population, no rise in creatinine was observed during the treatment period with sofosbuvir and ribavirin. Therefore, no renal biopsies were performed to diagnose subclinical graft rejection. In fact, there was a mean decrease in creatinine during the treatment period: from 1.45 ± 0.48 mg/dL to 1.15 ± 0.37 mg/dL at week 24 (P = .026). In contrast, a rise in GFR was noted from the start to the end of therapy, from 63.70 ± 17.49 mL/min to 80.77 ± 16.05 mL/min at week 24 (P = .038) (Table 2).
Although liver enzyme levels decreased from baseline values, a statistically significant decline was noted only in levels of alanine transaminase (P = .070). The mean value of serum hemoglobin remained stable in the majority of patients throughout the course of sofosbuvir and ribavirin therapy (Table 2); however, 4 patients required ribavirin dose modification owing to anemia.
All patients received azathioprine (54.1%) followed by cyclosporine (44.4%) for immunosuppression. Because there was no documented rise in creatinine, no immunosuppression-level testing was performed, in accordance with institutional protocol.
Other than anemia in 4 patients, no other adverse events were noted among our patients. Of the 4 patients with decompensated HCV cirrhosis, resolution of ascites occurred in 2.
Here we report on the successful eradication of HCV in RTRs using a combination of sofosbuvir and ribavirin. This combination was effective and well tolerated in our study population with no major adverse events. Sofosbuvir and ribavirin combination therapy not only efficiently eradicated HCV genotypes 1, 2, 3, and 4 but was effective in RTRs which had mixed infection with HCV genotypes 1 and 3.
In Pakistan, the prevalence of HCV is 4.9% of the general population, with the most common type being genotype 3.9 Although no local study has demonstrated the incidence of HCV in RTRs, Western studies have reported it to be from 1.8 to 8.0%.10 Hepatitis C virus acquired before renal transplant has been reported to have inconsistent consequences; some studies have shown detrimental results, while others have negated those findings.3,11-13 However, a meta-analysis of observational studies in RTRs with HCV demonstrated increased all-cause mortality and all-cause graft loss in these patients.14
In RTRs who become infected with HCV after transplant, the duration from receiving a transplant to acquiring the infection was an important predictor of survival.15 In our study, 25 of 37 patients had developed HCV infection after renal transplant. As per institutional policy, anti-HCV-positive kidney donation was not acceptable to avoid organ-related virus transmission. Although both recipients and donors were tested for anti-HCV antibodies, and HCV PCR was performed before transplant, there was a remote likelihood of HCV infection being missed on account of intermittent viremia due to virus sequestrated in liver and peripheral cells.5
Owing to the increased risk of acute allograft rejection, adverse events, and decreased efficacy, interferon is contraindicated in RTRs except in cases of life-threatening vasculitis or fibrosing cholestatic hepatitis.4,5,16 Because there is no recommended treatment regimen for HCV in RTR, avoiding antilymphocyte antibodies, decreasing corticosteroid dose, and switching from tacrolimus to cyclosporine are among case management strategies.5 However, recently approved DAAs have revolutionized the treatment of HCV owing to their shorter treatment duration, little to no drug resistance, and interferon-free regimen. These agents target nonstructural viral proteins such as NS3A, NS4A, NS4B, NS5A, and NS5B.17
Recent studies and case reports in RTRs have demonstrated the effectiveness of sofosbuvir-based DAA regimens for HCV eradiation with no allograft rejection.4,5,7,8 In our study, we used sofosbuvir, an NS5B inhibitor, along with ribavirin for 24 weeks because this was the only DAA licensed in Pakistan. Charlton and associates18 reported 70% SVR in liver transplant recipients using a similar regimen. Sawinski and associates4 and Kamar and associates7 used sofosbuvir and ribavirin in only 3 RTRs out of 20 and 25 patients who also achieved 100% SVR.
The drug sofosbuvir is excreted by the kidneys, and is currently not recommended in patients with GFR< 30 mL/min.6 In our study population, all patients had GFR above the aforementioned value (range, 32-96 mL/min). Of these, 33 patients (89.2%) demonstrated RVR, while early virologic response and end-of-treatment response were achieved in 100% of patients. Kamar and associates7 reported similar results using various sofosbuvir-based DAA drug regimens in their study population. Sustained virologic response is considered to be an indicator of HCV eradication, and SVR 12 is currently considered an endpoint for testing all oral DAA therapies.17 We demonstrated 100% SVR 12 in our study population. By the time of this writing, 14 patients had achieved SVR 24.
Owing to the risk of drug–drug interactions with immunosuppressive agents, RTRs were not enrolled in the initial clinical trials of sofosbuvir. For HCV, the guidelines of the American Association for the Study of Liver Diseases19 and the European Association for the Study of the Liver20 have not established any such interactions between sofosbuvir and azathioprine, cyclosporine, everolimus, mycophenolate mofetil, or tacrolimus. This fact was borne out in our study population, none of whom required immunosuppressive therapy modification.
This was the first study to demonstrate the efficacy of sofosbuvir and ribavirin combination therapy in 37 treatment-naïve and treatment-experienced RTRs with HCV infection. In our study population, the majority of patients had HCV GN 1, followed by GN 3, and for the first time, we reported the effectiveness of this regimen in patients with mixed HCV GN 1 and 3 (n = 4). Among 4 RTRs with decompensated cirrhosis, along with achieving SVR 12, ascites was also documented to resolve 2 patients. All of these patients remained on active surveillance for hepatocellular carcinoma.
Limitations of the study include a small study population and a short follow-up. In view of the fact that there is no recommendation for using DAAs in RTRs for HCV eradication, achieving a 100% SVR 12 rate with sofosbuvir and ribavirin, 2 widely available antiviral agents, is encouraging. Although medical advancements will make multiple new agents available, in developing countries, these novel agents are not readily available. We were also not able to demonstrate the effectiveness of sofosbuvir and ribavirin for treating extrahepatic HCV-related complications.
This study also raises several questions. First, what is the optimal time for starting HCV-eradication therapy (pretransplant or posttransplant)? Second, can early posttransplant HCV treatment prevent transplant-related complications such as proteinuria, glomerulonephritis, etc.? Third, what are the long-term effects of curing posttransplant HCV on a patient’s survival and allograft outcome? Fourth, what should the treatment strategy be if RVR is not achieved because other DAAs are not available? Should treatment with sofosbuvir and ribavirin be continued because “futility of treatment” is not yet defined in this subset of patients?
Sofosbuvir and ribavirin are well tolerated and effective in eradicating HCV in RTRs. Their effectiveness is not limited to HCV GNs 1, 2, 3, and 4 but extends to RTRs with mixed GNs, for example, 1 and 3.
Volume : 15
Issue : 1
Pages : 63 - 67
DOI : 10.6002/ect.mesot2016.O50
From the 1Department of Hepatogastroenterology, 2Transplantation, and
3Gastrointestinal Surgery, Sindh Institute of Urology and Transplantation,
Acknowledgements: The authors declare that they have no sources of funding for this study, and they have no conflicts of interest to declare.
Corresponding author: Farina M. Hanif, Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi-74200, Pakistan
Phone: +92 219 921 5752
Table 1. Clinical Characteristics of the Study Population (N = 37)
Table 2. Laboratory Parameters of Renal Transplant Recipients Correlated With Treatment Duration