Objectives: Recurrent hepatitis C is universal after liver transplant when viremia is present at the time of transplant, and this affects survival. Previous treatments with pegylated interferon and ribavirin with or without boceprevir or telaprevir have yielded modest sustained virologic response rates and frequent adverse effects. A combination of new antiviral agents has been used for recurrent hepatitis C. We aim to describe the outcomes of recurrent hepatitis C in liver transplant patients treated with simeprevir, sofosbuvir, and ribavirin.

Materials and Methods: Fifty-three consecutive patients with recurrent hepatitis C genotype 1 were included. All patients had liver biopsy before enrollment if cirrhosis was not evident. Standard doses of simeprevir and sofosbuvir were used for 12 weeks. Ribavirin was adjusted based on hemoglobin levels. In 53 patients, 50 completed 12 weeks of treatment.

Results: All 50 patients who completed 12 weeks of treatment achieved sustained virologic response. One patient who completed only 6 weeks also achieved sustained virologic response. Overall, the antiviral treatment was well tolerated, with no interactions with immunosuppressive drugs.

Conclusions: The combination of simeprevir and sofosbuvir with or without ribavirin yields a high sustained virologic response rate of 96% in a historically difficult to treat patient population (recurrent hepatitis C genotype 1).

Key words : Direct-acting agents, NS3 protease inhibitor, NS5b polymerase inhibitor.

Introduction

Allograft reinfection with hepatitis C virus (HCV) is universal when HCV RNA is present at the time of liver transplant.¹ The development of fibrosis and graft dys­function after liver transplant occurs at an ac­ce­l­erated rate, with an associated increased mortality.^2-6

In the past, treatment of HCV after liver trans­plant with pegylated interferon and ribavirin, as well as with the addition of first-generation protease inhibitors (boceprevir and telaprevir), have resulted in sustained virologic response (SVR) rates of 20% to 60%.7-13 These regimens have been hampered by numerous adverse effects, frequent dose adjust­ments, and need for intense immuno­suppressive mo­nitoring.^7-13 On the other hand, the newer regimens have better safety and efficacy profiles. Sofosbuvir, a potent inhibitor of the HCV NS5B polymerase inhibitor with pan-genotypic activity and high barrier to resistance, was approved for treatment of HCV in 2013.¹⁴ Sofosbuvir has shown minimal interactions with calcineurin inhibitors.^15,16 Simeprevir, an HCV NS3/4A protease inhibitor, also was approved for treatment of HCV genotype 1 infection and has been used in combination with sofosbuvir with or without ribavirin.^17-19 Hepatitis C virus NS3 Q80K poly­morphism, which is shown in up to 34% of North American patients with genotype 1A, is associated with reduced response to simeprevir. However, given the high SVR rates, the presence of Q80K mutation does not preclude treatment with the combination of simeprevir and sofosbuvir.^17,19,20

The efficacy of the newer antiviral regimens in the setting of recurrent HCV has been previously described. Sofosbuvir in combination with ribavirin for 24 weeks (83% genotype 1) resulted in a 12-week posttreatment SVR of 70%.21 Twelve to 24 weeks of sofosbuvir and ledipasvir with ribavirin (98% genotype 1) had a 12-week posttreatment SVR of 60% to 98%.²² A 24-week regimen containing the NS5A inhibitor ombitasvir coformulated with ritonavir-boosted protease inhibitor paritaprevir, a non­nucleoside NS5B polymerase inhibitor, and dasabuvir with ribavirin for genotype 1 resulted in 24-week posttreatment SVR of 97%.²³ Most recently, single center data have emerged reporting the use of simeprevir and sofosbuvir with or without ribavirin with 12-week posttreatment SVR rates of 75% to 100%.^24-31

In this study, we report our results with a sofosbuvir and simeprevir combination regimen with or without ribavirin in recurrent HCV after liver transplant in genotype 1-infected patients.

Materials and Methods

Fifty-three consecutive liver transplant patients with recurrent HCV genotype 1 infection who received antiviral HCV therapy between January 1, 2014, and September 1, 2014, were included in this report. Records of all patients were reviewed for demographics, liver function tests, complete blood count, HCV RNA levels, and liver biopsy findings. This retrospective data collection was approved by the Institutional Review Board of the University of Tennessee Health Sciences Center. Because this study only involved retrospective review of medical records, no consent from patients was required by the Institutional Review Board.

Patients received 400 mg of sofosbuvir, 150 mg of simeprevir, and ribavirin daily for 12 weeks. The starting dose of ribavirin was 800 mg daily but was increased up to a maximum of 1200 mg if tolerated. Four patients did not receive ribavirin because they had baseline hemoglobin levels of under 10 g/dL. Erythropoietin was used when hemoglobin levels declined to less than 10 g/dL, with ribavirin dose reduced to 400 mg daily in patients who had a decrease in hemoglobin levels to less than 8 g/dL.

Liver function tests, complete blood count, and immunosuppression drug levels were followed every 2 weeks. Immunosuppression regimens were not changed during treatment. Hepatitis C virus RNA was determined at baseline, at 4-week intervals during treatment, and at 4, 12, and 24 weeks after the completion of therapy.

Results

The patient’s clinical characteristics are summarized in Table 1. Among 53 patients, 34 (64%) were male, 34 (64%) were white, and 16 (30%) were African Americans. Forty-seven patients (88%) had HCV genotype 1a infection. All patients were non-CC IL28-B genotype, 12 had TT, and 41 had CT. The IL28-B results were obtained before transplant. The mean time for starting treatment was 1.2 ± 0.9 years after liver transplant. Two patients started treatment within 6 months of receiving a liver transplant. None of the patients received prophylactic antiviral therapy. Thirty-eight patients (72%) were on tacrolimus monotherapy, 4 patients (8%) were on sirolimus monotherapy, 6 patients (11%) were on tacrolimus and sirolimus, and 5 patients (9%) were on tacrolimus and mycophenolate mofetil. No patients in this cohort had received a transplant from an HCV-positive donor.

Thirty patients received pegylated interferon and ribavirin treatment, with 18 patients treated before transplant and 12 patients treated after liver transplant. None of the patients had received either telaprevir or boceprevir. Two patients had baseline renal insufficiency, with creatinine clearance of < 40 mL/min.

Six patients had cirrhosis, with 2 decompensated with ascites requiring paracentesis during treatment. Six patients were initiated on antiviral treatment within 2 months of receiving pulse-dose steroids for acute cellular rejection. These patients were on dual immunosuppression (tacrolimus and myco­phenolate mofetil or tacrolimus and sirolimus) and had jaundice at the beginning of HCV treatment.

Safety/tolerability
Fifty patients completed 12 weeks of treatment (Figure 1). Three patients required discontinuation of antiviral therapy. One patient with a history of coronary artery disease and decompensated cirrhosis who continued to deteriorate regarding liver function also had an acute myocardial infarction at week 6 of treatment and died as a consequence of this. This patient had previous significant history of coronary artery disease. A second patient with severe recurrent HCV and jaundice developed congestive heart failure (ejection fraction of 15%) at week 6 of treatment. The treatment was discontinued. His cardiac function improved after 6 months, with an echocardiogram showing an ejection fraction of 30%. Although his antiviral treatment was discontinued at week 6, he achieved SVR. A third patient discontinued treatment at week 2 due to hospitalization for uncontrolled diabetes and sepsis.

A patient with membranous proliferative glomerulonephritis and baseline creatinine level of 2.5 mg/dL continued to have deterioration in her renal function. She developed end-stage renal disease requiring hemodialysis 8 weeks after completion of antiviral treatment.

One patient required transfusion of packed red blood cells and discontinuation of ribavirin due to anemia (hemoglobin < 7 g/dL). Six patients had hemoglobin levels below 10 g/dL during treatment and were treated with erythropoietin without ribavirin dose reduction.

Figure 2 highlights changes in hemoglobin and bilirubin levels. The median decrease in hemoglobin level was 2 g/dL from baseline, which promptly returned to baseline after discontinuation of treatment. The 6 patients with elevated bilirubin levels tolerated treatment well with eventual normalizations of bilirubin. One patient with elevated bilirubin level and decompensated cirrhosis deteriorated and expired as discussed above.

Treatment efficacy
Of 53 patients, 51 (96%) achieved 12-week post­treatment SVR. All 52 patients (excluding the patient who stopped treatment at 2 weeks) had undetectable HCV RNA at week 4. All 50 patients who completed 12 weeks of treatment achieved 12-week and 24-week posttreatment SVR (100% SVR; Figure 3). One patient showed low-level viremia (36 IU/mL) at the end of treatment but subsequently achieved SVR. One patient had detectable HCV RNA 4 weeks after the completion of treatment, but  this was undetectable at week 12 and 24 post­treatment.

Immunosuppression
No significant interactions between sofosbuvir and simeprevir treatment were seen with the immuno­suppressant regimens. The drug levels were within expected ranges during treatment, and no significant changes in immunosuppression regimen were made during antiviral treatment. Two patients had acute cellular rejection at weeks 4 and 8 after completion of antiviral treatment. Both patients had low tacrolimus levels and responded to increases in immunosuppression.

Discussion

Our study included 53 consecutive patients with chronic HCV genotype 1a or 1b who had recurrent HCV after liver transplant. The combination of simeprevir and sofosbuvir with or without ribavirin was found to be highly effective. All 50 patients who were able to complete 12 weeks of treatment achieved 12-week and 24-week posttreatment SVR (100% SVR per protocol). One patient, who interrupted treatment at 6 weeks, also achieved SVR. The SVR rates of our study are in accordance with those of the “COSMOS” (Combination of Simeprevir and Sofosbuvir in HCV Genotype 1-Infected Patients) study¹⁹ but sig­nificantly higher than the SVR rates shown in real-world experiences postmarketing.³²

We elected to use ribavirin in our transplant recipients because this agent historically has had a lower response rate to antiviral therapy.^7,8,11,12 It has been described that ribavirin has some activity against sofosbuvir-resistant strains.³³ Moreover, in human immunodeficiency virus-coinfected patients, addition of ribavirin to the sofosbuvir regimen resulted in a 76% SVR rate.³⁴ Moreover, a 12-week regimen of ledipasvir and sofosbuvir with ribavirin resulted in SVR rates equivalent to those shown with 24-week ledipasvir and sofosbuvir regimen without ribavirin.²² These studies suggest a potential role for ribavirin in sofosbuvir-containing regimen in the difficult to treat patient population. It is possible that the lower than expected results in the HCV-TARGET study was partly due to a lower use of ribavirin in some of the difficult to treat population.

Liver transplant recipients are at a higher risk of ribavirin-induced anemia due to reduced glo­merular filtration rates from calcineurin inhibitor toxicity coupled with myelosuppressive effects of immuno­suppressive drugs. As anticipated, the addition of ribavirin resulted in higher incidence of anemia. One patient required red blood cell transfusion, and ribavirin was discontinued. The remaining 45 patients, who completed 12 weeks of treatment, tolerated ribavirin and continued with at least 800 mg/day.

Although in the United States there is about 34% Q80K mutation in genotype 1a and this has been associated with modest SVR rates when simeprevir and pegylated interferon have been used, we chose not to test our patients for this polymorphism.^17,20 In our cohort, the vast majority of patients were genotype 1a, but the SVR rates were not affected. We believe that when simeprevir and sofosbuvir are combined the relevance of the Q80K mutation is of limited significance. Our SVR rates are in agreement with the “COSMOS” study, which reported similar results with the combined simeprevir and sofos­buvir regimen.¹⁹ Q80K testing is expensive, and its use in the clinical setting appears doubtful when the com­bination of simeprevir and sofosbuvir is planned.

Nonischemic cardiomyopathy has been described as a potential adverse effect of calcineurin and mammalian target of rapamycin inhibitors.³⁵ Simeprevir and sofosbuvir have not been recognized as cardiotoxic, although some reports showed that early NS3 protease inhibitors had potential of producing cardiomyopathy.^36,37 The only patient who developed heart failure was on sirolimus, tacrolimus, simeprevir, and sofosbuvir, making it difficult to dissect whether this event was caused by antiviral therapy. The only death among our patients occurred after a myocardial infarction in a patient who had underlying heart disease and deteriorating liver function while on treatment.

We obtained a high SVR rate despite the presence of previously recognized adverse factors for antiviral response, such as ongoing high level of immuno­suppression from recent episodes of acute cellular rejection, cirrhosis, higher percentage of African American patients, and a large number of before treatment failures.³⁸ Similar results with simeprevir and sofosbuvir also have been shown.^36,37

Other regimens have been used for treatment of recurrent HCV after liver transplant. The Solar 1 study yielded 12-week posttreatment SVR rates of 96% to 98% for F0 to F3 Child-Pugh score, 96% for F4 Child-Pugh score class A, 83% to 85% for F4 Child- Pugh score class B, and 60% to 67% for F4 Child-Pugh score class C.²² A 24-week regimen containing the ombitasvir, ritonavir-boosted protease inhibitor paritaprevir, and dasabuvir with ribavirin for genotype 1 patients with mild fibrosis resulted in 24-week posttreatment SVR of 97%.²³

On the other hand, 24 weeks of sofosbuvir and ribavirin had inferior results (12-wk posttreatment SVR of 70%) compared with our data, the Solar-1 and Coral studies.^21-23 The short duration and the excellent tolerability of simeprevir and sofosbuvir with or without ribavirin make this combination a com­petitive option versus other available regimens.

In conclusion, our study demonstrated that treatment with the combination of simeprevir and sofosbuvir with or without ribavirin was safe and well tolerated without major interactions with immuno­suppressants. The simeprevir and sofosbuvir with or without ribavirin regimen yields excellent 12-week posttreatment SVR rates of 96% in a historically difficult to treat population. For this reason, this regimen should be considered a first treatment option for genotype 1 recurrent HCV after liver transplant. The short duration of treatment makes the adverse effect with ribavirin manageable and possibly adds efficacy to the antiviral regimen in this patient population.

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