Elbasvir/Grazoprevir Use in Postliver Transplantation Patients on Hemodialysis : Transplantation

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Original Clinical Science—Liver

Elbasvir/Grazoprevir Use in Postliver Transplantation Patients on Hemodialysis

Martin, Michelle T. PharmD, BCPS, BCACP1; Koppe, Sean MD2

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doi: 10.1097/TP.0000000000001758
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Infection with chronic hepatitis C virus (HCV) is the most common known indication for liver transplantation (LT), accounting for 26% (over 4000) of patients on the United States waitlist.1 HCV recurrence after LT is almost universal.2 Post-LT patients with HCV infection have higher mortality compared to non-HCV infected post-LT patients, and decreased 5-year graft survival compared to patients who underwent LT for other reasons.1,3 Use of direct-acting antiviral (DAA) agents with high sustained virologic response (SVR) rates can improve a patient’s clinical outcome via HCV eradication.4

Six DAA regimens comprised of 3 medication classes (NS3 protease inhibitors (PIs), NS5A replication complex inhibitors, and NS5B polymerase inhibitors) are currently Food and Drug Administration (FDA)-approved for treatment of HCV in genotype (GT) 1. National guidelines currently recommend the use of 2 different regimens for treatment of HCV in GT 1 post-LT patients, depending on treatment history and stage of disease: ledipasvir/sofosbuvir (SOF) ± ribavirin (RBV), and daclatasvir (DCV) + SOF ± RBV, whereas 2 other regimens are listed as alternative options: simeprevir + SOF ± RBV, and paritaprevir/ritonavir/ombitasvir with dasabuvir (PrOD) + RBV.5 No guidance is given for HCV treatment in post-LT recipients on hemodialysis or those with severe renal impairment. Therapeutic options for HCV treatment are limited to PrOD and elbasvir (EBR)/grazoprevir (GZR) in renally impaired patients because SOF is renally eliminated.

EBR/GZR is FDA-approved and recommended for HCV treatment in GT 1 patients with creatinine clearance less than 30 mL/min and in patients on dialysis.5 Recommendations stem from the C-SURFER trial, in which 94% (115/122) of patients with creatinine clearance less than 30 mL/min (76% on dialysis) achieved SVR after 12 weeks of treatment with once daily EBR/GZR.6 Most patients were treatment naive (83%) and noncirrhotic (94%). Guidelines recommend against the use of EBR/GZR in the post-LT patient population due to the lack of clinical trial data in this patient population and the presence of drug-drug interactions (DDIs) with immunosuppressants.

PrOD is also recommended as 12-week treatment in GT 1b patients with renal impairment. It is merely an alternative regimen for renally impaired GT 1a patients, in whom low-dose 200 mg daily RBV must be included, and patients must have a hemoglobin greater than 10 g/dL at baseline.5 Guideline recommendations are based on the RUBY-1 trial of 20 noncirrhotic treatment-naive GT 1 patients with stage 4 or 5 chronic kidney disease who were treated for 12 weeks with PrOD with low-dose (200 mg/day) RBV (GT 1a, n = 13) or without RBV (GT 1b, n = 7); the SVR rate was 90%.7

Unlike EBR/GZR, the PrOD regimen also has some data in LT recipients. The CORAL-1 trial, a small multicenter study of 34 patients with F0-F2 disease resulted in a 96% SVR rate after treatment with PrOD and weight-based RBV for 24 weeks.8 Results of this trial contributed to the recommendation for PrOD as an alternate agent for post-LT patients.5 However, this regimen is not recommended in post-LT patients with advanced fibrosis (F3-F4) due to risk of decompensation, and it requires preemptive dose adjustments for use in combination with cyclosporine and tacrolimus due to the inclusion of ritonavir, a potent CYP 3A4 inhibitor.9

The other caveat to use of regimens that include a PI in post-LT patients is that most PIs have varying degrees of CYP3A4 inhibition as a class effect. Immunosuppression agents, such as tacrolimus and cyclosporine, undergo CYP 3A4 metabolism, hence, coadministration of tacrolimus with a CYP3A4 inhibitor results in an increase in the tacrolimus area under the curve. Depending on the PI, drug interaction sources recommend monitoring for associated adverse drug reactions (ADRs) during concurrent treatment, and either (1) preemptive dose adjustments, or (2) close monitoring for changes in renal function and tacrolimus levels.9 (Table 1).

T1-30
TABLE 1:
DDIs with DAAs and tacrolimus

This case series describes the safe and effective use of EBR/GZR for HCV treatment at an urban academic medical center in 3 post-LT patients who underwent close immunosuppression level monitoring.

MATERIALS AND METHODS

Authors performed a retrospective review of the electronic medical records of post-LT patients who were treated for HCV. The data collected included: demographics, past medical history, stage of liver disease, HCV treatment regimen, baseline medications and laboratory values, and any changes throughout and up to 12 weeks after completion of HCV treatment. This study was approved by the institutional review board.

RESULTS

Three male treatment-naive post-LT GT 1a HCV patients on dialysis were treated with EBR/GZR. Baseline NS5A resistance was assessed in all 3 patients. Patients 1 and 3 did not have any baseline resistance-associated substitutions (RASs), had compensated cirrhosis, were 20 years and 5.25 years post-LT, respectively, and were treated for 12 weeks. Patient 2 had a M28V RAS at baseline, had F0 disease, was 3 months post-LT, and was treated with EBR/GZR daily and RBV 200 mg every other day for 16 weeks. Treatment length in patient 2 was augmented to a 16-week duration with RBV to mimic the guideline recommendations for nondialysis patients due to the presence of his NS5A RAS. Patient 2’s hemoglobin ranged from a baseline of 10.6 g/dL to a nadir of 8.3 g/dL during treatment, with a high of 12.9 g/dL at 4 weeks after treatment, and 11.3 g/dL at 12 weeks after treatment. The patient did not report RBV-related ADRs during HCV treatment. See Table 2 for other patient details.

T2-30
TABLE 2:
Patient characteristics

No patients were taking prednisone at the time of HCV treatment. Patient 1 was taking mycophenolate mofetil and had no changes in immunosuppression during HCV treatment. Patients 2 and 3 were taking mycophenolic acid and tacrolimus; both required changes in tacrolimus doses during the course of HCV treatment. See Table 2 for baseline doses and see Figure 1 for patient 2 and patient 3's tacrolimus levels during and after HCV treatment. Tacrolimus changes were minor for patient 3 (ie, one 50% dose decrease, and 1 increase back to baseline dose), but more extensive for patient 2, who was recently transplanted (ie, 6 dose changes with dose changes fluctuating between 25% and 50% above baseline dose).

F1-30
FIGURE 1:
Tacrolimus values during and after HCV treatment. A, Patient 2a. B, Patient 3a.

All 3 patients had undetectable viral loads at week 4 of treatment and all patients achieved SVR. All patients' alanine aminotransferase levels decreased during treatment. No patients experienced serious adverse events or discontinued treatment due to ADRs. Additionally, no patients died during treatment and no patients experienced organ rejection. See Table 2 for patient details.

DISCUSSION

Currently, no guidelines offer recommendations for HCV treatment in post-LT patients on dialysis. Use of the EBR/GZR regimen resulted in a 100% SVR rate in 3 treatment-naive HCV GT 1a post-LT patients on dialysis. However, a major limitation of this case series is the small number of patients included, and the variability in time from transplant.

Providers assessed the available HCV regimens and selected the regimen that was most appropriate for each dialysis patient. PrOD, although an option in hemodialysis patients, was not chosen due to its need for preemptive tacrolimus dose adjustments. The PrOD regimen’s more severe CY3A4 inhibition due to the inclusion of ritonavir complicates the clinical management of post-LT patients more so than EBR/GZR. Additionally, the clinical trial that supports use of PrOD in renally impaired and dialysis patients was considerably smaller than that of the EBR/GZR trial. The RUBY-1 and CORAL-1 PrOD trials did not include cirrhotic patients; PrOD is only an alternative regimen (not a recommended regimen) for F0-F2 post-LT patients. Two of the 3 patients were cirrhotic, so use of PrOD would not have been safe or appropriate. The recently transplanted noncirrhotic patient was also taking other medications that would have interacted with PrOD, but not EBR/GZR, further complicating its use.

Guidelines did not recommend the assessment of NS5A mutations in renally impaired GT 1a patients based on the C-SURFER trial, in which all patients were treated with EBR/GZR for 12 weeks. In that trial, 1 patient with an L31M mutation relapsed.6 Providers chose to test for NS5A mutations as this regimen was recently FDA-approved at the time of treatment, and 1 patient’s treatment length was extended to 16 weeks and low dose RBV was added (200 mg every other day) due to the presence of the M28V mutation. The augmentation of the HCV regimen in patient 2 was not supported by current guidelines, yet was successful in eradicating the virus without causing ADRs.

No patients died or discontinued treatment due to ADRs, implicating the safety of this regimen in this small set of patients. Providers monitored patients’ immunosuppression levels closely during HCV treatment. Two of the 3 patients (both patients taking tacrolimus) required adjustment of their tacrolimus doses. Patient 3's tacrolimus levels were less variable than patient 2's levels, because patient 2 was recently transplanted. Patients did not have tacrolimus trough levels checked at the same times after treatment initiation due to their different times since transplantation.

Providers are advised to monitor for immunosuppression level changes during treatment. Per labeling, providers also must monitor for elevation in liver function tests every 4 weeks during the course of treatment. This case series demonstrates that EBR/GZR is an effective treatment for post-LT patients on hemodialysis that can be safely used with close monitoring. Safety and efficacy were also demonstrated with the use of a longer duration while coadministering low-dose RBV in a recently transplanted patient (patient 2).

CONCLUSIONS

Despite the lack of guideline recommendations, a clinical argument can be made for the use of EBR/GZR in severely renally impaired GT 1 post-LT patients in need of HCV eradication. Knowledge of DDIs and appropriate monitoring can lead to safe and effective treatment of HCV-infected post-LT patients on hemodialysis.

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