Objectives: Available data have suggested that direct-acting antivirals for hepatitis C virus may decrease calcineurin inhibitor concentrations. In this study, our aim was to determine the effects of hepatitis C direct-acting antivirals on calcineurin inhibitor doses and trough levels.
Materials and Methods: This retrospective, single-center study included 52 abdominal transplant recipients treated with sofosbuvir-based regimens between 2014 and 2017. The primary outcome was percent change in calcineurin inhibitor troughs and total daily doses between the week before treatment with direct-acting antivirals, days 21 to 35 of treatment, and days 21 to 35 after treatment. Secondary outcomes included sustained virologic response and biopsy-proven acute rejection rates.
Results: The median percent difference in calcineurin inhibitor troughs from pretreatment to during treatment was -20.5% (interquartile range, -36.2% to 13.1%) and from pretreatment to posttreatment was -13.5% (interquartile range, -33.7% to 10.7%). Corresponding percent changes in calcineurin inhibitor doses were 0% (interquartile range, 0%-0%) and 0% (interquartile range, -10.5% to 33.3%), respectively. Patients on tacrolimus experienced statistically significant changes in troughs but not doses. During treatment, 65% of patients required no dose change, 23% underwent a dose increase, and 12% had a dose decrease. The sustained virologic response rate was 98%, and the biopsy-proven acute rejection rate was 0%.
Conclusions: Hepatitis C direct-acting antiviral therapy may decrease calcineurin inhibitor levels, but this was not associated with clinically different dosing requirements or rejection rates.
Key words : Direct-acting antivirals, Drug interactions, Immunosuppression, Tacrolimus
Hepatitis C virus (HCV) is one of the leading causes of hepatic failure requiring liver transplant and is also common in patients with end-stage renal disease.1,2 The advent of interferon-free, direct-acting antiviral (DAA) therapy for hepatitis C has greatly expanded the number of patients eligible for treatment of HCV, and these agents have shown favorable results in the posttransplant setting. As an example, treatment with ledipasvir-sofosbuvir has demonstrated sustained virologic response (SVR) rates of 90% to 100% in liver and kidney transplant recipients.2,3 Additional agents have recently been approved, which serve as promising options for different HCV genotypes. Despite the proven success of these agents in the transplant population, there are special considerations that must be made to ensure safe and effective treatment in the setting of complicated medication regimens.
Calcineurin inhibitors (CNIs) are a cornerstone of transplant immunosuppressive therapy and are prone to many drug-drug interactions due to their metabolism by cytochrome P450/3A4 (CYP3A4) and P-glycoprotein. Therapeutic drug monitoring is required for CNIs to avoid potential toxicity when supratherapeutic levels are reached or rejection if subtherapeutic levels occur. In general, DAAs with known CYP3A4 or P-glycoprotein-inhibiting properties (such as ombitasvir-paritaprevir-ritonavir-dasabuvir) are avoided in transplant recipients because of interactions with CNIs. However, it has been suggested that even HCV treatment with DAA regimens without known effects on hepatic metabolizing enzymes may also lead to changes in CNI levels. Overall, the current data have suggested that treatment of HCV with sofosbuvir-containing regimens may be associated with a decrease in CNI trough concentrations requiring CNI dose increases.2-17 Of note, these studies have frequently reported CNI levels or doses as secondary endpoints with varying methodologies, and several are only available in abstract form. It could be hypothesized that the effects on CNI levels during HCV treatment are not due to direct drug-drug interactions but rather are due to improvements in hepatic function; however, this has not been fully elucidated.4,5 Because these immunosuppressant agents have a narrow therapeutic index, it is essential to anticipate monitoring and dosing requirements regardless of the potential mechanism of altered metabolism. The purpose of this study is to determine the effects of treatment for HCV with sofosbuvir-based DAA regimens on CNI dosing requirements in kidney and liver transplant recipients.
Materials and Methods
This was a retrospective, single-center cohort study at Duke University Hospital, with data obtained from patients seen between October 1, 2014 and March 31, 2017. The study was approved by the hospital institutional review board and performed in accordance with the Helsinki Declaration of 1975. Liver and kidney (combined or single transplant) transplant recipients aged 18 years and older were identified by querying prescriptions for one of the following DAA regimens: ledipasvir-sofosbuvir, daclatasvir-sofosbuvir, or velpatasvir-sofosbuvir. Manual electronic chart review was performed to confirm that patients met inclusion criteria and to collect data.
Patients were excluded if they initiated or discontinued a moderate-to-strong CYP3A4 inhibitor (ritonavir, erythromycin, clarithromycin, fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole, isavuconazole, diltiazem, or verapamil) or inducer (rifampin, rifabutin, carbamazepine, or phenytoin) during the study timeframe. Other exclusion criteria included an undetectable CNI trough at the time of DAA initiation or not achieving a therapeutic CNI level before initiation of DAA therapy; discontinuation of CNI before completion of DAA treatment; change in goal CNI trough range or route of administration during the study timeframe; or discontinuation of DAA 1 month before concomitant therapy with a CNI.
The most common induction immunosuppression regimen for kidney transplant at our institution during this period was methylprednisolone with or without rabbit antithymocyte globulin or basiliximab, depending on patient risk factors. The most common maintenance regimen was tacrolimus (goal of 8-10 ng/mL during year 1 and individualized levels thereafter), mycophenolic acid, and a weekly steroid taper with an ultimate dose of 5 mg daily. The standard induction regimen for liver transplant was methylprednisolone followed by a maintenance regimen of tacrolimus (goal of 6-8 ng/mL during year 1, 4-6 ng/mL during years 1-3, 3-5 ng/mL during years 3-10, and 2-3 ng/mL during ≥ year 10), mycophenolate mofetil weaned off over several years, and a biweekly steroid taper with most patients being steroid-free by 3 to 6 months. Depending on tolerability issues and provider discretion, some patients were switched from tacrolimus to cyclosporine or from mycophenolate to azathioprine. Liquid chromatography with tandem mass spectrometry was utilized to measure tacrolimus and cyclosporine levels. Biopsies were only performed for cause based on clinical suspicion for rejection.
The primary outcome was percent change in the average CNI troughs and total daily doses from the week before DAA treatment, days 21 to 35 during treatment, and days 21 to 35 after completion of treatment. Secondary outcomes included SVR and biopsy-proven acute rejection (BPAR) rates. The primary outcome was also evaluated based on the DAA regimen used, type of transplant, and time from transplant to initiation of antiviral therapy.
Categorical variables were summarized with frequency counts and percentages. Chi-square test and Fisher exact test were used to determine whether there was an association between 2 variables. Continuous variables were summarized with mean, median, standard deviation, interquartile range (IQR), and minimum and maximum. Two-sample t test and analyses of variance or Wilcoxon-Mann-Whitney test and Kruskal-Wallis test were used to compare the 2 groups or multiple groups, depending on whether the continuous variables were normally or nonnormally distributed. Significance was assessed at α = .05. Analysis was conducted using SAS 9.4 software (SAS Institute Inc., Cary, NC, USA).
We screened 108 liver, kidney, or combined liver and kidney transplant recipients for inclusion. Of these, 52 met the inclusion criteria and were included in the analyses (Table 1). One patient received a kidney from a living related donor, and all other patients received organs from deceased donors. The most common reason for exclusion was never being on concomitant CNI and DAA therapy (n = 20), which usually occurred because patients had been treated for HCV prior to transplant. Other common reasons for exclusion included an insufficient number of accurate troughs to assess the primary endpoint (n = 16), incomplete data at the time of study completion (n = 9), or CNI goal change (n = 5). One patient was excluded for discontinuing a CYP3A4 inhibitor (posaconazole) during the study period. There were no patients who initiated or continued on other CYP3A4-interacting medications.
The most commonly used DAA was ledipasvir-sofosbuvir for 12 weeks. Overall, treatment was well tolerated, and no patients discontinued DAA treatment prematurely. Ribavirin combination treatment was commonly used (73%), and ribavirin doses were frequently adjusted for side effects. The most common side effect of ribavirin was a decrease in hemoglobin. There were no significant changes noted in serum creatinine from pre- to posttreatment, with values of 1.2 mg/dL (IQR, 1.0-1.5) versus 1.2 mg/dL (IQR, 1.1-1.6). Hepatic enzymes significantly improved from pre- to posttreatment, with a median aspartate aminotransferase pre- and posttreatment of 31 versus 21 U/L (P < .001) and ALT of 31 versus 17 U/L (P < .001). Additional CNI and DAA regimen details are reported in Table 2.
Percent changes in CNI doses and troughs are summarized in Table 3. The median percent difference in CNI troughs for the full cohort from before to during DAA therapy was 20.5% (IQR, -36.2% to 13.1%); from pre- to post-DAA therapy, the difference was -13.5% (IQR, -33.7% to 10.7%). Corresponding percent changes in CNI doses were 0% (IQR, 0%-0%) and 0% (IQR, -10.5% to 33.3%), respectively. The median trough goal ranges were 5 to 6 ng/mL for tacrolimus and 50 to 100 ng/mL for cyclosporine.
Because of the large differences in the absolute values of troughs and doses between tacrolimus and cyclosporine, tests for significance were performed separately for each group. Patients on tacrolimus (n = 47) experienced a trough decrease from before to during treatment of 5.6 to 4.7 ng/mL, which was statistically significant (P < .001); this difference was maintained after completing therapy at 4.7 to 4.8 ng/mL (Figure 1). Tacrolimus doses were not significantly different from before to during treatment, but they were significantly different from before to after treatment (Figure 1). These results did not differ based on transplant type, DAA, fibrotic stage, or time from transplant (< 12 mo, 12-59 mo, or > 60 mo). By organ group, the median pretreatment doses compared with doses at week 5 of therapy for kidney, liver, and combined kidney plus liver transplant recipients were 3 mg (range, 2-5 mg), 2 mg (range, 1.5-4 mg), and 4 mg (range, 1.5-5 mg) versus 3 mg (range, 2-4.5 mg), 3 mg (range, 1.5-4 mg), and 4 mg (range, 1.5-5 mg), respectively. Because there were only 5 patients on cyclosporine, further statistical analyses could not be reported for this subgroup.
In total transplant recipients, 65% did not require a CNI dose change by week 5 of DAA therapy, 23% underwent a dose increase, and 12% underwent a dose decrease. In the cohort of kidney transplant recipients (n = 11), 73% did not require a dose change, 9% underwent a dose increase, and 10% underwent a dose decrease. In liver transplant recipients (n = 31), 64% did not require a dose change, 26% underwent a dose increase, and 10% underwent a dose decrease. None of the combined liver plus kidney transplant recipients (n = 5) required a dose change up to week 5 of therapy. One patient had a detectable viral load at 12 weeks after DAA treatment, which corresponded with an SVR rate of 98% for the study group. The BPAR rate during the study period was 0%, and only 1 liver transplant recipient required an allograft biopsy.
Our study is among the first to formally investigate the effects of HCV treatment with DAA therapy on CNI dosing in both liver and kidney transplant recipients. The data from this study showed differences in CNI troughs and doses during HCV treatment with DAA agents, but these changes may not be clinically meaningful. There were no episodes of rejection during or up to 12 weeks after DAA therapy. We found that CNI doses and troughs remained stable after patients completed HCV treatment, suggesting that these changes may be partially attributable to improvements in hepatic function instead of simply a drug-drug interaction.
Evidence has suggested that the chronic inflammatory state caused by HCV can repress certain enzymes that metabolize medications, such as CYP3A4.18 Therapeutic drug monitoring of other CYP3A4 substrates, including human immunodeficiency virus protease inhibitors and midazolam, has shown that patients with HCV have higher plasma levels of these agents than healthy individuals.19,20 It could be hypothesized that the rapid clearance of HCV would lead to improved inflammation and increased metabolic capacity of enzymes such as CYP3A4. In our study, liver enzyme values significantly improved after DAA treatment, supporting this possibility. Our results did not show a difference in CNI dose adjustments based on fibrotic stage. Other studies have actually found that patients with lower-stage fibrosis experienced greater changes in tacrolimus doses than those with more severe fibrosis.7 The reasons for this are not clear, but there may be varying levels of reversibility of CYP3A4 dysfunction with different stages of fibrosis. This area warrants further investigation.
The exact degree of adjustment needed for CNI doses when initiating HCV therapy is variable when reviewing the literature. The overall reported rates of patients requiring CNI dose adjustments have ranged from 18% to 80%, depending on the study.1,6-13 For example, the large multicenter studies from Mansour and colleagues, which investigated 108 liver, kidney, heart, lung, or multiorgan transplant recipients treated with simepivir-sofosbuvir or ledipasvir-sofosbuvir, found that 45% of patients required CNI adjustments. These adjustments were not statistically significant, as the average daily dose before HCV therapy was 3.1 versus 3.2 mg/day at week 4 of therapy; tacrolimus levels were 5.0 versus 5.9 ng/mL.21 Colombo and associates evaluated 114 kidney patients who were treated with ledipasvir-sofosbuvir and found that 18% of patients required adjustments, with 7 patients requiring dose decreases, 10 requiring dose increases, and 4 requiring both.1 The SOLAR-1 trial investigated 229 liver transplant patients treated with ledipasvir-sofosbuvir and found that 24 patients required adjustments, which was thought to be due to improved hepatic function.2 These results are similar to the results of our study, which found no statistical difference in dose or levels before versus during therapy, although 35% of patients underwent a dose adjustment while on HCV treatment.
Data are also variable when considering the specific transplanted organ. Our study found no statistically significant difference between the specific organ transplanted and the need for CNI adjustment. Available studies have shown that 45% to 80.6% of kidney transplant patients treated with DAAs underwent CNI dose adjustments. In a study of 20 kidney transplant recipients, who were approximately 2.5 years from transplant, investigators found that 45% of patients treated with sofosbuvir-based DAA regimens required CNI dose adjustments (9 with simeprevir-sofosbuvir and 7 with ledipasvir-sofosbuvir).6 The median tacrolimus level was 5.9 ng/mL before start of DAA therapy and 4.5 ng/mL at 3 months after end of therapy (P = .006), which is similar to our results. Fernandez-Ruiz and associates found that 80.6% of patients on tacrolimus required a median 66.7% dose increase during DAA therapy (P = .043) in a study of 49 kidney transplant recipients.7 The median time from transplant was 9.6 years, and the most common DAA regimen was ledipasvir-sofosbuvir. The daily tacrolimus dose at baseline compared with at end of DAA therapy was 2.6 versus 3.5 mg; the mean change in tacrolimus level was 7.6 ng/mL at baseline versus 6.2 ng/mL at week 4.
Overall, the data in liver transplant recipients have suggested that this population requires fewer CNI adjustments compared with kidney transplant recipients, with 32% to 35% of patients requiring dose changes. Our study was consistent with other literature, showing 36% of liver transplant recipients requiring a dose change by week 5 of DAA therapy (with 72% requiring dose increases and 28% requiring dose decreases). In their study of 204 liver transplant patients treated with ledipasvir-sofosbuvir for recurrent HCV, Kwok and colleagues also found that 32% of patients required a tacrolimus dose adjustment; of these, 72% required a dose increase and 28% required a dose decrease.16 Only 16% of patients required a dose adjustment after treatment completion. The mean time from transplant to treatment in this cohort was 4.8 years, and 20% of patients had a METAVIR fibrosis stage of F3 to F4. The SOLAR-1 trial investigated 229 patients who received liver transplants and were treated for HCV 2.8 years posttransplant with varying hepatic function. Only 24 of these patients required adjustments to their CNI.
A speculative reason for kidney transplant patients requiring more CNI dose adjustments may be due to a greater degree of enzyme damage reversibility in their native liver compared with liver transplant recipients. Other reasons could be explained by different patient characteristics, such as differences in trough goals, which could have allowed for more freedom to adjust doses. The reported rates of CNI dose adjustment in liver transplant recipients varies depending on the DAA used in the study. Because most of our study patients were treated with ledipasvir-sofosbuvir and tacrolimus, it is most appropriate to compare our results with studies that utilized the same agents.
It is important to note that most of these studies were designed to evaluate the efficacy of HCV treatment after transplant and not to formally assess interactions with immunosuppression. Therefore, data with regard to CNI goal levels, frequency of CNI level monitoring, use of other interacting medications, and concurrent doses and levels are limited. The design of the studies and methods for collecting CNI dosing information may explain the variable magnitude of CNI adjustments reported among different studies. Time from transplant to DAA treatment may also affect the magnitude of CNI dose and trough changes, as therapeutic targets are followed more frequently and strictly in the early posttransplant period than later after transplant. Our study did not find a statistical difference in dose or trough changes based on time from transplant (< 12 mo, 12-59 mo, or > 60 mo), but this could be due to the relatively small sample size. In clinical practice, it would be prudent to closely monitor CNI levels during DAA treatment in patients who are highly sensitized, have a history of rejection, or are being treated in the early posttransplant phase.
The use of DAAs in transplant recipients is generally considered safe based on the available evidence. These agents are well-tolerated, and side effects are typically mild. Patients with more advanced liver disease might be more prone to certain adverse effects than those with mild liver disease.17 Graft dysfunction or rejection during or after DAA treatment may occur, but these rates are low compared with previous HCV treatment modalities. One study demonstrated a 3.4% incidence of immune-mediated graft dysfunction followed by DAA therapy in 978 liver transplant recipients; however, none of these events resulted in graft loss.22 These investigators found that elevated liver enzyme tests during and after DAA were significantly associated with DAA immune-mediated graft dysfunction. There were no episodes of BPAR in our study, and no patients had to stop DAA therapy early. It is prudent to monitor closely for side effects or graft dysfunction during and shortly after DAA therapy; elevated liver enzyme tests or decreased renal function during treatment should be considered a signal for further investigation and earlier intervention.
Strengths of this study include the systematic description of concurrent CNI doses and troughs, exclusion of patients who had trough goal changes, and evaluation of both liver and kidney transplant recipients. Inherent limitations to this retrospective study include the possibility for incomplete information or the presence of confounding variables. Nearly all of the patients in this study received ledipasvir-sofosbuvir with tacrolimus; therefore, our findings may not be generalizable to other DAA and CNI combinations. Most patients were liver transplant recipients; thus, the findings might be different in a population of only kidney transplant recipients. In addition, the overall CNI trough goals and doses were relatively low for many patients further out from their transplant, which may have decreased the number of dose adjustments performed. Patients who were treated in the latter part of the study period had more frequent therapeutic drug monitoring compared with those who were treated in earlier years. This likely represented an era effect due to the increased awareness in the literature of possible need for CNI dose adjustments while on HCV DAA therapy. Although our sample size was comparable to other literature on this topic, the limited number of patients makes it difficult to assess the impact of these potential variables on the primary outcome. Additionally, there is a chance that a statistical significance was not detected for certain outcomes due to the small sample size.
Our study findings are overall consistent with existing studies evaluating the effects of sofosbuvir-containing DAA regimens on CNIs. It adds to the literature by describing these changes in a more controlled design. The overall trend during DAA therapy was a decrease in CNI trough levels despite similar or higher CNI doses. There is likely not a need to empirically adjust CNI doses when initiating HCV therapy, but it underscores the importance of frequent therapeutic drug monitoring during and shortly after HCV treatment to assess for potential immunosuppressant changes. Sofosbuvir-containing regimens appear safe and effective in liver and kidney transplant recipients, as there were no BPARs in this cohort, all patients completed DAA therapy, and nearly all patients achieved SVR. Further investigations should be performed to assess whether certain patient or treatment characteristics impact the magnitude of CNI changes seen in patients who are being treated for HCV.
DOI : 10.6002/ect.2019.0289
From the 1Augusta University Medical Center Department of Pharmacy, Augusta, GA,
USA; and the 2Duke University Hospital Department of Pharmacy and
University Hospital Department of Medicine, Durham, North Carolina, USA
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Melissa Laub, 1120 15th St, AD 3401, Augusta, GA 30912, USA
Phone: +1 580 318 3611
Table 1. Baseline Characteristics (N = 52)
Table 2. Calcineurin Inhibitor and Direct-Acting Antiviral Regimens
Table 3. Percent Change in Calcineurin Inhibitor Troughs and Doses
Figure 1. Absolute Changes in Tacrolimus Troughs and Doses (N = 47)