Objectives: Our objective was to determine the safety, efficacy, and pharmacokinetics of telaprevir plus pegylated interferon alfa 2a and ribavirin for chronic, posttransplant genotype 1 hepatitis C virus infection.

Materials and Methods: A prospective, single-arm, multicenter, open-label, phase 2b study was conducted at 22 North American sites to assess the safety, efficacy, and pharmacokinetics of pegylated interferon alfa 2a, ribavirin, and twice daily telaprevir in liver transplant recipients with recurrent, chronic hepatitis C without cirrhosis. Baseline liver biopsies were read by a central pathologist. There were planned safety reviews after a sentinel cohort reached treatment weeks 4 and 16. Serial pharmacokinetic sampling was performed for calcineurin inhibitors, telaprevir, and ribavirin.

Results: Sixty-one patients were enrolled and received ≥ 1 dose of study medication; 37 (61%) achieved sustained virologic response. Thirteen of 18 treatment-naive patients (72%), 10 of 11 patients with no or minimal fibrosis (91%), 13 of 15 patients (87%) with interleukin 28B genotype CC, and 36 of 45 patients (80%) with either undetectable or unquantifiable hepatitis C virus RNA at treatment week 4 achieved sustained virologic response. Nine patients (15%) had ≥ 1 drug-related serious adverse event and 7 (11%) discontinued all study drugs due to an adverse event. There were no deaths or acute cellular rejection episodes. During telaprevir treatment, median doses of tacrolimus and cyclosporine were 0.5 mg weekly and 25 mg daily. Target exposures were achieved for telaprevir with twice daily dosing and for ribavirin with reduced initial dosing.

Conclusions: Telaprevir combination therapy for post­transplant hepatitis C virus infection yielded superior efficacy than historical controls. Adverse events were similar to, but exceeded, those in immunocompetent patients. Calcineurin inhibitor dosing levels were substantially reduced with telaprevir.

Key words : Hepatitis C, Liver transplantation, Telaprevir

Introduction

Chronic hepatitis C virus (HCV) infection is a leading indication for liver transplant.¹ For patients viremic at transplant, allograft infection is universal with accelerated fibrosis posttransplant; 6% to 30% of patients develop cirrhosis in 3 to 5 years.^2,3 If cirrhosis develops, 40% decompensate within 1 year,^4-6 with allograft loss in 25% to 30% of patients.^7,8

Pegylated interferon (Peg-IFN) and ribavirin yield reduced sustained virologic response rates (SVR) but with increased adverse events in patients with posttransplant HCV versus in immunocompetent patients.^9-11 The SVR rate for genotype 1 HCV posttransplant is 20% to 29%.¹⁰ The reduced efficacy reflects higher viral loads, unfavorable interleukin 28B (IL-28B) genotypes, prior treatment failure, and reduced tolerability.^9-12 When achieved, SVR after liver transplant is durable and enhances survival.¹³

In immunocompetent patients or those coinfected with human immunodeficiency virus, a first-generation HCV NS3/4A protease inhibitor (PI), telaprevir or boceprevir, added to Peg-IFN and ribavirin substantially increased SVR.^14-19 Routine use of these agents was recommended in 2011.²⁰

Neither telaprevir nor boceprevir has been ap­proved for posttransplant HCV. Despite the benefits, concerns include adverse events and drug inter­actions with tacrolimus and cyclosporine via cytochrome P450 3A4 inhibition. Pharmacokinetic studies in healthy volunteers have demonstrated 70.3-fold higher exposures for tacrolimus and 4.6-fold for cyclosporine with telaprevir coadminis­tration.²¹

Although interferon-free regimens are effective against posttransplant HCV, many patients have limited access. The present study was designed to determine the safety and efficacy of telaprevir with Peg-IFN-α2a and ribavirin in a phase 2b, open-label, prospective, multicenter study, which included detailed pharmacokinetics analyses of telaprevir, tacrolimus, cyclosporine, and ribavirin.

Materials and Methods

Compliance with ethical requirements
Twenty American and 2 Canadian sites conducted this prospective, open-label phase 2b study. All procedures followed were in accordance with the ethical standards of the responsible institutional committees on human experimentation per Good Clinical Practice guidelines of the International Conference on Harmonisation Guideline E6 and Helsinki Declaration of 1975, as revised in 2008. The study was reviewed and approved by the 22 Institutional Review Boards listed in Table 1. All study participants provided written informed consent before study enrollment. The trial was registered at ClinicalTrials.gov (NCT01467505).

Design overview
Patients received 12 weeks of telaprevir plus Peg-IFN-α2a and ribavirin followed by 36 weeks of Peg-IFN-α2a and ribavirin. Telaprevir (1125 mg) was administered twice daily with food (not low fat), 180 μg of Peg-IFN-α2a (Pegasys, Hoffman-La Roche, Nutley, NJ, USA) was injected subcutaneously weekly, and ribavirin (Copegus, Hoffman La-Roche) was administered twice daily. The initial ribavirin dose was 600 mg/d adjusted per the principal investigator’s discretion. Dose adjustments for telaprevir were prohibited. If Peg-IFN-α2a or ribavirin were discontinued, telaprevir was discontinued. For patients who received tacrolimus, the first dose with telaprevir administration was reduced 10-fold; the minimum dose was 0.5 mg. The first dose of cyclosporine was reduced 4-fold; the minimum dose was 25 mg. Tacrolimus or cy­closporine adminis­tration was guided by drug levels on days 1-5, 7, and 10 and weeks 2, 3, 4, 6, 8, 10, and 12. After telaprevir discontinuation, dosing was guided by levels on days 1-7, 10, 11, 14, 21, and 28 and monthly. Goal tacrolimus and cyclosporine trough levels were at the principal investigator’s discretion.

Inclusion criteria included age 18 to 65 years, genotype 1 chronic HCV infection, RNA > 10 000 IU/mL, transplant within 6 months to 10 years, stable tacrolimus or cyclosporine doses for ≥ 1 month, and prednisone ≤ 5 mg daily. Enrollment was capped for hepatocellular carcinoma history (n ≤ 18), uncategorized prior treatment response (n ≤ 8), and prior posttransplant treatment (n ≤ 10).

Exclusion criteria included cirrhosis, retransplant, cytomegalovirus infection within 3 months, or history of nonhepatocellular carcinoma malignancy within 5 years. Exclusion laboratories included hemoglobin < 11 g/dL, platelets < 75 000 × 10⁹/L, and glomerular filtration rate < 65 mL/s. The central pathologist, blinded to patient details, excluded rejection and staged fibrosis by the METAVIR scoring system.

Efficacy
For assessment of hepatitis C virus RNA, we used the Cobas TaqMan version 2.0 (Roche Molecular Systems, Branchburg, NJ, USA) system with lower limit of quantification (LLOQ) of 25 IU/mL and limit of detection of 15 IU/mL. The LLOQ defined the SVR, and the limit of detection defined the on-treatment response. Sustained virologic response was the primary endpoint, defined as HCV RNA < LLOQ posttreatment week 12 (SVR12). Relapse was defined as HCV RNA < LLOQ at planned end of treatment with subsequent quantifiable RNA.

Safety
Adverse events were recorded for all patients receiving ≥ 1 dose of study drug through 4 weeks after last dose. Except for rash, all adverse events were graded per the Division of Acquired Immunodeficiency Syndrome Table for Grading the Severity of Adult and Pediatric Adverse Events (December 2004). Treatment-emergent adverse events were summarized using the Medical Dictionary for Regulatory Activities, version 15.0. The Custom Medical Dictionary for Regulatory Activities queries combined multiple terms from the dictionary for anemia, rash, and pruritus. The study sponsor conducted planned safety reviews after a sentinel cohort reached treatment week 4 and again when the sentinel cohort reached treatment week 16. All study drugs were discontinued at weeks 4, 8, or 12 for HCV RNA ≥ 1000 IU/mL or if detectable at weeks 24 or 36.

Pharmacokinetics
Serial pharmacokinetics sampling for telaprevir was performed at week 4, over 12 hours in the sentinel cohort, and over 6 hours otherwise. Random ribavirin pharmacokinetics sampling was performed at weeks 4 and 8.

Safety review and interim analyses
When the sentinel cohort (n = 15) reached treatment week 4, the study sponsor conducted a safety, pharmacokinetics, and efficacy evaluation before continuing enrollment. When these patients reached treatment week 16, the study sponsor conducted another interim analysis.

Statistical analyses
Statistical review of the study was performed by Mohammad Bsharat, PhD (Vertex Pharmaceuticals). Sample size was selected to provide safety, efficacy, and pharmacokinetics data. The safety and efficacy datasets included all 61 participants who enrolled and received ≥ 1 dose of study drug. The small size of the study did not permit hypothesis testing regarding predictors of SVR.

Premature termination of study
The study sponsor terminated the study early in January 2014 due to a modified development plan for telaprevir (not for safety or efficacy concerns). Enrollment was planned for 75 participants. The study was terminated at the primary efficacy endpoint (SVR12). The pharmacokinetics analysis was limited to data from the second interim analysis. Of the 61 patients who received ≥1 study drug, 1 discontinued the study for adverse events, 4 withdrew consent, and 31 discontinued the study after SVR12 but before planned end of study.

Results

Baseline characteristics
Sixty-one patients received ≥ 1 dose of telaprevir. Most patients were men (80%), white (79%), and had genotype subtype 1a (77%). Regarding IL-28B genotype, 49% had CT and 25% TT. Most patients (82%) had high baseline HCV RNA levels (median 6.79 [range 4.1-7.6] log10 IU/mL), showed ≥ stage 2 fibrosis (82%), and had previous treatment with Peg-IFN and ribavirin (70%) (Table 2). In addition, most patients (84%) were receiving tacrolimus.

Efficacy
Our results showed that 37 patients (61%) had SVR (Figure 1). Hepatitis C virus was undetectable by week 4 in 30 patients (49%), by week 12 in 44 patients (72%), and at both weeks 4 and 12 in 29 patients (48%). Study medications were discontinued for viral stopping rules in 4 patients (7%) at week 4, in 1 patient (2%) at week 8, in 2 patients (3%) at week 12, and in 7 patients (11%) at week 24 or week 36.

One patient completed only 24 weeks of treatment, missed the SVR12 visit, achieved SVR at week 24, and was included as SVR. Viral relapse occurred in 4 of 41 patients (10%). Two of these patients achieved SVR at week 4 but missed later visits. Three other patients had unquantifiable virus at the end of a truncated treatment course. One received 24 weeks of treatment but was lost to follow-up. Two others discontinued treatment at < 8 weeks and had quantifiable virus thereafter.

Regarding SVR, 13 of 18 naïve patients (72%) and 9 of 12 patients with prior relapse (75%) reached SVR (Table 3). We found that SVR occurred in 13/15 patients (87%) with IL-28B genotype CC and 10/11 patients (91%) with no or minimal fibrosis. We also found that SVR was similar for HCV subtypes 1a and 1b and that SVR was reached in 7/10 patients (70%) on cyclosporine and in 30/51 patients (59%) on tacrolimus.

SVR was reached in 24/30 patients (80%) with undetectable HCV RNA at treatment week 4, 36/40 patients (80%) with undetectable or < LLOQ RNA at treatment week 4, and only 1/14 patients (7%) with quantifiable virus at treatment week 4.

Safety
All patients had ≥ 1 study drug-related adverse event. The most common adverse effects were fatigue (70%), anemia (57%), nausea (54%), headache (52%), diarrhea (44%), rash (41%), pruritus (38%), anorectal discomfort (28%), dizziness (23%), and neutropenia (20%). Seven patients (11%) discontinued all study drugs for an adverse event. One patient discontinued the study during the first treatment week. Administration of tacrolimus for this patient was not held on telaprevir initiation. He was hospitalized for nausea/vomiting (indicated as a severe adverse event) on day 5. Another patient continued tacrolimus when telaprevir was started; the patient experienced adverse events of nausea, vomiting, and generalized body aches on day 4. Tacrolimus levels were supratherapeutic for both of these events.

There were no deaths or acute cellular rejections. Fourteen patients (23%) had ≥ 1 serious adverse event; 9 patients (15%) had ≥ 1 study drug-related serious adverse event. Nausea (4 patients, 7%), vomiting (4 patients, 7%), and anemia (2 patients, 3%) were the only serious adverse events occurring in more than 1 patient. Other serious adverse events were muscular weakness and rhabdomyolysis, retinal detachment, pneumonia and pleural effusion, coronary artery disease, and herpes zoster infection.

The following adverse events resulted in discontinuation of study drug in 1 patient each: anal pruritus, impaired gastric emptying, nausea, vomiting, generalized edema, autoimmune hepatitis, herpes zoster, hyperuricemia, muscular weakness, rhabdomyolysis, and mood swings. Two patients discontinued telaprevir for an adverse event (1 each for anemia and blood creatinine level increase).

Using the customized queries, ≥ 1 event occurred in 40 patients (66%) for anemia, 29 patients (48%) for rash, and 26 patients (43%) for pruritus. With the exception of 9 patients (15%) who had severe anemia events, all other adverse events were mild or moderate. No event was potentially life threatening (Table 4) or resulted in discontinuation of all study drugs.

Mean hemoglobin levels decreased from baseline to treatment week 4, stabilized throughout the remainder of treatment, and increased modestly 4 weeks after stopping medication (Figure 2). Ribavirin was dose reduced or interrupted in 34 patients (56%) and discontinued in 8 patients (13%). Our results showed that 25 patients (41%) received erythro­poietin and 12 patients (20%) received more than 1 blood transfusion.

Glomerular filtration rate decreased during treatment and improved modestly at safety follow-up (Figure 2). Seven patients (11%) had a mild or moderate adverse event of renal insufficiency, with 5 considered related to study drugs. None of the renal events led to discontinuation of study drugs (ribavirin was reduced in 2 patients), with all being resolved.

Pharmacokinetics
Pharmacokinetics data were available for 44 patients (72%) who received calcineurin inhibitors, 37 patients (61%) who received telaprevir, and 39 patients (64%) who received ribavirin.

Regarding calcineurin inhibitors, substantial dose and interval adjustments were required with telaprevir initiation. Greater modifications were required for tacrolimus than for cyclosporine (Table 5). The median intervals between doses to maintain therapeutic levels during telaprevir administration were 168 hours for tacrolimus and 24 hours for cyclosporine. With telaprevir discontinuation, the calcineurin inhibitor dose and dose interval rebounded, usually within 3 days. Several patients required higher than baseline doses after telaprevir discontinuation.

For our protocol, the initial ribavirin dose was 600 mg. Principal investigators modified dosing at their discretion. The initial doses of ribavirin were 200 mg (1 patient), 400 mg (2 patients), 600 mg (36 patients), 800 mg (2 patients), 1000 mg (1 patient), and 1200 mg (4 patients). Most patients who were initially treated with ribavirin 600 mg daily remained on that dose at week 4 (74%) and week 8 (57%). Patients taking 600 mg daily had a mean (standard deviation) ribavirin blood concentration of 2115 (683) ng/mL at week 4 and 2690 (991) ng/mL at week 8 (Table 6).

With twice daily dosing, target concentrations of telaprevir were achieved at week 4 (Table 7).

Discussion

Treatment of genotype 1 HCV with first-generation PIs plus Peg-IFN and ribavirin was first approved in 2011. The use of these in liver transplant recipients was initially limited by the absent safety, efficacy, and drug interaction data. Uncontrolled results emerged from cohorts in which patient selection, HCV RNA assays, and adverse event characterization were variable and difficult to interpret.^22-29 The specific PI, Peg-IFN, and whether to use a lead-in were not standardized.^28,29 In contrast, this prospective study was designed to evaluate the efficacy and safety in a defined population. Additionally, this is the only published study that used twice daily telaprevir and described the pharmacokinetics of the calcineurin inhibitors, ribavirin, and telaprevir.

This study showed superior efficacy of telaprevir combination therapy for recurrent posttransplant genotype 1 HCV infection compared with historical controls. Despite 3 participants with undetectable virus who were lost to follow-up (and counted as nonresponders), the 61% SVR rate was comparable to that in other telaprevir posttransplant case series.^22-27,29 Although the rate was lower than the 79% observed in treatment-naïve, immunocompetent patients,¹⁵ it exceeded the 20% to 29% SVR rate shown with posttransplant Peg-IFN and ribavirin.¹⁰

The small size of the study did not permit hypothesis testing regarding predictors of SVR. However, certain characteristics were associated with numerically higher SVR rates, including prior treatment status (naïve or relapsed), IL-28B genotype CC, mild liver histology, and cyclosporine use, but not HCV subtype. There were too few black patients or patients with low viral loads enrolled to assess these predictors. SVR was identical for patients with undetectable RNA at treatment week 4 (24/30, 80%) and with detectable, but LLOQ, RNA at treatment week 4 (12/15, 80%).

As expected, adverse events with telaprevir combination therapy exceeded those in immuno­competent patients.¹⁵ Seven patients (11%) discontinued all study drugs for an adverse event. Nine patients (15%) had 1 or more study drug-related serious adverse event. In 2 participants, tacrolimus was not held when telaprevir was initiated, leading to a serious adverse event of nausea and vomiting in 1 patient and an adverse event of nausea, vomiting, and generalized body aches in the other. These events underscore the importance of adjusting calcineurin inhibitor doses when initiating PIs, whether telaprevir or later-generation PIs. Subsequent dosing of calcineurin inhibitors must be based on therapeutic drug levels. Although serious cutaneous adverse reactions have been reported with telaprevir,³⁰ severe or treatment-limiting rash was not observed in this study. Anemia was common and often required erythropoietin and/or blood trans­fusion, but no patient discontinued all study drugs for anemia. No patients discontinued all study drugs for pruritus. Infections and hospitalizations were less common than when telaprevir was used in transplant recipients with cirrhosis or fibrosing cholestatic hepatitis.^28,29

The detailed pharmacokinetics results for calcineurin inhibitors, ribavirin, and telaprevir were unique. Median tacrolimus dose changed from 1 mg every 12 hours to 0.5 mg every 168 hours. Cyclo­sporine dose levels changed from 75 mg every 12 hours to 25 mg every 24 hours. When telaprevir was discontinued, cytochrome P450 3A4 reconstituted within several days. These data underscore the importance of adjusting calcineurin inhibitor doses to use telaprevir (or other PIs) safely after transplant. This was exemplified by the 2 patients whose tacrolimus was maintained after telaprevir initiation who experienced adverse events with suprathera­peutic tacrolimus levels.

In this study, a median ribavirin dose of 600 mg daily yielded similar levels to those observed when nontransplant HCV patients received 1200 mg daily.³¹ There is no defined therapeutic range, but high ribavirin exposures correlate with at least moderate anemia.³² There is also no defined therapeutic range for telaprevir; however, twice daily dosing yielded exposures similar to that shown in immunocompetent patients.³³

The first-generation PIs have been supplanted in many countries by oral, second-generation direct-acting antiviral agents with higher efficacy and fewer adverse events. A combination of ombitasvir, paritaprevir, dasabuvir, ritonavir, and ribavirin was the first approved regimen for transplant recipients with normal hepatic function based on a study in which 33/34 patients with ≤ METAVIR 2 fibrosis (97%) achieved SVR.34 Adverse events were common, although milder than in our study. As predicted by our pharmacokinetics data, calcineurin inhibitor coadministration with a PI requires close monitoring. Sustained virologic response rates above 90% have been reported in genotype 1 HCV after transplant with simeprevir (a PI) and sofosbuvir with or without ribavirin.35-38 Even higher SVR rates have been described with 12 weeks of sofosbuvir, ledipasvir, and ribavirin, leading to its approval to treat liver transplant recipients with genotype 1 or 4, including those with compensated cirrhosis.³⁹

If access to newer direct-acting antiviral agents was universal, their improved efficacy and safety would favor interferon-free regimens for post­transplant genotype 1 hepatitis C. However, newer direct-acting antiviral agents are prohibitively expensive in some locations, leaving telaprevir combination therapy a viable option. Our present study demonstrates that select patients have a good chance of SVR with manageable adverse events.

This study has several limitations. It was small, constraining the interpretation of safety and efficacy. The results cannot be extended to other immuno­suppressants, such as sirolimus or everolimus. Importantly, this study excluded patients with cirrhosis (although 1 enrolled) or fibrosing cholestatic hepatitis. Moreover, enrollment was limited for participants with certain clinical characteristics. A history of hepato­cellular cancer was capped (n ≤ 18, 30%) to avoid the potential confounder of recurrent malignancy and treatment interruption, which could affect the assess­ment of safety and efficacy of telaprevir. Uncategorized prior response was limited (n ≤ 8, 13%) to observe for trends of efficacy in naïve or relapsed patients versus prior nonresponding or null participants. Lastly, prior treatment after liver transplant was constrained (n ≤ 10, 16%) to avoid enriching the study dispro­portionately with participants with particularly poor prospects for SVR. These enrollment caps limit the generalizability of the findings. However, the incremental improvement in SVR rate compared with Peg-IFN and ribavirin was similar to what was seen in nontransplant patients,15 increasing the confidence in the improved efficacy of telaprevir combination therapy in the posttransplant setting.

Conclusions

The addition of twice daily telaprevir to Peg-IFN-α2a and ribavirin led to a higher SVR rate in this prospective study of patients with recurrent posttransplant genotype 1 HCV infection than in historical controls. The safety and tolerability results were consistent with the established profile for telaprevir combination therapy, with possibly fewer significant rash events. With few exceptions, the drug interactions between telaprevir and the calcineurin inhibitors were manageable. No acute cellular rejections or deaths occurred. In parts of the world without access to interferon-free regimens, these findings support the consideration of telaprevir combination therapy in select patients with recurrent posttransplant HCV.

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