SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENT
  7. REFERENCES

The safety, efficacy, and effect on immunosuppression levels of telaprevir (TVR) or boceprevir (BOC) in combination with peginterferon (PEG-IFN) and ribavirin (RBV) in recipients of liver transplantation (LT) with hepatitis C virus (HCV) genotype 1 have not been defined. We report our 3 centers' preliminary experiences with administering triple antiviral treatment protocols containing PEG-IFN, RBV, and TVR or BOC. Patients with biopsy-proven HCV recurrence (METAVIR grade ≥ 3 and/or stage ≥ 2) received TVR with PEG-IFN/RBV for 12 weeks and then PEG-IFN/RBV for 36 weeks or BOC with PEG-IFN/RBV for 44 weeks after 4 weeks of lead-in PEG-IFN/RBV. Maintenance immunosuppression was changed to cyclosporine whenever possible, and the levels were followed closely. PEG-IFN/RBV dose adjustments were based on patients' tolerance. Sixty patients started triple antiviral treatment, and they were followed for up to 66 weeks (mean = 35 weeks); all were followed at least 12 weeks. Thirty of the 35 patients treated with TVR (86%) achieved undetectable HCV RNA levels after an average of 6 weeks, whereas 12 patients (48%) in the BOC-treated group achieved undetectable HCV RNA levels after a mean of 11 weeks. According to an intention-to-treat analysis, 14 of 21 TVR-treated patients (67%) and 10 of 22 patients who received BOC (45%) achieved undetectable HCV RNA levels at week 24 without viral breakthrough at the last follow-up. Cytopenias complicated both regimens; all patients required dose reductions of PEG-IFN and/or RBV or the administration of hematological growth factors. One death occurred in each group on triple antiviral treatment. In conclusion, TVR or BOC combined with PEG-IFN/RBV achieved on-treatment virological response rates of approximately 50% to 60% in patients with recurrent HCV after LT, but significant side effects were common. Liver Transpl 19:690–700, 2013. © 2013 AASLD.

Abbreviations
BOC

boceprevir

BPAR

biopsy-proven acute rejection

cEVR

complete early virological response

CHF

congestive heart failure

CNI

calcineurin inhibitor

GFR

glomerular filtration rate (mL/minute)

HCV

hepatitis C virus

IL-28B

interleukin-28B rs12979860

LLOD

lower limit of detection

LLOQ

lower limit of quantification

LT

liver transplantation

PEG-IFN

peginterferon

RBV

ribavirin

RVR

rapid virological response

SD

standard deviation

SVR

sustained virological response

TIW

three times per week

TVR

telaprevir

Hepatitis C virus (HCV) infection is the leading indication for liver transplantation (LT) in the United States.[1] HCV recurrence is universal and occurs immediately after LT.[2] Although the severity and clinical course of HCV infections after LT are variable, severe histological recurrence is the most common cause of death and graft loss in LT recipients with HCV infections and accounts for approximately half of deaths and two-thirds of graft losses by the tenth postoperative year.[3-5] Graft and patient survival can be improved with successful antiviral treatment.[3-5] Unfortunately, treatment with peginterferon (PEG-IFN) and ribavirin (RBV) is less effective and more poorly tolerated in the posttransplant setting in comparison with nontransplant patients, with sustained virological response (SVR) rates of 24% to 45%.[5, 6]

Recently, 2 protease inhibitors, telaprevir (TVR) and boceprevir (BOC), were approved by the Food and Drug Administration for the treatment of HCV genotype 1 infections. The administration of these protease inhibitors in combination with PEG-IFN/RBV resulted in substantial improvements in SVR rates in comparison with treatment with PEG-IFN/RBV alone in treatment-naive patients.[7-9] The SVR rates were also higher in patients who were nonresponders to previous treatment with PEG-IFN/RBV and in prior relapsers.[10, 11]

Although there is an urgent need for effective treatments for HCV recurrence after LT, significant concerns have been expressed about the safety and efficacy of HCV protease inhibitors in this setting because of the side effect profile and the potential for drug-drug interactions with immunosuppressive agents.[12] Both cyclosporine and tacrolimus are substrates of cytochrome P450 3A and P-glycoprotein. The coadministration of TVR, a potent cytochrome P450 3A4 substrate and inhibitor with the potential to saturate or inhibit intestinal P-glycoprotein, substantially increases the blood levels of the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus.[13] Lesser drug-drug interactions between BOC and both CNIs have also been observed.[14] Additionally, levels of sirolimus and everolimus would also be expected to increase significantly if they were taken with protease inhibitors through the same mechanisms. Recently, Werner et al.[15] described their initial 12-week experience in a pilot study using TVR with tacrolimus, cyclosporine, or sirolimus in 9 patients.[15]

We report our preliminary experience with both protease inhibitors in combination with PEG-IFN/RBV for the treatment of recurrent HCV genotype 1 infections after LT in 3 LT centers.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENT
  7. REFERENCES

Clinical treatment protocols were prospectively developed for LT recipients with HCV genotype 1 who had histological evidence of HCV recurrence at Mayo Clinic in Jacksonville, FL; at Mayo Clinic in Scottsdale, AZ; and at Mayo Clinic in Rochester, MN. Staff from each site agreed to both protocols, and a retrospective review of the safety and efficacy of these investigational protocols was approved by the Mayo Clinic institutional review board. All patients considered for triple antiviral treatment (an HCV protease inhibitor combined with PEG-IFN/RBV) had an allograft biopsy sample that showed significant fibrosis (stage ≥ 2) and/or moderate to severe lobular hepatitis (grade ≥ 3) according to the METAVIR system.[16] Exclusion criteria for antiviral treatment included evidence of biopsy-proven acute rejection (BPAR) in the past 2 months and/or any medical contraindication for PEG-IFN/RBV use. Mycophenolate mofetil and corticosteroids were discontinued before the initiation of antiviral treatment whenever possible.

Figure 1 is a timeline comparison of the immunosuppressive agent and triple antiviral treatment used in the treatment protocols. In both protocols, the maintenance immunosuppressive agent was converted to cyclosporine. A stable trough level of cyclosporine for 4 weeks was required before the initiation of antiviral treatment. Individual patients who did not tolerate the conversion to cyclosporine were considered for antiviral treatment while they were on either tacrolimus or sirolimus. Close monitoring of trough levels of the immunosuppressive agent was mandated during the first 14 days after the initiation of the protease inhibitor and again during the first 7 days of its discontinuation. Once trough level of the immunosuppressive agent was stable, it was performed every 1 to 2 weeks throughout the triple antiviral treatment and every 2 to 4 weeks during the dual antiviral treatment with PEG-IFN/RBV.

image

Figure 1. Timeline comparison of the immunosuppressive agent and triple antiviral treatment used in the 2 treatment protocols.

Download figure to PowerPoint

The treatment regimen consisted of PEG-IFNα2a (Pegasys), RBV, and either TVR or BOC. TVR was used at Mayo Clinic in Jacksonville, FL, whereas BOC was selected at Mayo Clinic in Scottsdale, AZ and at Mayo Clinic in Rochester, MN with the plan of performing an interim analysis assessing the safety and efficacy of the 2 protocols after they were implemented.

In the TVR-based regimen, PEG-IFN was administered subcutaneously at 135 μg/week, and RBV was prescribed orally at 800 mg/day for the patients with a glomerular filtration rate (GFR) ≥ 60 mL/minute, at 400 to 600 mg/day for those with a GFR of 30 to 59 mL/minute, and at 200 mg thrice weekly up to 200 mg/day for those with a GFR < 30 mL/minute. TVR was prescribed orally at 750 mg every 7 to 9 hours with food for the first 12 weeks without a lead-in phase (except for 3 patients who were on PEG-IFN/RBV for 4 to 8 weeks before TVR initiation to ensure tolerability). In the BOC-based regimen, the 4-week lead-in was initiated with PEG-IFN (135 μg/week subcutaneously) and RBV (at a dose adjusted for renal function similarly to the TVR-based regimen). BOC was prescribed orally at 800 mg every 7 to 9 hours with food for 44 weeks after the lead-in phase. At both centers, PEG-IFN and RBV doses were adjusted according to patients' tolerance, side effects, and laboratory results, and they were planned to be used for a total of 48 weeks.

Hematological growth factors were used aggressively in our protocols. An erythropoiesis-stimulating agent [epoetin alfa (Procrit) at 40,000 U/week or darbepoetin alfa (Aranesp) at 100 μg/week] was administered subcutaneously to patients who had hemoglobin levels < 10 g/dL and/or symptoms, and an agent was initiated whenever the hemoglobin level dropped >2 g/dL from the baseline in patients with a history of coronary artery disease. Filgrastim (Neupogen) was administered subcutaneously at 300 or 480 μg/week (depending on the body weight) to patients with absolute neutrophil counts < 500/mm3. Eltrombopag (Promacta) was prescribed orally at 25 to 75 mg/day to select patients without cirrhosis who developed severe thrombocytopenia to maintain platelet counts ≥ 20,000/mm3.

Plasma HCV RNA levels were measured with the COBAS TaqMan HCV test, version 2.0 (Roche Molecular Systems, Inc.), with a lower limit of quantification (LLOQ) of 43 IU/mL and a lower limit of detection (LLOD) of 10 IU/mL. In the TVR protocol, HCV RNA was monitored weekly until the first instance of undetectable HCV RNA levels and then every 4 weeks for the duration of the treatment. TVR was discontinued in patients with HCV RNA levels ≥ 1000 IU/mL at week 4 (with a confirmed increase in HCV RNA at week 5), with HCV RNA levels ≥ 1000 IU/mL at week 12, or with detectable HCV RNA levels at week 24. In the BOC protocol, HCV RNA was monitored every 4 weeks. BOC was discontinued in patients with HCV RNA levels ≥ 100 IU/mL at week 12 (week 8 after the initiation of BOC) or with detectable HCV RNA at week 24 (week 20 after the initiation of BOC). The option of continuing PEG-IFN/RBV was considered on the basis of patients' tolerance and biochemical responses on treatment along with the fibrosis stage.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENT
  7. REFERENCES

At the time of this writing, 60 eligible patients had been enrolled and started on triple antiviral treatment. Thirty-five of these patients were started on the TVR-based regimen, whereas the remaining 25 patients were treated with the BOC-based regimen. Three patients were considered to have experienced cholestatic HCV recurrence: 2 in the TVR cohort and 1 in the BOC cohort. These patients were followed for a median of 35 weeks (mean = 35 weeks, range = 12-66 weeks).

Table 1 summarizes the demographics and patient characteristics for both treatment groups. There were no differences in terms of age, sex, race, time from LT, HCV genotype 1 subtype, recipient interleukin-28B rs12979860 (IL-28B) polymorphism, history of previous treatment with PEG-IFN/RBV, fibrosis stage on last liver biopsy, or duration of treatment at the last follow-up. Figure 2 is a flow diagram of the patients enrolled in the 2 treatment protocols.

Table 1. Demographics and Patient Characteristics According to the Treatment Groups
 TVR Group (n = 35)BOC Group (n = 25)
  1. a

    Nine patients only before LT, 2 patients only after LT, and 9 patients both before LT and after LT.

  2. b

    Four patients only before LT, 2 patients only after LT, and 9 patients both before and after LT.

  3. c

    Three patients only before LT, 2 patients only after LT, and 7 patients both before and after LT.

  4. d

    One patient only before LT, 2 patients only after LT, and 1 patient both before and after LT.

  5. e

    One patient only before LT and 1 patient only after LT.

Recipient age (years): mean ± SD58 ± 860 ± 6
Sex: male [n (%)]22 (63)19 (76)
Race [n (%)]  
Caucasian28 (80)23 (92)
African American2 (6)0
Hispanic1 (3)2 (8)
Other4 (11)0
Time from LT (months)  
Mean ± SD51 ± 3671 ± 72
Median (range)40 (1-135)38 (3-283)
HCV genotype [n (%)]  
1a23 (66)17 (68)
1b11 (31)8 (32)
Unable to subtype1 (3)0
Recipient IL-28B polymorphism [n (%)]  
CC3 (9)1 (4)
CT23 (66)12 (48)
TT9 (26)6 (24)
Unknown06 (24)
History of any prior PEG-IFN/RBV treatment [n (%)]  
Null responders20 (57)a15 (60)b
Partial responders12 (34)c4 (16)d
Relapsers02 (8)e
History of post-LT PEG-IFN/RBV treatment [n (%)]  
Null responders11 (31)11 (44)
Partial responders9 (26)3 (12)
Relapsers01 (4)
Fibrosis stage on last liver biopsy [n (%)]  
F0-F215 (43)12 (48)
F3-F420 (57)13 (52)
HCV RNA at baseline  
Mean ± SD (log10 IU/mL)6.47 ± 1.376.96 ± 0.64
≥800,000 IU/mL [n (%)]29 (83)22 (88)
Duration of treatment (weeks)  
Mean ± SD32 ± 1439 ± 13
Median (range)30 (12-58)41 (15-66)
image

Figure 2. Flow diagram of the patients enrolled in the 2 treatment protocols. *Same patient. SVR[n] represent sustained virological response at [n] weeks after discontinuation of treatment.

Download figure to PowerPoint

TVR-Based Treatment Regimen

Pretreatment Preparation

Thirty-three of the 35 patients who were started on TVR combined with PEG-IFN/RBV were successfully changed to cyclosporine or were on cyclosporine as a maintenance immunosuppressive agent before antiviral treatment. The remaining 2 patients did not tolerate the conversion to cyclosporine: one developed evidence of posterior reversible encephalopathy syndrome necessitating a conversion to sirolimus, whereas the other patient had severe thrombocytopenia on cyclosporine, which completely resolved when tacrolimus was reintroduced in its place.

Immunosuppression Modification While on TVR

On the first day of TVR, the cyclosporine dose was reduced to approximately 75% to 100% of the original twice daily (every-12-hour) dose, and the dosing interval was reduced to once daily. Subsequently, the dose was adjusted on the basis of trough levels. In the steady state, the cyclosporine dose to achieve target trough levels (100 ng/mL for patients with renal insufficiency and 150 ng/mL for others) was approximately 50% to 100% (mean = 70%) of the original every-12-hour dose administered once daily. The sole patient on sirolimus required a significant dose reduction and took only 0.5 mg orally every 4 days, whereas the patient on tacrolimus required only 0.5 mg orally every 7 days.

After the discontinuation of TVR, the pre-TVR every-12-hour dose and interval for cyclosporine were resumed. Subsequently, 6 patients changed from cyclosporine back to tacrolimus because of renal insufficiency (3 patients), neuropsychiatric side effects (1 patient), severe gingival hyperplasia (1 patient), or personal preference (1 patient).

Adverse Events

Table 2 summarizes the adverse events that occurred during antiviral treatment. Cytopenias were very common, and all patients required dose reductions of PEG-IFN and/or RBV or the administration of hematological growth factors. Mild transient increases in serum creatinine from the baseline were noted in almost all patients during the first 12 weeks of TVR administration (range = 0-1.4 mg/dL, mean = 0.6 mg/dL, median = 0.5 mg/dL). Figure 3 presents chronological changes in the average estimated GFRs during antiviral treatment.

Table 2. Adverse Events According to the Treatment Groups
 TVR Group (n = 35)BOC Group (n = 25)
  1. a

    Effectively treated with oral antihistamines and/or topical steroids.

  2. b

    Two patients with a urinary tract infection (weeks 4 and 23), 1 patient with sinusitis (week 11), 1 patient with lower extremity cellulitis (week 7), 1 patient with pneumonia (week 5), and 1 patient with trigeminal herpes zoster reactivation (week 5).

  3. c

    One patient with a periodontal abscess (week 31).

Leukopenia  
PEG-IFN dose reduction [n (%)]27 (77)19 (76)
Filgrastim use [n (%)]6 (17)14 (56)
Initiating point: average (range)Week 5 (0-15)Week 8 (0-21)
Anemia  
RBV dose reduction [n (%)]31 (89)25 (100)
Temporary RBV interruption1 (3)1 (4)
Permanent RBV discontinuation03 (12)
Erythropoiesis-stimulating agent use [n (%)]27 (77)24 (96)
Initiating point: average (range)Week 4 (0-14)Week 7 (0-20)
Packed red blood cell transfusion [n (%)]16 (46)16 (64)
Units per patient: average (range)5 (2-12)11 (4-22)
Thrombocytopenia [n (%)]  
Temporary PEG-IFN interruption2 (6)2 (8)
Eltrombopag use (25-75 mg/day)3 (9)0
Renal insufficiency  
Increase in serum creatinine (mg/dL): average0.60.5
Increase in serum creatinine (mg/dL): median (range)0.5 (0-1.4)0.4 (0.1-1)
Increase in serum creatinine > 0.5 mg/dL [n (%)]14 (40)9 (36)
Symptomatic skin rashes [n (%)]a4 (11)2 (8)
Anorectal complaints [n (%)]a2 (6)2 (8)
Dysgeusia [n (%)]1 (3)2 (8)
Infectious complications [n (%)]6 (17)b1 (4)c
BPAR [n (%)]2 (6)1 (4)
Hepatic decompensation [n (%)]  
Ascites and/or fluid overload2 (6)3 (12)
Hepatic encephalopathy1 (3)1 (4)
Cardiovascular complications [n (%)]1 (3)1 (4)
Death [n (%)]1 (3)1 (4)
image

Figure 3. Chronological changes in the average estimated GFRs of the 2 cohorts during the triple antiviral treatment.

Download figure to PowerPoint

BPAR developed in 2 patients with subtherapeutic cyclosporine levels, with the first episode occurring in a patient at week 3 of the protocol. This was treated successfully with intravenous corticosteroids and an adjustment of the cyclosporine dose. The patient continued on triple antiviral treatment and became HCV RNA–negative at week 12, but subsequently, viral breakthrough was noted at week 20; PEG-IFN/RBV was discontinued at week 24. The second patient received antiviral treatment for cholestatic HCV recurrence and developed BPAR at week 3, which was treated with intravenous corticosteroids. Allograft function declined precipitously despite a significant HCV RNA reduction; the patient developed multiorgan failure from sepsis and died 1 week later.

Because of significant anemia, 1 patient developed unstable angina at week 3 and required coronary angiography and single-vessel angioplasty. TVR was discontinued, but the patient requested to continue PEG-IFN/RBV and achieved undetectable HCV RNA levels at week 6. PEG-IFN and RBV were subsequently discontinued at week 28 because of psychological side effects, but HCV RNA remained undetectable at the last follow-up (week 55, SVR at 27 weeks after discontinuation of treatment).

Four additional patients discontinued antiviral treatment prematurely (Fig. 2). Six individual patients developed infectious complications, and all were treated successfully with appropriate treatments (Table 2). The triple antiviral treatment was not interrupted. Three patients with pretreatment cirrhosis developed hepatic decompensation (Table 2).

Preliminary Virological Response

Figure 4A presents the HCV RNA levels of all 35 patients treated with the TVR-based regimen. At week 1, the mean HCV RNA reduction was 3.14 log10 IU/mL (range = 1.07-4.95 log10 IU/mL), with no difference in the degree of HCV RNA reduction between patients with IL-28B polymorphisms CC (mean = 3.01 log10 IU/mL) and CT/TT (mean = 3.15 log10 IU/mL, P = 0.7). At week 4 of triple antiviral treatment, 30 of the 35 patients (86%) had HCV RNA levels < 1000 IU/mL, and HCV RNA was undetectable [rapid virological response (RVR)] in 6 patients (17%) and detectable at <43 IU/mL in 18 patients (51%). A patient who discontinued treatment at week 3 due to adverse events was considered a failure based on an intention-to-treat analysis. Two of the 4 remaining patients with HCV RNA levels ≥ 1000 IU/mL at week 4 discontinued TVR at week 5, whereas 2 patients continued on triple antiviral treatment and achieved an undetectable HCV RNA level by weeks 7 and 14. At week 12 of triple antiviral treatment, 28 of the 35 patients (80%) achieved undetectable HCV RNA levels [a complete early virological response (cEVR)]. One of the 3 patients with a detectable HCV RNA level < 43 IU/mL never achieved undetectable HCV RNA levels, and antiviral treatment was discontinued at week 24. The other 2 patients achieved undetectable HCV RNA levels at weeks 14 and 16: HCV RNA remained undetectable at the last follow-up (week 34) in the former patient, whereas the latter patient developed viral breakthrough at week 18. Twenty-four weeks after the initiation of triple antiviral treatment, 14 of 21 patients (67%) achieved undetectable HCV RNA levels without viral breakthrough at the last follow-up. One of the 7 remaining patients (all genotype 1a) died after BPAR, sepsis, and multiorgan failure (discussed previously); 2 patients discontinued antiviral treatment at week 5; and after meeting treatment futility rules, another patient discontinued antiviral treatment at week 24. Three patients developed viral breakthrough at weeks 18, 20, and 22 after they achieved undetectable HCV RNA levels at weeks 16, 12, and 5, respectively.

image

Figure 4. HCV RNA levels in (A) the TVR-based triple antiviral treatment group and (B) the BOC-based triple antiviral treatment group. Each solid black line represents an individual patient with an on-treatment virological response. Each solid red line represents an individual patient with treatment failure. The LLOQ was 43 IU/mL. The LLOD was 10 IU/mL.

Download figure to PowerPoint

Overall, 30 patients (86%) achieved undetectable HCV RNA levels on average at week 6 (median = week 6, range = weeks 1-16). At the last follow-up, 27 patients still had undetectable HCV RNA levels.

BOC-Based Treatment Regimen

Pretreatment Preparation

All except 2 patients were successfully changed to or were on cyclosporine as a maintenance immunosuppressive agent before antiviral treatment. The remaining 2 patients did not tolerate the conversion to cyclosporine because of uncontrolled hypertension and migraine exacerbation, and they resumed taking tacrolimus.

Immunosuppression Modification While on BOC

On the first day of BOC, the cyclosporine dose was reduced to approximately 50% of the original every-12-hour dose, but the dosing interval remained every 12 hours. Subsequently, the dose was adjusted on the basis of trough cyclosporine levels. In the steady state, the cyclosporine dose to achieve target trough levels (100 ng/mL for patients with renal insufficiency and 150 ng/mL for others) was approximately 33% to 100% (mean = 56%) of the original every-12-hour dose administered twice daily. The 2 patients on tacrolimus required significant dose reductions from 1 mg orally twice daily to 0.5 mg every other day and from 0.5 mg orally every 12 hours to 0.5 mg orally twice weekly. After the discontinuation of BOC, the pre-BOC dose and interval of cyclosporine or tacrolimus were resumed.

Adverse Events

Table 2 summarizes adverse events that developed during triple antiviral treatment. Cytopenias were very common, with all patients requiring dose reductions of PEG-IFN and/or RBV or the administration of hematological growth factors. Serum creatinine increased from the baseline throughout the 44 weeks of BOC administration (range = 0.1-1.0 mg/dL, mean = 0.5 mg/dL, and median = 0.4 mg/dL). Figure 3 demonstrates chronological changes in the estimated GFRs during antiviral treatment.

No BPAR developed during antiviral treatment. One patient had BPAR following BOC discontinuation after the futility rule was met because the cyclosporine dose was not appropriately increased; BPAR was treated successfully with intravenous corticosteroids. Six patients prematurely discontinued antiviral treatment because of adverse events (Fig. 2). Three patients with preexisting advanced fibrosis or cirrhosis developed hepatic decompensation (Table 2). One patient who discontinued antiviral treatment at week 9 because of worsening hepatic encephalopathy subsequently died from allograft dysfunction and multiorgan failure.

Preliminary Virological Response

Figure 4B presents the HCV RNA levels of all 25 patients treated with the BOC-based regimen. At week 4 after the lead-in phase of PEG-IFN/RBV, the mean HCV RNA reduction was 1.31 log10 IU/mL (range = 0.03-4.58 log10 IU/mL). At week 8 of antiviral treatment (week 4 after the initiation of BOC), 10 of 25 patients (40%) had HCV RNA levels < 100 IU/mL: HCV RNA was undetectable (RVR) in 6 of these patients (24%) and detectable at <43 IU/mL in 4 patients (16%). Eleven of the 15 remaining patients with HCV RNA levels ≥ 100 IU/mL at week 8 discontinued all treatment after week 12 because the HCV RNA level was ≥100 IU/mL with or without side effects, whereas 4 patients with detectable HCV RNA at <43 IU/mL at week 12 continued triple antiviral treatment. At week 12 of antiviral treatment (week 8 after the initiation of BOC), 10 of 25 patients (40%) achieved undetectable HCV RNA levels (cEVR), whereas the remaining 4 patients had detectable HCV RNA levels < 43 IU/mL. One of the 10 patients with undetectable HCV RNA levels developed viral breakthrough at week 19 and discontinued antiviral treatment. Two of the 4 patients with detectable HCV RNA levels < 43 IU/mL at week 12 never achieved undetectable HCV RNA levels, and antiviral treatment was discontinued at weeks 17 and 20, respectively. The other 2 patients achieved an undetectable HCV RNA level at weeks 16 and 19, and HCV RNA remained undetectable at the last follow-up. At week 24 of antiviral treatment, 10 of 22 patients (45%) were HCV RNA–negative without viral breakthrough at the last follow-up. Five of the 12 remaining patients prematurely discontinued antiviral treatment because of side effects (discussed previously), 5 patients (4 with genotype 1a) discontinued antiviral treatment after they met futility rules at week 12, 1 patient (genotype 1a) never achieved HCV RNA and discontinued antiviral treatment at week 20 after viral rebound, and 1 patient (genotype 1a) developed viral breakthrough at week 19 after achieving undetectable HCV RNA levels at week 11.

Overall, 12 patients (48%) achieved undetectable HCV RNA levels at week 11 on average (median = week 9, range = weeks 8-19). At the end of follow-up, 11 patients still had undetectable HCV RNA levels, whereas 1 patient developed viral breakthrough.

Intention-to-Treat Analysis of Virological Responses

Table 3 presents preliminary data for on-treatment virological responses based on an intention-to-treat analysis. Because of the small number of patients with recipient IL-28B polymorphism CC, no meaningful analysis could be performed to assess the correlation between the recipient IL-28B polymorphism and the on-treatment virological response. In the TVR group, the patients with genotype 1b achieved undetectable HCV RNA levels at week 24 at a significantly greater rate than the patients with genotype 1a (100% versus 50%, P = 0.047). In the BOC group, there was no significant difference in the rates of patients achieving undetectable HCV RNA levels at week 24 between genotypes 1a and 1b (43% versus 50%, P = 1.0). There was no difference in the numbers of patients achieving undetectable HCV RNA levels at week 24 between the patients with early fibrosis (F0-F2) and those with advanced fibrosis (F3-F4) in both the TVR-based regimen (64% versus 70%, P = 1.0) and the BOC-based regimen (58% versus 30%, P = 0.2). In addition, we found no difference in the achievement of undetectable HCV RNA levels at week 24 between the patients with low baseline HCV RNA levels (<800,000 IU/mL) and the patients with high baseline HCV RNA levels (≥800,000 IU/mL) in both the TVR group (67% versus 67%, P = 1.0) and the BOC group (50% versus 45%, P = 1.0).

Table 3. Intention-to-Treat Analysis of On-Treatment Virological Responses According to the Treatment Groups
 TVR GroupBOC Group
HCV RNA at week 4 of protease inhibitor therapy [n/N (%)]  
<1000 IU/mL (TVR)30/35 (86) 
<100 IU/mL (BOC) 10/25 (40)
Undetectable6/35 (17)6/25 (24)
HCV RNA at week 12 of treatment plan [n/N (%)]  
<1000 IU/mL (TVR)31/35 (89) 
<100 IU/mL (BOC) 14/25 (56)
Undetectable28/35 (80)10/25 (40)
HCV RNA at week 24 of treatment plan [n/N (%)]  
Undetectable14/21 (67)10/22 (45)
Genotype 1a7/14 (50)6/14 (43)
Genotype 1b7/7 (100)4/8 (50)
F0-F27/11 (64)7/12 (58)
F3-F47/10 (70)3/10 (30)
Baseline HCV RNA < 800,000 IU/mL2/3 (67)1/2 (50)
Baseline HCV RNA ≥ 800,000 IU/mL12/18 (67)9/20 (45)

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENT
  7. REFERENCES

This report describes our initial experience in treating recurrent HCV in a large series of LT recipients using either TVR or BOC in combination with PEG-IFN/RBV. This multicenter analysis has enabled us to present our experience using standardized treatment protocols with both protease inhibitors. Our study has produced some important insights into the management of immunosuppression while patients are on these medications and into the frequency and severity of adverse events as well as early virological response data. We have demonstrated that TVR- or BOC-containing antiviral protocols can be used after transplantation and result in moderately successful early virological responses, but these regimens are associated with important toxicities that mitigate their potential benefit. In addition, we have identified several factors that affect an early virological response.

Concerns have been expressed about the safety of protease inhibitors in the posttransplant setting because of the potential for drug-drug interactions documented in healthy volunteers.[12-14] All 3 centers in this report decided that using cyclosporine instead of tacrolimus would pose less risk for adverse consequences from subtherapeutic or supratherapeutic CNI levels because of the lack of any clinical data during protocol development. We determined that drug-drug interactions could be managed with careful monitoring. Drug-drug interaction data for TVR and BOC were derived from studies in patients with HCV infections and with single or few drug doses. One of the key contributions of our study is that it provides data on dose adjustments for CNIs in LT recipients. For patients placed on TVR, the dose of cyclosporine needed to be reduced to approximately 75% to 100% of the original every-12-hour dose, and the dosing interval was reduced to once daily. Patients treated with BOC required their cyclosporine dose to be reduced to approximately 50% of the original every-12-hour dose, although the dosing interval remained every 12 hours. These changes produced CNI trough levels that were comparable to those obtained before the initiation of protease inhibitors. The incidence of BPAR during antiviral treatment was low (5%) and similar to the rates previously reported (3%-7%) in studies using antiviral treatment with PEG-IFN/RBV.[5] Despite the consistent control of CNI trough levels, we observed frequent declines in GFR during the administration of protease inhibitors in both patient cohorts. The effect was greatest during the first 12 weeks in the TVR cohort and throughout the latter 44 weeks in the BOC cohort. Severe renal dysfunction (grade III or higher according to the Risk, Injury, Failure, Loss, and End-Stage Kidney Disease criteria) was not observed. Because neither TVR nor BOC has been reported to be nephrotoxic, we suspect that the deterioration in renal function may have been related to changes in CNI pharmacokinetics during antiviral treatment. Our report supports the initial experience of other groups demonstrating that CNIs can be coadministered relatively safely with either TVR or BOC as long as careful attention is paid to CNI dosing at the initiation and discontinuation of the protease inhibitor and there is ongoing, close follow-up.[17-21] Further studies will be required to determine the optimal combination of protease inhibitors with CNIs that maximizes the virological response while minimizing treatment-related adverse events.

As seen in all studies using PEG-IFN/RBV in the treatment of recurrent HCV after LT, we observed a high frequency of cytopenias in comparison with nontransplant populations.[5] In our current study, the frequencies of cytopenias were similar in the TVR and BOC cohorts, with dose reductions of PEG-IFN/RBV almost universal. Erythropoiesis-stimulating agents and packed red cell transfusions were required in more than half of the patients (Table 2) in order to continue RBV therapy with acceptable hemoglobin levels, whereas smaller numbers of patients required filgrastim and eltrombopag to prevent PEG-IFN discontinuation. Although recent data suggest that RBV dosing can be modestly lowered in nontransplant patients treated with TVR without a loss of efficacy,[22] the doses of RBV that were tolerated in our patients might be expected to attenuate efficacy. The decline in renal function seen in both the TVR cohort and the BOC cohort may have contributed to the poor tolerability of RBV, which is primarily renally excreted. The optimal doses of both PEG-IFN and RBV in the posttransplant setting when a protease inhibitor is used will require additional investigation.

The addition of a protease inhibitor to PEG-IFN/RBV in the posttransplant setting resulted in rapid suppression of HCV replication. In the TVR cohort, 86% of patients achieved HCV RNA levels < 1000 IU/mL at week 4, whereas only 17% had undetectable HCV RNA levels at week 4 (RVR). By week 12, 80% of this group had undetectable HCV RNA levels (cEVR), and this represents a significant improvement in response rates in comparison with previously published studies using only PEG-IFN/RBV in LT recipients. Futility rules were met in 3 patients who had IL-28B polymorphism CT or TT and were infected with genotype 1a. Viral breakthrough occurred in 3 patients with genotype 1a who completed 12 weeks of the triple treatment and were on the PEG-IFN/RBV dual treatment. In the BOC cohort, 40% and 56% achieved HCV RNA levels < 100 IU/mL after 4 and 8 weeks, respectively, of triple antiviral treatment, whereas 40% achieved undetectable HCV RNA levels at week 12 (cEVR). By week 24, 45% of the patients were HCV RNA–negative. After the exclusion of those patients who prematurely discontinued the BOC-based regimen because of adverse events, all but 1 patient who met futility rules or developed viral breakthrough were infected with genotype 1a and had IL-28B polymorphism CT or TT. Thus, we found that triple antiviral treatment using either protease inhibitor combined with PEG-IFN/RBV had limited efficacy in patients with HCV genotype 1a and IL-28B polymorphism CT or TT. In contrast to the nontransplant setting or dual PEG-IFN/RBV treatment, no correlation was demonstrated between the on-treatment virological response and the fibrosis stage or baseline HCV RNA levels for either regimen.

We observed that effective monitoring of patients on treatment was resource-intensive and required the input of experienced mid-level providers and physicians at regularly scheduled clinic visits to address patient concerns. Despite this structured approach at all 3 centers, 2 patients (3%) died while they were receiving triple antiviral treatment. The patient who died on the TVR-based regimen had recurrent cholestatic HCV and developed septic complications after the treatment of BPAR. The death in the BOC group occurred in a patient with established hepatic decompensation before the initiation of antiviral treatment. In addition, 6 patients with preexisting advanced fibrosis or cirrhosis developed hepatic decompensation during triple antiviral treatment. The effort required to follow patients on triple antiviral treatment with the currently available protease inhibitors and the observed outcomes highlight the challenges of such demanding treatment regimens in these patient populations and counterbalance the likely benefit of successful therapy among those responding to treatment.

There are several limitations to our report. First, SVR data were not available because the majority of the patients were still undergoing antiviral treatment. A future analysis of SVR data at weeks 12 and 24 after the discontinuation of antiviral treatment will be required to assess overall treatment efficacy. Second, our treatment protocols were not developed to be directly compared to PEG-IFN/RBV dual therapy. There is no Food and Drug Administration–approved treatment for recurrent HCV after LT. More effective treatments of recurrent HCV are urgently needed, and we believe that our protocols serve as pragmatic and patient-centered responses to the issue of severe and progressive HCV recurrence. Waiting for the results from large-scale, randomized studies is simply not an option for patients affected in this way. Although our preliminary results are encouraging, we recognize the inherent risks associated with the use of these new agents. Third, our treatment protocols were not designed to compare the efficacy of TVR- and BOC-based regimens. Our data appear to indicate that both regimens may be considered in treating recurrent HCV, with the choice of agent resting with the treating physician and the patient.

In conclusion, we have reported our preliminary experience with TVR and BOC combined with PEG-IFN/RBV to treat recurrent HCV after LT. These medications could be administered with a CNI as long as there were appropriate adjustments in CNI dosing and close monitoring during protease inhibitor exposure. On treatment, virological response rates of approximately 50% to 60% were achieved, but numerous side effects (particularly cytopenias) as well as 2 deaths highlight the potential hazards of these treatment regimens. Determining the overall efficacy in achieving SVR of either TVR or BOC combined with PEG-IFN/RBV to treat recurrent HCV in LT recipients requires longer follow-up.

ACKNOWLEDGMENT

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENT
  7. REFERENCES

The authors thank the post-LT nurse coordinators at all participating sites: Bonnie J. Chase, R.N.; Mary J. Cline, R.N.; Amy W. Conley, R.N.; Adam B. Faulkner, R.N.; Kevin A. Gaustad, R.N.; Phillip Gwost, R.N.; Kimberly A. Maloy, R.N.; Amanda R. Miller, R.N.; Mary E. Miller, R.N.; Danielle J. Rusch, R.N.; Paytra N. Stein, R.N.; Sandra C. Thomas, R.N.; Rachel E. Trewhella, R.N.; Susan M. Weinhold, R.N.; Kimberly M. Wright, R.N.; and Lorrie A. Yell, R.N.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENT
  7. REFERENCES
  • 1
    National Institutes of Health. National Institutes of Health consensus development conference statement: management of hepatitis C: 2002—June 10-12, 2002. Hepatology 2002;36(suppl 1):S3S20.
  • 2
    Wiesner RH, Sorrell M, Villamil F; for International Liver Transplantation Society Expert Panel. Report of the first International Liver Transplantation Society expert panel consensus conference on liver transplantation and hepatitis C. Liver Transpl 2003;9:S1S9.
  • 3
    Charlton M, Ruppert K, Belle SH, Bass N, Schafer D, Wiesner RH, et al. Long-term results and modeling to predict outcomes in recipients with HCV infection: results of the NIDDK liver transplantation database. Liver Transpl 2004;10:11201130.
  • 4
    Forman LM, Lewis JD, Berlin JA, Feldman HI, Lucey MR. The association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology 2002;122:889896.
  • 5
    Wang CS, Ko HH, Yoshida EM, Marra CA, Richardson K. Interferon-based combination anti-viral therapy for hepatitis C virus after liver transplantation: a review and quantitative analysis. Am J Transplant 2006;6:15861599.
  • 6
    Berenguer M, Schuppan D. Progression of liver fibrosis in post-transplant hepatitis C: mechanisms, assessment and treatment. J Hepatol 2013;58:10281041.
  • 7
    Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, et al.; for ADVANCE Study Team. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011;364:24052416.
  • 8
    Sherman KE, Flamm SL, Afdhal NH, Nelson DR, Sulkowski MS, Everson GT, et al.; for ILLUMINATE Study Team. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med 2011;365:10141024.
  • 9
    Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al.; for SPRINT-2 Investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011;364:11951206.
  • 10
    Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, et al.; for REALIZE Study Team. Telaprevir for retreatment of HCV infection. N Engl J Med 2011;364:24172428.
  • 11
    Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, et al.; for HCV RESPOND-2 Investigators. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011;364:12071217.
  • 12
    Charlton M. Telaprevir, boceprevir, cytochrome P450 and immunosuppressive agents—a potentially lethal cocktail. Hepatology 2011;54:35.
  • 13
    Garg V, van Heeswijk R, Lee JE, Alves K, Nadkarni P, Luo X. Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus. Hepatology 2011;54:2027.
  • 14
    Hulskotte E, Gupta S, Xuan F, van Zutven M, O'Mara E, Feng HP, et al. Pharmacokinetic interaction between the hepatitis C virus protease inhibitor boceprevir and cyclosporine and tacrolimus in healthy volunteers. Hepatology 2012;56:16221630.
  • 15
    Werner CR, Egetemeyr DP, Lauer UM, Nadalin S, Königsrainer A, Malek NP, Berg CP. Telaprevir-based triple therapy in liver transplant recipients with hepatitis C virus: a 12-week pilot study providing safety and efficacy data. Liver Transpl 2012;18:14641470.
  • 16
    Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. The French METAVIR Cooperative Study Group. Hepatology 1994;20(pt 1):1520.
  • 17
    Coilly A, Roche B, Botta-Fridlund D, Leroy V, Pageaux PG, Si-Ahmed SN, et al. Efficacy and safety of protease inhibitors for severe hepatitis C recurrence after liver transplantation: a first multicentric experience [abstract]. J Hepatol 2012;56(suppl 2):S21.
  • 18
    McCashland TM, Olivera-Martinez MA, Garcia-Saenz de Sicilia M, Mukherjee S, Rochling FA, Schafer DF, Sorrell MF. Early experience with triple drug therapy (telaprevir, pegylated interferon α2A and ribavirin) in patients on cyclosporine A for hepatitis C recurrence after liver transplantation [abstract]. Liver Transpl 2012;18(suppl 1):S99.
  • 19
    Kwo PY, Ghabril M, Lacerda MA, Vinayek R, Fridell JA, Tector AJ, Vianna RM. Use of telaprevir plus PEG interferon/ribavirin for null responders post OLT with advanced fibrosis/cholestatic hepatitis C [abstract]. Gastroenterology 2012;142(suppl 1):S934.
  • 20
    Mantry PS, Mubarak A, Weinstein JS, Madani B, Nazario HE, Mejia A, et al. Early virological response in patients with HCV recurrence after liver transplant treated with triple therapy: a single center experience [abstract]. Gastroenterology 2012;142(suppl 1):S931S932.
  • 21
    Burton JR Jr, Everson GT. Initial experience with telaprevir for treating hepatitis C virus in liver recipients: virologic response, safety, and tolerability [abstract]. Am J Transplant 2012;12(suppl 3):188.
  • 22
    Sulkowski M, Roberts SK, Afdhal NH, Andreone P, Diago M, Pol S, et al. Ribavirin dose modification in treatment-naïve and previously treated patients who received telaprevir combination treatment: no impact on sustained virologic response in phase 3 studies [abstract]. Gastroenterology 2012;142(suppl 1):S919.