EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Hepatitis C virus infection universally recurs in liver transplant recipients. Peginterferon/-ribavirin achieves a sustained virologic response rate of 30% in recipients infected with hepatitis C virus genotype 1. Consensus-interferon plus ribavirin yields sustained virologic response rates to 30% in patients failing to achieve sustained virologic response with peginterferon/ribavirin pretransplant, but it has not been studied posttransplant. We sought to evaluate the efficacy and tolerability of consensus-interferon and ribavirin in treating posttransplant hepatitis C virus.

Materials and Methods: Clinical, laboratory, and virologic data were collected retrospectively from all patients who received at least 1 dose of consensus-interferon after transplant between January 2008 and December 2011. A standardized treatment protocol was used. The primary aim was sustained virologic response defined by undetectable hepatitis C virus RNA at 24 weeks after completing therapy.

Results: Twenty-three patients were treated with consensus-interferon/ribavirin; 15 with prior non-response (87%) or breakthrough (6.7%) during peginterferon/ribavirin, and 8 as initial therapy. The intention-to-treat sustained virologic response with consensus-interferon was 30%. Anemia, leukopenia, and growth factor requirement were similar between peginterferon and consensus-interferon cohorts.

Conclusions: Consensus-interferon may rescue liver recipients who are nonresponders to peginterferon-based therapy. The efficacy of interferon-based treatment regimens may benefit from substitution of consensus-interferon for peginterferon.

Key words : Interferon alfacon, Viral hepatitis therapy

Hepatitis C virus (HCV) infection is the leading indication for liver transplant (LT) in the United States.¹ Liver recipients who are viremic at LT universally experience recurrent HCV infection.² Recurrent HCV has an accelerated natural history with 20% to 54% of patients developing allograft cirrhosis within 5 years and reduced allograft and recipient survival.^3-12

Historically, recurrent HCV has been treated with peginterferon (PEG) and ribavirin (RBV) with rates of sustained virologic response (SVR) (undetectable HCV RNA at 6 months after end of treatment) of 28% to 45%.^13-19 Contributing to this relatively low SVR is a high prevalence of patients with HCV genotype 1 and the presence of cytopenias limiting the use of maximal dosing of PEG and RBV.^17,20,21 Interferon alfacon-1 or consensus interferon (CIFN) (Infergen, Boehringer Ingelheim, Austria, GmbH) is a synthetic interferon that has been shown to be effective in the retreatment of PEG/RBV nonresponders and partial responders pre-LT to achieve a SVR in 7% to 30% of patients depending on fibrosis stage and prior response to PEG/RBV.²² There are no published studies of CIFN in the post-LT patient. We sought to evaluate our experience with use of CIFN/RBV for recurrent HCV.

Materials and Methods

Study design
This was a retrospective chart review conducted at the University of Colorado of all post-LT patients receiving at least 1 dose of CIFN between January 1, 2008, and December 31, 2011. Demographic and clinical data were collected from the University of Colorado Liver Transplant Database and the University of Colorado Hospital electronic medical record. The study was approved by the Colorado Multiple Institutional Review Board. All of the protocols conformed to the ethical guidelines of the 1975 Helsinki Declaration.

Treatment protocol
Twenty-two patients were infected with HCV GT1, and 1 patient was infected with HCV GT4. All patients were treated by a single physician (JB) using a written treatment protocol. A low-accelerating dosage regimen for initiating PEG, CIFN, and RBV was used to achieve a maximum dosage of interferon (peginterferon-α2a, 180 mcg weekly, peginterferon-α2b 1.5 mcg/kg weekly, and CIFN 15 mcg daily) and RBV (1000 and 1200 mg daily based on weight < 70 kg and ≥ 70 kg). Interferon dosage was reduced for absolute neutrophil count < 1000 cells/μL and platelets < 35 000/μL and ribavirin dosage was reduced for hemoglobin < 10 g/dL. Granulocyte colony-stimulating factor and erythropoietin were used to treat cytopenias. Patients were treated for 48 weeks after achieving HCV RNA negativity. Nonresponse to interferon was defined as < 1 log drop in HCV RNA at week 4 or < 2 log drop in HCV RNA at 12 weeks. Breakthrough was defined as detectable HCV RNA while on therapy after previously having undetectable HCV RNA. End of treatment response (EOTR) was defined as undetectable HCV RNA at treatment completion. Relapse was defined as re-emergence of detectable HCV RNA during posttreatment follow-up. Sustained virologic response (SVR) was defined as undetectable HCV RNA 24 weeks after completing therapy. Quantitative HCV RNA was measured with real-time PCR assay using the Cobas AmpliPrep/COBAS TaqMan (Roche; Indianapolis, IN, USA) platform with lower limit of detection of
43 IU/mL or 18 IU/mL (the later assay replaced the former, during course of this study).

Two CIFN treatment cohorts were defined (Figure 1). One group (cohort A1) consisted of patients started on PEG/RBV with nonresponse or breakthrough who were subsequently transitioned to CIFN/RBV (cohort A2). The second cohort consisted of patients who were started directly on CIFN/RBV (cohort B) without receiving PEG/RBV post-LT.

Descriptive characteristics were tabulated and compared with Wilcoxon rank sum tests for independent continuous variables, Wilcoxon signed rank tests for paired continuous variables, the chi-square, or the Fisher exact tests for independent categorical variables, and McNemar’s test for paired categoric data. Changes over time were assessed by calculating the difference in log HCV RNA from baseline levels and comparing the changes at 4, 8, 12, 16, 20, and 24 weeks using Wilcoxon tests, as described above. The proportion of patients who were viral load negative each time was compared between cohorts using an independent exact chi-square test. The comparison for A1 versus A2 also was made using an exact McNemar’s test for paired data. All statistical analysis was undertaken using SAS Version 9.3 (Cary, NC, USA).

Patients
Twenty-three patients received at least 1 dose of CIFN post-LT - 15 (65%) in cohort A and 8 in cohort B (35%) (Table 1). Primary immunosuppression was done with tacrolimus (74%) and mycophenolate mofetil or mycophenolic acid (70%), with 17% on sirolimus and 13% on cyclosporine. There were no statistically significant differences in baseline characteristics between the 2 treatment cohorts.

Virologic responses
Figure 1 summarizes the treatment cohorts and outcomes. Of the 15 patients in cohort A1, 87% (13/15) were nonresponders to PEG/RBV post-LT, 6.7% (1/15) had a breakthrough on PEG/RBV at week 48 (16 weeks after achieving HCV RNA negativity), and 6.7% (1/15) were transitioned to CIFN at 7 weeks after achieving a 1.58 HCV log drop. Three patients were transitioned from PEG to CIFN before 12 weeks, to those who had < 1 log response at 4 weeks, and 12 were transitioned to CIFN after a median of 12 weeks of PEG. After transitioning to CIFN, (cohort A2), 10 of 15 had undetectable HCV RNA, 3 were nonresponders to CIFN, 1 died of cholestatic hepatitis 4 weeks after starting CIFN, and 1 stopped CIFN at 4 months, despite > 2 log decline in HCV RNA, because of adverse events. Of the 10 patients who had undetectable HCV RNA, 1 stopped secondary to developing posterior reversible en-cephalopathy syndrome, 1 died of recurrent hepato-cellular carcinoma diagnosed after starting antiviral therapy with undetectable HCV RNA, 2 had a viral breakthrough, and 6 had an EOTR. Of the 6 with an EOTR, 5 achieved SVR, and 1 relapsed.

In cohort B, 3 of 8 patients had undetectable HCV RNA (Figure 1), 1 died of cholestatic hepatitis, 3 were nonresponders, and 1 stopped early after hospital-ization for an upper respiratory infection despite a > 2 log HCV RNA decline at 4 weeks. Two of the 3 patients with an EOTR achieved SVR, and 1 relapsed.

Predictors of virologic response
The overall intention-to-treat SVR rate was 30% (7/23) (33% [5/15] in cohort A2, and 25% [2/8] in cohort B [P = .99]). The SVR was 44% (7/16) for patients with stage 0 to 2 fibrosis and 0% (0/7) for patients with stage 3 to 4 fibrosis (P = .057). The SVR was 33% (4/12) and 33% (1/3) for patients with < 1 and ≥ 1 log drop in HCV RNA at 4 weeks of PEG (P = .99) The SVR was 27% (3/11) and 0% (0/1) for patients with < 2 and ≥ 2 HCV log drop at 12 weeks of PEG (P = .99).

Figure 2 describes the virologic response to PEG/RBV for cohort A1 and CIFN/RBV for cohort A2 and cohort B. There was a statistically significant greater decline in median HCV RNA from baseline during treatment with CIFN (cohort A2) compared with treatment with PEG/RBV (cohort A1) (P = .010 at 8 weeks and P = .008 at 12 weeks). Likewise, the decline in HCV RNA in the patients in cohort B was significantly greater than was the decline in HCV RNA during treatment of cohort A1 with PEG (P = .008 at 8 weeks and .004 at 12 weeks). There were no statistically significant differences between the median HCV RNA decline from baseline during CIFN treatment between cohorts A2 and B.

Figure 3 shows the number of patients with undetectable HCV RNA and the total number of patients on treatment in each cohort at each week. There were no statistically significant differences at any time between cohort A1 and B or cohorts A2 and B. Assuming independence, there appeared to be more patients with undetectable viral loads in A2 versus A1 at weeks 8 and 12 (P = .043 and P = .001); however, paired comparisons showed that only week 12 was statistically significant (P = .031). Of note, the paired comparisons between A1 and A2 included 15, 14, 11, 9, 4, and 1 patients at 0, 4, 8, 12, 24, and 48 weeks.

Tolerability
Table 2 summarizes the median doses of PEG, CIFN, and RBV, and the percentage of patients needing dosage reductions, developing cytopenias, and needing growth factors. The median dosage of PEG was 180 mcg weekly, median dosage of RBV was 800 mg daily, and median dosage of CIFN was 12 mcg daily. There was a significant difference between the RBV dosage in cohort A1 and in cohort A2 (P = .016), reflecting a larger range of RBV dosages in cohort A1. There also was a significant difference between the filgrastim (Neupogen) requirements between cohorts A2 and B (P = .023). One patient stopped CIFN/RBV because of adverse events, though had similar difficulties tolerating PEG/RBV. None of the patients experienced acute rejection.

This study shows that daily CIFN/RBV is an effective treatment in a difficult to treat patient population of liver transplant recipients, 65% of whom failed PEG/RBV. In the DIRECT trial patients with stage 0 to 2 fibrosis and a less than a 2-log drop with PEG had a SVR of 7.4%. Whereas, the SVR in the current study of transplant recipients was 44% in patients with stage 0 to 2 fibrosis with less than a 2-log drop in HCV RNA with PEG at 12 weeks. The higher rate of SVR in this study may be attributable to direct transition from PEG to CIFN in cohort A1 to cohort A2. The DIRECT trial had a median washout interval of 506 days between PEG and CIFN initiation,²² whereas all our patients were transitioned directly. The SVR rate in this study also was greater than a veterans administration trial showing a 6% and 31% SVR rate in nonresponders and relapsers.²³ Although our study and the veterans administration trial had a similar proportion of patients with cirrhosis, the veterans administration trial had a larger proportion of African Americans at 28%, and human immunodeficiency virus coinfection at 14%. Transplant recipients are particularly motivated to achieve SVR and may tolerate a greater extent of adverse events to those of nontransplant patients because graft loss is devastating and retransplant often is not an option.

Daily CIFN injections may be less tolerable than weekly peginterferon injections, but we did not find this to be true. The differences in RBV dosages between cohorts A1 and A2 were not clinically significant, as the medians were the same. The differences between filgrastim requirements between cohorts A2 and B were likely related to duration of therapy and CIFN/RBV dosing. Many of the patients in cohort A were started on filgrastim while on PEG, and received a longer total duration of interferon therapy. Additionally, the range of CIFN dosing for cohort A2 was greater than that for cohort B, though this was not statistically different. There were no differences in the rates of neutropenia, need for dosage reductions, or nadir blood counts between the cohorts. One patient did stop CIFN because of adverse events; however, his tolerability of PEG was equally poor. Although 3 patients died while on therapy, 2 from cholestatic hepatitis and 1 from recurrent hepatocellular carcinoma, mortality was likely related to disease progression rather than to adverse events of treatment.

This study has several limitations. It is a nonrandomized, retrospective review with a small sample size leading to risk for bias and low power for statistical analysis. Cohort A did serve as an internal control; however, there was not a PEG/RBV only group to directly determine the SVR rate with therapy extended to 48 weeks of HCV RNA negativity compared with 48 weeks of total therapy, as is routinely done. Additionally, enrollment into cohort A and cohort B was not randomized and imbalanced over time, with the number of patients started directly on CIFN (cohort B) being higher in 2011 compared with 2008 because of the observation that CIFN/RBV appeared to be more effective than PEG/RBV over time. Although all patients failing PEG/RBV were considered for transition to CIFN/RBV, other difficult to quantify factors (eg, insurance approval of CIFN) contributed to which patients received CIFN/RBV. Despite these limitations, based on these results, we feel that the evidence is stronger for CIFN/RBV than for PEG/RBV alone in nonresponders with less than stage 2 fibrosis because the lack of virologic response (< 1 log at 4 weeks and < 2 log at 12 weeks) with PEG/RBV conveys nearly a 100% negative predictive value for SVR.^24-26

Despite the promising efficacy of interferon-free direct acting antiviral therapies, we think it is still applicable to HCV treatment in select liver transplant recipients. The price of direct-acting antiviral regimens presents a challenge in high-income countries, and is an even greater burden to low- and middle-income countries that bear 80% of the global HCV burden. Although generic direct-acting antiviral manufacturing has been announced in several low-income countries, middle-income countries have been excluded from these increasing direct acting antiviral access strategies, leaving prices to be set by pharmaceutical companies.^27,28Triple therapy with NS3/4A protease inhibitors in conjunction with interferon and ribavirin can yield SVR rates of 50% to 63%, though this is attenuated in patients with prior nonresponse to PEG/RBV, and limited by discontinuation related to adverse events in 15% to 20% of patients.^29,30 As HCV treatment in middle-income countries may still use interferon in the near future, the use of CIFN instead of PEG may offer improved SVR, especially in difficult-to-treat patient populations such as liver transplant recipients with prior nonresponse to PEG/RBV.

In conclusion, this study shows that CIFN/RBV can achieve SVR in nonresponders to PEG/RBV after liver transplant. Future studies are needed to determine if using CIFN/RBV with new direct acting antivirals instead of PEG/RBV may lead to even higher rates of SVR in this difficult to treat patient population.

Volume: 13 Issue: 6 December 2015

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