Recurrent hepatitis C virus (HCV)-related liver dysfunction remains the leading cause of graft loss and death in HCV-infected liver transplant (LT) recipients.1,2 The HCV treatment with sustained virologic response (SVR) improves post-LT survival,3-7 and in patients with recurrent advanced fibrosis, may lead to stabilization or improvement in histology8-15 and diminished risk of hepatic decompensation.4,12 Given the high rates of decompensation and death in post-LT patients with recurrent cirrhosis (up to 42% with decompensation within 1 year),16,17 and poor outcomes with retransplantation for HCV, these patients have the most to gain from effective viral eradication and disease stabilization. Unfortunately, recurrent advanced fibrosis or cirrhosis is associated with poor treatment response with peg-interferon (P-IFN) and ribavirin dual therapy.3,10,13,18-20 Furthermore, data are limited on the treatment of patients with cholestatic HCV, a severe form of recurrent HCV associated with high mortality when untreated.19,21-24
Direct-acting antiviral agents, including NS3/4A protease inhibitors (PIs), NS5B polymerase inhibitors, and NS5A inhibitors are a major advance for HCV therapeutics. When used in combination with P-IFN and ribavirin, the PIs, telaprevir and boceprevir, increased rates of SVR in treatment-naive25-29 and treatment-experienced30-32 immunocompetent patients with genotype 1 HCV. These triple therapy regimens are also effective in patients with advanced fibrosis and cirrhosis in the nontransplant setting, though with somewhat diminished response rates and more significant toxicities.33-36 Up until late 2013, PI-triple therapy with telaprevir or boceprevir was regarded as the best treatment option patients with genotype 1 HCV disease, including LT recipients. The risk of graft loss especially in patients’ advanced fibrosis or cholestatic hepatitis led many centers to use PI-based regimens in LT recipients even in the face of concerns regarding significant medication interactions between the PIs and standard immunosuppressive agents [most prominently calcineurin inhibitors37,38 and mammalian target of rapamycin inhibitors (mTOR)39], as well as worsening of the kidney dysfunction and cytopenias often present after LT. In this study, we focus on the efficacy and safety of triple antiviral therapy in LT recipients with advanced fibrosis and cholestatic hepatitis and identify key factors associated with a successful outcome.
In many countries, PI-triple therapy with telaprevir and boceprevir has been only recently approved and will remain the mainstay of treatment in the near future. Although those with less advanced disease may be able to await newer treatment options, including P-IFN–free regimens, LT patients with advanced fibrosis may need to be considered for PI triple therapy. Thus, our detailed experience in patients with advanced fibrosis is particularly relevant even as HCV treatment evolves.
MATERIALS AND METHODS
This is a retrospective multicenter cohort study of adult LT recipients with recurrent advanced disease treated with either telaprevir or boceprevir-based triple therapy in the ConsoRtiUm to Study Health Outcomes in HCV Liver Transplant Recipients (CRUSH-C), a group of 6 LT centers in the United States. The overall study results have been previously published.40 For the current study, all patients with genotype 1 HCV RNA-detectable infection and advanced fibrosis defined by evidence of chronic hepatitis on liver biopsy with either Metavir or Scheur fibrosis stages 3 to 4, or cholestatic hepatitis were included. Cholestatic hepatitis was diagnosed based on the hepatologist’s assessment with consideration of standard biochemical and histologic criteria.41,42 Biopsies were not centrally reread for the purposes of this study. This study was approved by the institutional review board at each center.
All patients had the opportunity to have completed the total expected duration of treatment and 12 weeks of posttransplant follow-up. The majority of patients in the cohort (94%) were treated with a lead-in of P-IFN and ribavirin before initiation of telaprevir or boceprevir. The target P-IFN dose was P-IFN α-2a 180 μg weekly, P-IFN α-2b 1.5 μg /kg weekly, or consensus IFN 12 μg /kg daily, whereas the target ribavirin dose was weight-based (adjusted for renal function). Thirteen percent of patients were treated with a prolonged (≥90 day) lead-in, 9% of patients with advanced fibrosis, and 33% of those with cholestatic hepatitis. These were generally patients with virologic nonresponse to P-IFN and ribavirin dual therapy that remained on treatment for disease stabilization while awaiting availability of new agents.
The choice of telaprevir (750 mg 3 times daily or 1125 mg twice daily for 12 weeks) or boceprevir (800 mg 3 times daily for 44 weeks) in combination with P-IFN and ribavirin was at the discretion of the investigator. Stopping rules included discontinuation of the PI in the setting of virologic failure or a significant adverse event. Virologic failure for those receiving telaprevir was defined as a viral load greater than 1000 IU/mL 4 to 12 weeks after starting telaprevir or detectable HCV RNA at 24 weeks. For those receiving boceprevir, virologic failure was defined as HCV RNA greater than 100 IU/mL after week 4 of boceprevir and detectable HCV RNA at week 28.
In general, erythropoietin and transfusion were used to maintain hemoglobin levels greater than 10 g/dL, granulocyte colony-stimulating factor was used to keep absolute neutrophil counts greater than 1000 per mm3 and eltrombopag to manage severe thrombocytopenia (<30 K per mm3). The choice of immunosuppression was also at the discretion of investigator. All patients had a steady state of immunosuppression before antiviral therapy was started, then the calcineurin inhibitor or mTOR inhibitor was dose reduced throughout the duration of PI therapy. Pretreatment and posttreatment calcineurin inhibitor doses were recorded in addition to the use of mTOR inhibitors, mycophenolate mofetil, and steroids. Antibacterial prophylaxis was considered if patients had clinically evident recurrent portal hypertension.
The primary endpoint was 12 week SVR (SVR12), defined as the proportion of patients with undetectable plasma HCV RNA 12 weeks after treatment completion. Secondary endpoints included rates of rapid virologic response (RVR), defined as undetectable HCV RNA 4 weeks after PI initiation, and extended RVR (eRVR), defined as undetectable HCV RNA 4 and 12 weeks after PI initiation. Additional virologic outcomes assessed include end-of-treatment response (EOTR), defined as undetectable HCV RNA at end of therapy, relapse, defined as posttreatment recurrence of detectable HCV RNA during the 12-week follow-up period, and breakthrough, defined as emergence of detectable HCV RNA after being undetectable or greater than 1 log increase in HCV RNA above nadir HCV RNA during treatment. Missing HCV RNA values were considered to be positive.
The HCV RNA levels were measured before treatment initiation and prior to PI initiation, at weeks 4, 12, and 24 weeks after starting the PI, at the end of treatment and 4 and 12 weeks after treatment discontinuation. Plasma HCV RNA levels were quantified by COBAS TaqMan HCV RNA assay, version 2.0 (Roche, Nutley, NJ) with lower limit of detection of 43 or 18 IU per mL at 5 of the 6 centers. One center (17% of total cohort) used a semiautomated real-time polymerase chain reaction assay (Abbott, Abbott Park, IL) with a lower limit of detection of 12 IU per mL.
All serious adverse events including mortality and the need for hospitalization were recorded. In addition, evidence of hepatic decompensation (defined as the development of ascites, encephalopathy, or portal hypertensive bleeding), allograft rejection, kidney dysfunction, and anemia requiring transfusion were noted. Laboratory assessment including blood counts and basic chemistries were collected at baseline, at the start of the PI, weeks 2 to 4, weeks 8, 12, 16, end of therapy, and 12 weeks after cessation of therapy. In addition, the use of growth factors (erythropoietin, granulocyte colony-stimulating factor, and eltrombopag) was assessed along with the incidence of dose reductions and early discontinuations of P-IFN, ribavirin and the PI.
The proportion of patients achieving SVR12 and secondary virologic outcomes are compared between patients with advanced fibrosis and cholestatic hepatitis. Dichotomous variables are described with frequencies (percent) and continuous variables as medians with range or interquartile range. Groups were compared using Fisher exact or Wilcoxon rank sum tests, as appropriate and a P-value less than 0.05 was considered significant. Logistic regression was performed to assess single variable predictors of SVR12 among patients with advanced fibrosis. Multivariable analysis was not performed due to the low overall number of SVR12 events in the cohort. All analyses were completed using SAS version 9.2 (Cary, NC).
A total of 54 patients were included in the analysis, 45 (83%) with advanced fibrosis and 9 (17%) with cholestatic hepatitis. The median (interquartile range [IQR]) age was 58 (55-61) years at the start of treatment, 74% were male, and 65% were white (Table 1). The majority of patients had unfavorable treatment characteristics, including a predominance of HCV genotype 1a (57%), IL28B non-CC genotype (67%), and previous posttransplant treatment failure with P-IFN and ribavirin dual therapy (63%). Despite advanced fibrosis, these patients were generally well compensated at the start of treatment with a median (IQR) model for end stage liver disease of 10 (8-14), and 87% Childs-Turcotte-Pugh (CTP) class A. However, 7 (13%) patients had both an albumin less than 3.5 mg/dL and platelets of 100,000/mm3 or lower. The median (IQR) time from transplant to initiation of treatment was 4.3 (2.5-8.9) years. Baseline characteristics were generally similar between patients with advanced fibrosis and cholestatic hepatitis (Table 1). Patients with cholestatic hepatitis were older (median age, 62 vs 57 years, P = 0.05), more recently transplanted (median 1.5 vs 4.6 years, post-LT, P = 0.009), and were more likely to be African American (33% vs 7%, P = 0.05), treatment naive (78% vs 29%, P = 0.009), and CTP class C at treatment initiation (22% vs 0%, P = 0.02).
All patients were treated with a combination of a PI (telaprevir in 91% or boceprevir in 9%), P-INF (α 2a in 93%) and ribavirin (Table 2). There were no significant differences in choice of antiviral treatment agents or duration of lead-in between the advanced fibrosis and cholestatic hepatitis groups. The median initial, minimum, and maximum doses of P-IFN and ribavirin were similar between groups. The median (IQR) total treatment duration for the cohort was 47 (26-51) weeks. Patients with cholestatic hepatitis had a significantly shorter median total treatment duration of treatment from the time of PI initiation compared to those with advanced fibrosis (21 vs 43 weeks, P = 0.04) due to early treatment discontinuation.
Forty-seven (87%) patients were on calcineurin inhibitors (20% tacrolimus and 67% cyclosporine) at the start of antiviral therapy, and 7 (13%) on mTOR inhibitors. In addition, 76% were on mycophenolate mofetil or mycophenolic acid, and 24% were on maintenance prednisone. Patients with cholestatic hepatitis were more likely to be on tacrolimus as their CNI (67% v. 11%, P = 0.001) and had a trend toward a higher incidence of steroid use (44% v. 20%, P = 0.19) than those with advanced fibrosis.
All patients had a reduction in CNI dosing at the start of the PI (Table 2). The median percent reduction in CNI dose was similar between groups (70% [IQR, 62-80] and 79% [IQR 70-89]) for advanced fibrosis and cholestatic hepatitis, respectively; P = 0.17).
Treatment response data are summarized in Figure 1. The SVR12 rates were statistically similar in patients with advanced fibrosis (51%; 95% confidence interval [95% CI], 36%-66%) and cholestatic hepatitis (44%; 95% CI. 14%-79%, P = 1.00). Rates of RVR, eRVR, and EOTR were also similar between groups. Four (13%) patients experienced relapse in the 12 weeks after treatment discontinuation, and relapse rates were similar between groups.
Predictors of Treatment Response
Early treatment response was the strongest predictor of SVR12. For patients who achieved eRVR, 83% went on to achieved SVR12 compared to only 8% of those without eRVR (P < 0.001). The overall positive and negative predictive values of eRVR to predict SVR12 were 83% and 92%, respectively.
Predictors of SVR12 among these 54 patients with advanced disease were also assessed, with significant associations in univariate analysis including Hispanic ethnicity (odds ratio, 0.16, P = 0.03), previous null/partial response (0.24, P = 0.02), IL28B genotype CC (7.0, P = 0.02), baseline albumin (3.87, P = 0.03), baseline platelets (1.01, P = 0.02), and steroid use (0.21, P = 0.03) (Table 3). On treatment, responses were also highly predictive of SVR12 including greater than 1 log drop in viral load in the lead-in phase of treatment (5.25, P = 0.007) and eRVR (55.0, P < 0.001).
Adverse events and safety data are summarized in Table 4. The use of erythropoietin (73% vs 89%, P = 0.43) and transfusion (53% vs 67%, P = 0.72) for anemia were similar between patients with advanced fibrosis and cholestatic hepatitis, respectively. Dose reductions of ribavirin and P-IFN were common and of similar frequency between groups, though early treatment discontinuation due to adverse events was more common in the cholestatic patients (56% vs 16%, P = 0.02).
Progression of liver disease including hepatic decompensation at any time on treatment occurred in 24% and progression from CTP class A to B/C while on P-IFN occured in 28% overall, including 31% of advanced disease patients and 11% of those with cholestatic hepatitis (P = 0.42). Six (11%) patients died, 5 (11%) with advanced fibrosis, and 1 (11%) with cholestatic hepatitis. All deaths were attributed to progressive complications of liver failure.
Albumin at the start of therapy (0.02; P = 0.001), the presence of encephalopathy (12.0; P = 0.04) and Hispanic ethnicity (odds ratio, 6.17; P = 0.01) were significantly associated with death or decompensation in univariate analysis. Patients with albumin less than 3.5 mg/dL (63% vs 8%, P < 0.001) or albumin less than 3.5 mg/dL and platelets 100,000/mm3 or lower (57% vs 19%, P = 0.049) were more likely to experience death or decompensation compared to patients without these features. Patients with platelets 100,000/mm3 or lower had similar rates of death or decompensation compared to those with platelets greater than 100,000 mm3 (29% vs 21%, respectively, P = 0.74).
Patients with recurrent advanced liver disease post-LT have the most urgent need for effective antiviral therapy. Although other reports of posttransplant PI-based triple therapy have recently been published,40,43-48 we aimed to report the safety and efficacy of this treatment specifically in this most difficult-to-treat and vulnerable patient group with recurrent advanced liver disease. SVR12 was achieved in 51% of patients with F3-F4 recurrent fibrosis, which is encouraging given the multiple negative prognostic factors present in many of these patients. This represents a significant advance from P-IFN and ribavirin dual therapy.
Early on treatment response (eRVR) was highly predictive of SVR12 in the cohort. This correlation was particularly pronounced in the advanced disease group with a negative predictive value of 95% for those who did not achieve eRVR. We would therefore advocate that the failure to achieve eRVR be considered a stopping rule in patients with advanced disease, and that the benefits of continuing treatment in these patients must be weighed against the considerable risks. This may be a particularly useful clinical predictor to consider when toxicities are encountered early in treatment. As in nontransplant patients with advanced disease, other significant predictors of SVR among this cohort included previous treatment experience, baseline laboratory parameters such as albumin and platelets.33
Immunosuppressive regimens including the proportion of patients on dual immunosuppression and baseline CNI dosing were similar between groups. The choice of baseline CNI was not significantly predictive of SVR12 in this small study, and it remains uncertain whether switching CNI from tacrolimus to cyclosporine is warranted. However, chronic steroid use at the time of treatment initiation was significantly associated with treatment failure. Thus, minimization of steroid use prior to HCV treatment could be considered.
This is also the first report of SVR12 rates in patients with cholestatic HCV treated with PI-based triple therapy. Although these patients represent a small percentage of post-LT patients, their treatment urgency and complexity are the greatest. In the few small series of cholestatic HCV patients treated with P-IFN and ribavirin, SVR rates range from 0% to 30%.21-24,41,49 PI-based triple therapy improved this significantly to 44% (95% CI, 14%-79%) SVR12, though overall response rates in this group remain poor, perhaps due to poor tolerability of this regimen. There are now case reports of successful treatment of these patients using the NS5A replication complex inhibitor daclatasvir either in combination with P-IFN and ribavirin,50 or with the polymerase inhibitor sofosbuvir.51 It is likely the future all oral regimens with improved potency and side effect profiles will significantly improve treatment outcomes in these patients.
Data on PI-based triple therapy in patients with advanced fibrosis in the nontransplant setting from the Compassionate Use of Protease Inhibitors in Viral C Cirrhosis study group revealed similarly high SVR 12 rates (74% for telaprevir and 54% for boceprevir).36 However, approximately 50% of patients experienced SAEs and 2.7% of patients died. Important and clinically useful predictors of death or severe complications identified in this study included albumin less than 35 g/dL and platelets 100,000/mm3 or lower. Adverse events were also common in our cohort, including anemia requiring transfusion, kidney dysfunction, hospitalization, and death. In addition, progressive hepatic decompensation was common, with 28% of the cohort advancing from CTP class A to B on the P-IFN and ribavirin lead-in and 22% and 33% experiencing clinical decompensation on treatment in the advanced fibrosis and cholestatic hepatitis groups, respectively. Predictors of clinical decompensation and death in our cohort included markers of more severe disease including the presence of hepatic encephalopathy at baseline and low albumin as well as Hispanic ethnicity. However, given the small number of Hispanic patients (n = 11) in the cohort and the small total number of events, these findings should be confirmed in larger studies.
With the recent approval of new direct acting antiviral agents, sofosbuvir and simeprevir, safe and effective IFN-free regimens are available in some countries. However, these medicines have not been extensively studied in LT recipients and may have limited applicability in patients with significant renal (sofosbuvir) or hepatic (simeprevir) impairment. In a recent phase 2 open-label study of 40 LT recipients who received sofosbuvir and ribavirin for 24 weeks, 100% of patients achieved RVR and EOTR; however, 70% achieved SVR12.52 Although these results are promising, this study included patients with genotypes 2 to 4, only 63% had advanced recurrent disease (Metavir stages 3–4) and no patients had evidence of hepatic decompensation, rendering this population somewhat easier to treat. A more comparable population to the advanced disease population reported here is that treated via the sofosbuvir compassionate use program.53 Of the 104 patients (19 had cholestatic hepatitis) with severe recurrent HCV enrolled and treated with sofosbuvir and ribavirin, with or without P-IFN for up to 48 weeks, 57% experienced clinical improvement, and the SVR12 rate was 59% among 92 patients who completed treatment. These results suggest that LT patients with advanced disease including those with cholestatic hepatitis remain in high need of more efficacious therapies.
This study has some methodological limitations due to its retrospective design. The liver histology was not centrally reviewed, and therefore we cannot exclude the possibility of misclassification, especially in the cholestatic hepatitis patients where the diagnostic criteria are less standardized.23,41,42,54 This misclassification is unlikely because all CRUSH-C centers are large academic transplant centers with experienced pathologists. The immunosuppression and HCV treatment regimens also varied between patients and centers likely leading to heterogeneity, which is compounded by a relatively small overall sample size. However, this represents a real world experience in the treatment of complex posttransplant patients with advanced disease, and this heterogeneity may enhance the study’s generalizability. Finally, follow-up for these patients was generally limited to SVR12, and serial biopsy data are not available. Thus, the long-term benefits of SVR, such as histological stabilization or regression of fibrosis, prevention of hepatic decompensation, and improved survival, cannot be evaluated.
In summary, substantially higher SVR12 rates are achieved with PI-based triple anti-HCV therapy in LT recipients with recurrent advanced disease than previously reported for dual therapy. Although these patients may benefit the most from viral clearance, treatment should be undertaken with care given the risk of hepatic decompensation on therapy. Moreover, to maximize benefits and minimize risk, stopping treatment in those who fail to achieve eRVR is recommended. Although HCV treatment is likely to rapidly evolve in the coming years with a focus on IFN-free regimens, these new agents, including sofosbuvir, may not yet be widely available worldwide and given the high risk of decompensation and death in LT recipients with recurrent advanced disease, many patients are unable to wait. Telaprevir- or boceprevir-based triple therapy therefore may remain a reasonable approach in selected patients if IFN-free therapy is not available. Clinical trials with new antiviral combinations, including IFN- and ribavirin-free regimens are urgently needed in this population with the goal of providing safer and more effective treatment before the development of advanced fibrosis.
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