Potential conflict of interest: Dr. Reddy has served on the advisory boards of Merck, Genentech-Roche, Gilead, Vertex, Janssen, Bristol-Myers Squibb, and Idenix and has served as an investigator for Merck, Genentech-Roche, Gilead, Vertex, Janssen, Bristol-Myers Squibb, and AbbVie.
Address reprint requests to: K. Rajender Reddy, M.D., Division of Gastroenterology and Hepatology, Hospital of the University of Pennsylvania, 3400 Spruce Street, 2 Dulles, Philadelphia, PA 19104. E-mail: firstname.lastname@example.org; fax: 215-662-4835.
Clinical perspectives in hepatology aims to engage two experts with opinions supporting differing perspectives on the management of a case. Typically, the case represents an area of debate or evolving practice in clinical hepatology.
The case described by Dr. Reddy provides an opportunity to discuss the benefits and risks of using a direct-acting antiviral as part of a treatment regimen for aggressive post–liver transplant (LT) hepatitis C.
Dr. Reddy: Case Presentation
A 54-year-old white man was diagnosed in 1995 with hepatitis C virus (HCV) infection genotype 1 (GT1), acquired from a blood transfusion in 1975. Between 1996 and 2002, the patient underwent three courses of treatment for HCV infection. He took traditional interferon (IFN) in 1996 for 6 months, IFN and ribavirin (RBV) for 7 months in 1998, and, last, pegylated interferon alfa-2b (PEG-IFN) and RBV in 2002. Unfortunately, he did not achieve viral clearance with any of these treatments. Over time, he had progressive liver disease and a liver biopsy revealed cirrhosis in 2003. His condition continued to decline with the development of complications of portal hypertension that included esophageal varices, mild hepatic encephalopathy, and ascites. In April 2007, the patient underwent a live donor LT, receiving a right lobe from his son. His post-transplant course was complicated by recurrent HCV infection and the development of chronic active hepatitis and bridging fibrosis. In June 2009, he began treatment for recurrent infection with PEG-IFN and RBV. The patient achieved a rapid virologic response, but relapsed after 48 weeks of treatment. A repeat biopsy performed in January 2011 demonstrated the development of cirrhosis. His IL28B genotype is C/T. Subsequently, when protease inhibitors became available, the decision was made to administer boceprevir as a part of a 48-week triple therapy (TT) regimen. A 4-week lead-in phase of PEG-IFN plus RBV (800 mg) was started, after which boceprevir was added. TT was administered for 32 weeks, after which boceprevir was discontinued and PEG-IFN and RBV alone were administered for 12 weeks. Within the first 8 weeks of therapy, the patient's HCV RNA was detectable, but not quantifiable. At week 12, HCV RNA was not detectable. The dose of tacrolimus was reduced because of the known drug-drug interactions (DDIs) between the calcineurin inhibitor (CNI) and boceprevir, and the level of tacrolimus was monitored closely with dosage alterations occurring when necessary. Adverse events (AEs) of therapy included fatigue, anemia, and syncope, requiring hospital admission. Anemia was managed with RBV dose reduction, erythropoietin-stimulating agent (ESA), and blood transfusion. Details of the course of his therapy, including management of his tacrolimus levels and dosage, are presented in Fig. 1. The patient successfully completed 48 weeks of therapy and is HCV RNA negative 12 weeks after cessation of therapy.
Dr. Reddy's Perspective
HCV recurrence after LT is almost universal and severity depends on several host, viral, donor, and transplant factors. Graft and patient survival are significantly reduced after LT in HCV-positive recipients.[1-4] A subset of patients (2%) may develop post-LT cholestatic hepatitis C, which is characterized by persistent cholestasis of at least 4 weeks in duration, high HCV RNA levels, hepatocyte ballooning, rapid progression to graft failure, and, in the absence of biliary and hepatic artery complications, sepsis and drug-related cholestasis. The overall outcome of antiviral therapy in this group of patients is suboptimal, although it can be successfully pursued in select patients. The unique challenges of HCV treatment in this population include management of AEs, adjusting immunosuppressive regimens because of DDIs in those on direct-acting antivirals (DAAs), and monitoring for graft rejection.
Although selection criteria for treatment of chronic HCV in LT patients is variable, antiviral therapy is generally considered in those who develop significant or progressive recurrent HCV disease, as defined by moderate-to-severe necroinflammatory activity (grade 3-4) and/or significant fibrosis (stage 2-4) on histologic evaluation. Treatment of recurrent HCV in LT recipients, particularly with successful viral eradication, is associated with increased graft and patient survival. In various experiences published, the majority of patients included were genotype 1, had a reduced dose of RBV (400-800 mg/day) and/or PEG-IFN, and had use of ESAs. The pooled estimate of sustained viral response (SVR) from prospective studies was 24%-40%, and virologic relapse was 21%-43%. Biochemical and histological responses were observed in approximately 50% of treated patients.[8, 9] Two thirds of patients required dose reductions of either PEG-IFN or RBV and one fourth discontinued treatment early.
The approval of two protease inhibitors, telaprevir and boceprevir, has ushered in a new era of HCV treatment. In those with chronic HCV, one of these have been used in combination with PEG-IFN and RBV, and the regimens have enhanced response rates and shortened duration of therapy, whereas they have added to the side-effect profile. Cost of treatment for boceprevir triple therapy is variable, and in instances of treatment duration similar to this case, the expense of therapy is approximately $71,000. However, there are other expenses of close monitoring and frequently following immunosuppression drug levels, which then increase the cost relative to a patient who has not had LT. An incremental rate and degree of anemia has been observed with both TT regimens, which does present a challenge in the transplant recipients who are prone to anemia. Furthermore, in transplant recipients, DDIs between CNI and protease inhibitors present enormous challenges that require labor-intensive follow-up and present risk of toxicity and graft rejection as a consequence of fluctuating levels of the CNIs.[12, 13] DDI studies have been conducted with CNIs (tacrolimus and cyclosporine) and the protease inhibitors, telaprevir and boceprevir.[11, 14, 15] Single-dose CNI exposure studies in healthy volunteers have demonstrated a several-fold augmentation of levels of CNIs after administration of boceprevir and telaprevir (cyclosporine 2.70- and 4.64-fold and tacrolimus 17.1- and 70.3-fold with boceprevir and telaprevir, respectively). Thus, the doses of either cyclosporine or tacrolimus are to be reduced several-fold while on a protease inhibitor and revamped back to their baseline after the protease inhibitor is removed from the treatment regimen. The management of anemia either with RBV dose reduction and with or without the addition of an ESA and/or the use of blood transfusions brings in another layer of complexity. Yet, the successful eradication of HCV in these patients who have a risk of progressive liver disease and graft failure is indeed rewarding and justifies intervention with protease inhibitor-based therapy.
Dr. Everson's Perspective
The main goal of treating the transplant recipient with recurrent infection with HCV is to achieve SVR (undetectable HCV RNA 12 weeks or more after the end of treatment). SVR preserves graft function, improves graft survival, and improves both patient outcome and survival. Today's options for antiviral treatment are PEG-RBV alone or with either telaprevir or boceprevir (TT) for GT1. Most centers treat patients who are 6 months or more post-transplant and have aggressive HCV recurrence. Dr. Reddy's patient was transplanted in 2007 and had early recurrence of hepatitis C, which progressed rapidly to advanced fibrosis by 2009. Treatment to prevent disease progression and graft loss was clearly indicated.
In nontransplant patients, certain characteristics have been associated with a favorable response to TT:
responsiveness to IFN, defined by favorable IL28b polymorphism (genotype CC), decline in HCV RNA during lead-In with PEG-RBV, or achieving undetectable HCV RNA during a previous course of PEG-RBV;
noncirrhotic stages of fibrosis; and
in patients with cirrhosis, compensated disease (no complications and normal international normalized ratio, bilirubin, and albumin).
Dr. Reddy's patient was treated with PEG-RBV both pre- and post-transplant and achieved undetectable HCV RNA during post-transplant PEG-RBV, but relapsed. He demonstrated responsiveness to IFN, lacked cirrhosis or complications of liver disease, and thus was a good candidate for retreatment with TT. However, use of TT after transplant presents unique challenges.
First, the treating physician must have a plan of management to define tolerability and response to PEG-RBV, DDIs, management of anemia and other side effects, and treatment duration. Our treatment protocols have been presented in a recent review. Dr. Reddy's plan included a lead-in with PEG-RBV, reduction in tacrolimus dose with introduction of boceprevir, support for anemia during treatment, an intended treatment duration of 48 weeks, and dose increases in tacrolimus after boceprevir was discontinued.
Side Effects: The Achilles' Heel of TT
A major concern in transplant recipients is the potential for toxicity from immunosuppressive drugs (tacrolimus, cyclosporine, sirolimus, and everolimus). All four immunosuppressants are metabolized by way of the hepatic enzyme, CYP3A, an enzyme that is inhibited by both telaprevir and boceprevir. Tacrolimus area under the curve (AUC) increases 70.3-fold and cyclosporine AUC increases 4.6-fold when coadministered with telaprevir. Tacrolimus AUC increases 17.1-fold and cyclosporine AUC increases 2.7-fold when coadministered with boceprevir. What this means to transplant hepatologists and patients is obvious: When using TT, major reductions in doses of tacrolimus, cyclosporine, sirolimus, and everolimus are required to avoid toxicity and drug levels must be monitored closely. Also, when telaprevir or boceprevir are discontinued, doses of these immunosuppressants must be increased and levels monitored to prevent rejection.
Telaprevir and boceprevir may also affect the metabolism of other medications, including antibiotics, sedatives, antipsychotics, statins, oral contraceptives, warfarin, proton-pump inhibitors, and others. A careful consideration of all potential DDIs is required before initiating TT.
Severe anemia has been a major management issue in treating patients after LT. Anemia during antiviral therapy is the result of the combination of hemolysis from RBV and bone marrow (BM) suppression from IFN and telaprevir or boceprevir. Hematopoiesis may be further compromised by immunosuppressive drugs. In our experience, hemoglobin drops by 1.5 g/dL during lead-in with PEG-RBV and by 2.5 g/dL in the first 1-4 weeks after the addition of telaprevir. Sixty-one percent (11 of 18) of our patients required erythropoietin (EPO); 6 of the 11 who required EPO were started during PEG-RBV lead-in. Eighty-three percent (15 of 18) had RBV dose reduction after the addition of telaprevir. A majority (10 of 18) of patients required at least one blood transfusion, with most (8 of 10) of these transfusions being given during the telaprevir phase of the protocol. Of the 10 patients receiving blood transfusion, a total of 60 units of blood were transfused (48 units during the telaprevir phase of the protocol). This experience emphasizes that intervention for anemia is required early during TT, decreases in hemoglobin can be precipitous, and multiple approaches to control anemia may be needed simultaneously.
Curiously, rash events have been extremely rare in our transplant recipients. Rash has been reported in over 50% of nontransplant patients taking telaprevir-based TT, and 5%-7% of these patients have had to stop telaprevir because of severe rash. Only rare patients in our experience have had rash. This observation suggests that the rash of telaprevir may be blocked by the immunosuppressive therapies used in transplant recipients.
Anticipated Rates of SVR in Transplant Recipients
Although early virologic responses with TT have been brisk,[16-19] there have been only rare case reports describing patients with SVR. Based on early response rates, the anticipated SVR for post-transplant patients with HCV GT1 treated with TT is 60%. Dr. Reddy's patient achieved SVR, despite shortening the treatment duration from 48 to 36 weeks.
Future Anti-HCV Therapies
Several new drugs are currently in clinical trials for treatment of chronic hepatitis C, including new types of IFNs, second- and third-generation protease inhibitors, polymerase inhibitors, NS5A inhibitors, and others. Given the intolerance of pre- and post-transplant patients to IFN-based therapy, the rapidly evolving strategy of IFN-free treatment is particularly appealing.
The first in line appears to be the NS3/4A protease inhibitor, simeprevir, the NS5B polymerase inhibitor, sofusbivir, and the NS5A protein inhibitor, daclatasvir. Their advantages over telaprevir or boceprevir include increased potency (potentially higher rates of SVR), daily dosing (as opposed to three times daily), lower risk for DDIs, and fewer, if any, side effects. The increased potency will also reduce risk for viral resistance.
Telaprevir and boceprevir have ushered in the new era of DAA therapy for the treatment of HCV. The emerging data suggest that current TT should be used with caution by experienced clinicians in liver centers and with very close monitoring of side effects and AEs. DDIs are common and potentially dangerous. The hope of future treatments includes pan-genotype coverage, reduced side effects, lack of BM suppression, elimination of DDIs, and, ultimately, U.S. Food and Drug Administration–approved indications for the use of antiviral treatment before and after LT. Our patients will benefit; the question is, when? Transplant hepatologists, pharmaceutical partners, and liver recipients should work together to push up the timelines!