October 22, 2013

HCV, Ribavirin, and Anemia: A New Dawn

Gastroenterology
Volume 145, Issue 5 , Pages 930-933, November 2013

Stanislas Pol

published online 23 September 2013.

See “Effects of ribavirin dose reduction vs erythropoietin for boceprevir-related anemia in patients with chronic Hepatitis C Virus genotype 1 infection—a randomized trial,” by Poordad F, Lawitz E, Reddy KR, et al, on page 1035.

Since 1995, the treatment of hepatitis C virus (HCV) infection is based on the combination of twice daily weight-based dosing of ribavirin (RBV) and a weekly subcutaneous injection of pegylated interferon alfa (PR), which achieved a sustained virologic response (SVR) in ∼45% of patients with HCV genotype 1, 65% with HCV genotype 4, 70% with HCV genotype 3, and 80% with HCV genotype 2 infection.1, 2 Although it has been well understood that RBV improves the SVR rate by significantly reducing the occurrence of relapse or virologic breakthrough, the mechanism of action has remained poorly understood, but likely includes immunoregulatory effects. Unfortunately, this clinical benefit has come with a price: RBV increases the incidence of adverse events,1, 2 including clinical symptoms (eg, pruritus, cutaneous rash, neurocognitive troubles) or biochemical perturbations (primarily anemia). RBV -associated anemia is a result of intrinsic hemolysis, suggested to be a result of the accumulation of RBV metabolites within erythrocytes, and enhanced by interferon-associated bone marrow suppression inducing a reduction in anemia-induced reticulocytosis.3

RBV was first approved at a dosing of 11 mg/kg per day, but it was soon appreciated that higher doses were more effective, with the recommended dose increased to 13–15 mg/kg per day. Specifically, retrospective analyses first indicated the dose-effect of RBV irrespective of the genotype, and subsequent data indicated the negative impact of decreased RBV dosing on SVR rates.4, 5 The IDEAL study in naïve genotype 1-infected patients, which compared a 48-week course of 2 different doses of interferon alpha 2b (1 and 1.5 mg/kg per week) versus interferon alpha 2a did not demonstrate any significant difference in the SVR rates across the 3 arms,6 but for the first time showed a positive impact of anemia on the SVR rate.7 In addition, the IDEAL study helped to establish the association between genetic polymorphisms in the inosine triphosphate pyrophosphatase activity (ITPA) gene and RBV-associated anemia in chronic hepatitis C treated patients. These data established the “dogma” that optimization of HCV therapy had to include (1) weight-based dosing of RBV, (2) monitoring of ribavirinemia in suboptimal virologic situation for RBV dose adjustment to reach (yet undefined) thresholds of efficacious RBV exposure, and (3) use of erythropoietin (EPO), instead of RBV dose reduction (RDR), to manage anemia while maintaining the required antiviral potency of the PR combination.8, 9 Thus, physicians were managing anemia associated with antiviral therapies on the scientifically verified basis that maintaining high-dose RBV therapy despite anemia, to not affect negatively the SVR rate,8, 9

A better understanding of the HCV lifecycle has recently resulted in the development of several potential direct-acting antiviral drugs targeting viral proteins (NS3/4A protease inhibitors, NS5B nucleos(t)idic and non nucleos(t)idic polymerase inhibitors, NS5A inhibitors).10 Their combination with or without interferon and/or RBV has established a new era in the management of chronic HCV infections. The first step for this therapeutic revolution was the recent approval in 2011 of the first-generation HCV NS3/4A protease inhibitors boceprevir and telaprevir. Their use for genotype 1–infected patients in triple combinations with PR improved the SVR rates from 45% to nearly 75% in genotype 1–infected, treatment-naïve patients,11, 12 as well as those who previously failed conventional PR treatment.13, 14 Although a major breakthrough, both agents carry a high pill burden: Telaprevir and boceprevir are dosed 2–3 times daily, with 6 and 12 pills per day, respectively (in addition to the 4–7 RBV pills).11, 12, 13, 14 Protease inhibitors are metabolized by CYP3A4- and -3A5, thus requiring consideration of potential drug–drug interactions in patients receiving other treatments.15 They result in significantly more side effects,16 which in addition to those seen for PR, may also include severe cutaneous adverse reactions (telaprevir), anal discomfort (telaprevir), and exacerbated anemia (telaprevir and boceprevir). In the recent studies, rare cirrhosis decompensations and deaths have been reported, mainly related to bacterial infections in Child A cirrhotic patients with albumin levels <35 g/L and platelets count <100,000/mL.17

Indeed, boceprevir or telaprevir triple therapy increases the risk of anemia by ∼20% compared with PR alone: The prevalence of anemia, defined as a hemoglobin of <10 g/dL, is ∼50% with boceprevir and 40% with telaprevir; however, treatment discontinuation owing to anemia is rare.11, 12, 13, 14 During pivotal Phase III trials, boceprevir studies permitted use of EPO, and ∼43% of patients received at least one dose in the course of their HCV therapy.12, 13 By contrast, the telaprevir studies did not permit use of EPO.11, 14 Notably, retrospective analyses of these Phase III studies suggested that reducing the dose of RBV did not alter the SVR rate in treatment-naïve patients,18 in contrast with what has been reported for patients treated with PR therapy.7 In all studies, the use of EPO did not have a positive effect on SVR. However, in the telaprevir study, the very early dose reduction of RBV was associated with a slight decrease in SVR rate.

Poordad et al19 conducted the first prospective randomized trial to determine the impact of RDR (n = 249) versus EPO administration (n = 251) on SVR, for the first-line management of boceprevir-related anemia in genotype-1–naive patients. When hemoglobin level fell to <10 g/dL at any time during treatment, patients were randomized to RDR (200–400 mg as a first step, then a 200-mg step down in RBV dose, to the minimal dosage of 600 mg/d) versus EPO administration at an initial dose of 40,000 IU/wk). A secondary intervention was planned when primary intervention failed: EPO for the RDR arm, RDR for the EPO arm, and blood transfusions. The SVR rates were similar between the 2 groups (71.5% and 70.9%, respectively), regardless of the timing of the first intervention (including the leading phase) or the magnitude of RDR. Moreover, this result was not modified when considering the subgroup of patients that had detectable HCV-RNA at time of randomization. Additionally, only 18% of patients in the RDR arm required EPO, whereas 37% of patients in the EPO arm needed RDR: This second therapeutic intervention did not impact the SVR rate (76% compared with 68% in patients receiving only primary anemia management; P = .146). In the RDR arm, there was a nonsignificant trend (perhaps owing to the limited number of patients) suggestive of higher SVR rates in patients who received secondary interventions: 82 versus 69% (P = .078). Finally, among patients with RDR, SVR rates were lower in those who received lower percentages of the total RBV dose (P = .007), although they received >80% of the assigned treatment duration. It is noteworthy that results were similar in patients with extensive fibrosis or cirrhosis than in those with moderate fibrosis, suggesting that anemia in previously untreated, well-compensated cirrhotic patients can be managed in a manner similar to noncirrhotic patients. Based on their findings, the authors concluded that RDR can be the primary approach for managing anemia in boceprevir triple therapy regimens.

This carefully executed study should help to establish a new standard for the routine management of patients treated by triple therapy: RDR should be the first therapeutic intervention, thereby limiting the potential side effects of blood transfusions and the costly use of EPO (around €917 or $1200 monthly) or its intrinsic risks17: Thromboembolic adverse events were 10-fold more frequent in EPO treated patients (3.1%) compared with patients without EPO (0.3%; P = .003), a risk that has to be balanced in the decision of anemia management.

The helpful therapeutic algorithm of anemia management that the authors propose should be tempered in “difficult-to-treat” patients, for example, cirrhotic or HIV co-infected patients, who are more prone to develop anemia and may have lower SVR rates. Indeed, <10% of randomized patients had cirrhosis and a slight decrease in SVR rate has been previously reported in patients with severe fibrosis who had been managed using RDR strategies. Thus, taking into account the results of phase III and post-approval studies, French guidelines for the management of anemia in telaprevir- and boceprevir-treated patients have recommended the following practices20: In noncirrhotic patients, RDR should be the first-line management of anemia, even when HCV-RNA is still detectable (ie, the dose of RBV can be gradually reduced by 200-mg steps to the minimal dosage of 600 mg/d); additional use of EPO must be discussed on a case-by-case basis, according to clinical symptoms, tolerance of anemia, and comorbidities, and failure of RDR to ameliorate anemia. In cirrhotic patients with detectable HCV-RNA, the RBV dose should be maintained, with management focused on use of EPO until HCV-RNA becomes undetectable. The Poordad's study suggests that we have to reconsider this last proposal in cirrhotic patients, first because, even if a secondary therapeutic intervention (RDR then EPO) should be more frequently expected, SVR seems to not be impacted by RDR, and second because we have to keep in mind safety issues, including thromboembolic adverse events.

With this recent change in management of chronic HCV (which we support as first-line management of anemia), we also become hopeful for further simplification of treatment guidelines. We know that second-wave direct-acting antiviral drugs have less hematologic toxicity and that the expected availability of interferon- and RBV-free regimens combining oral direct-acting antiviral drugs will rapidly make these recommendations obsolete. Nonetheless, vigilance regarding treatment-induced anemia is important, and may remain as part of the management plan for resource limited countries that continue to use PR as the therapeutic backbone for chronic HCV treatment.

Acknowledgments

S. Pol thanks Dr Matthew Albert for his help in the preparation of the manuscript.

References

Conflicts of interest S. Pol has received consulting and lecturing fees from Bristol-Myers Squibb, Boehringer Ingelheim, Tibotec, Vertex, Gilead, Roche, MSD, Novartis, Abbott/Abbvie, Sanofi and Glaxo Smith Kline, and grants from Bristol-Myers Squibb, Gilead, Roche, and MSD.

PII: S0016-5085(13)01364-4

doi:10.1053/j.gastro.2013.09.036

© 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

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