Reply:
Authors: Thierry Thévenot, Vincent Di Martino, Françoise Lunel-Fabiani
Journal: Hepatology (2007)

We thank Dr. Howard J. Worman for his relevant comments and the opportunity to clarify some of the burning issues regarding the "off-label" use by French hepatologists of hematopoietic growth factors (HGFs), namely the granulocyte colony-stimulating factor (G-CSF) and erythropoietin (EPO), in addition to the treatment of hepatitis C virus (HCV) infection.1 Recently, we conducted a French national retrospective survey of hospital practitioners to evaluate the magnitude of EPO and/or G-CSF prescriptions in patients treated for chronic hepatitis C. The crude result was that 46% of practitioners used EPO and 31% used G-CSF, and that 8.8% and 4% of HCV-infected patients under antiviral therapy received EPO and G-CSF per year, respectively. French physicians, like others, prescribe HGFs to counteract adverse effects of both ribavirin and interferon, including ribavirin-induced hemolysis and interferon-related neutropenia, which in turn may reduce or interrupt the dose of both molecules and may jeopardize treatment outcome. Worman points out 2 crucial issues: (1) the absence of reliable data regarding the impact of HGFs on the sustained responses rates, and (2) the potential life-threatening effect of EPO. We are totally in agreement with these statements and, in our article, we clearly notify that "HGFs are not yet an official adjuvant therapy for chronic hepatitis C" and we claim in the conclusion that further clinical trials are urgently required to evaluate the sustained virological response (SVR). A French prospective study, called "PEGEPO", was deemed necessary to evaluate the SVR rate and is still in progress. To date, only one prospective, randomized, controlled trial focusing on this topic was recently published.2 This study was designed to investigate if initiating EPO at the start of antiviral therapy could improve SVR in patients with chronic HCV genotype 1. Unfortunately, EPO did not improve SVR in the group treated with a standard dose of ribaririn but SVR was significantly greater in patients receiving a higher starting dose of ribavirin (15.2 mg/kg/day). Of note, this pilot study included 3 groups of nearly 50 patients of whom 39% were African Americans, a subgroup well-known to have a lower chance of SVR than other races. An important message of this article was that the initial high dose of ribavirin along with EPO may be the main factor for the virological success. It was also acknowledged that EPO allows maintenance of the optimal dose and duration of ribavirin while improving the quality of life,3 and in accordance with the study by Shiffman et al.,2 EPO could increase the SVR rate in patients treated with a high dose of ribavirin. However, further trials with EPO including larger series of patients need to be performed to confirm these interesting results. We should also focus our energy to start clinical trials in "difficult-to-treat" patients with a greater risk for developing anemia-related complications including patients coinfected with HIV and HCV, patients with end-stage renal disease, liver transplant recipients, and patients with cirrhosis. Indeed, evolving experience suggests that HGFs could be be of particular interest in this special population, explaining why HGFs are widely prescribed as an adjuvant therapy with pegylated interferon and ribavirin, especially for hepatitis C recurrence after liver transplantation; in fact, EPO and G-CSF were used in 85% and 55% of patients in the study by Carrion et al., and in 58% and 25% in the study by Castells et al., respectively.4, 5 The second concern raised an important question regarding the potential cardiovascular side effects of EPO. Indeed, Phrommintikul et al. presented a meta-analysis of randomized controlled trials in patients with anemia caused by chronic kidney disease and they observed an excess risk of major adverse events (including death) when hemoglobin is raised to 12-16 g/dL.6 We cannot translate these observations to the hepatitis C population but we can recommend to have a hemoglobin target of 10-12 g/dL if EPO was use in clinical practice. We also acknowledge that accumulating studies demonstrated that some human tumors express Epo-receptor, secrete a small amount of EPO and promote angiogenesis in a paracrine manner.7, 8 Moreover, 2 recent randomized controlled trials raised the possibility of a potentially negative impact of EPO treatment on survival thought to be due to tumor progression in patients with anemia associated with cancer chemotherapy.9, 10 The results of both these studies need to be interpreted with caution because the majority of patients included achieved an hemoglobin level higher than recommended by evidence-based guidelines and baseline imbalance in prognostic factors may have favored the placebo groups in both studies. Also, the mechanism underlying the enhanced growth of tumors with EPO remains uncertain. Anyway, all these observations underline the need to record all adverse events of our HCV-infected patients treated with HGF. Hepatologists should also administer EPO sparingly with appropriate safeguards for patients with cirrhosis, considering the risk of promoting hepatocellular carcinoma progression. Despite the routine use of HGFs in France and other countries, which is not currently approved by the US Food and Drug Administration and also the Agence Française de Sécurité Sanitaire des Produits de Santé (AFSSAPS), the main task of scientific societies will be to clarify the suitable role of HGF as a complement to HCV therapy. Thierry Thévenot*, Vincent Di Martino*, Françoise Lunel-Fabiani , * Service d'Hépatologie et de Soins Intensifs Digestifs, Hôpital Universitaire Jean Minjoz, Besançon, France, Laboratoire de Bactériologie-Virologie et Hygiène hospitalière, Hôpital Universitaire d'Angers, Angers, France.