Peripheral blood cytopenia before treatment in HCV patients: is it a limitation for HCV treatment in the era of DAA?

Peripheral blood cytopenia is frequently observed in HCV patients as in other chronic liver disease (1–3). Several pathophysiological mechanisms may be responsible for the onset of anaemia, neutropenia or thrombocytopenia in HCV patients. Antiviral therapy with pegylated interferon and ribavirin is able to cure HCV and avoid liver disease progression in patients who achieve sustained virological response (SVR). However, the presence of haematological abnormalities before treatment may limit the eligibility to HCV therapy, as treatment with pegylated interferon and ribavirin is associated with variable degrees of myelosuppression and haemolysis (4, 5). Both European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Disease (AASLD) guidelines report peripheral blood cytopenia as a relative contraindications for HCV treatment (6, 7). The relevance of peripheral blood cytopenia as a factor potentially limiting the initiation and the outcome of antiviral therapy in HCV patients remains unknown up to now. In this issue, Giannini et al. (8) reported that the prevalence of peripheral blood cytopenia among a large cohort of HCV patients consecutively referred to their unit for HCV antiviral therapy during the last decade. Among the initial cohort of 3059 HCV patients, 49.7% were deemed not eligible for treatment according to EASL guidelines because of clinically significant co morbidities (31.8%), presence of decompensated liver disease and/or hepatocellular carcinoma (7.6%), or advanced age >75 years (10.3%). Among the 1538 patients meeting eligibility criteria for treatment, the prevalence of peripheral blood cytopenia was studied according to the cut-offs suggested by the EASL-HCV clinical practice guidelines which defined anaemia as a haemoglobin level < 12g/dl for women, 13g/dl for men, neutropenia as an absolute neutrophil count < 1.5 9 10/L and thrombocytopenia as a platelet count < 90 9 10/L. Those cut-offs are usually also used in clinical trials. According to those cut-offs, the prevalence of any peripheral blood cytopenia was 15.1%. Anaemia was observed in 8.9%, neutropenia was observed in 3.2% and thrombocytopenia was observed in 6.5% of patients. These haematological abnormalities were, as expected, closely related to cirrhotic status, and therefore, associated with higher serum bilirubin level and lower serum albumin level and also advanced age. Among the 233 patients with cytopenia, antiviral treatment was initiated in 40% and SVR was achieved in 37% of these patients; however, 58% of these patients were withdrawn from treatment. Looking at factors linked to treatment withdrawal, only low platelet count was significantly linked to treatment withdrawal but not anaemia, neutropenia or the presence of cirrhosis. The results of this study help to better characterize the extent of peripheral blood cytopenia as a relative contraindication, per se, to antiviral treatment with pegylated interferon and ribavirin. One HCV patient of seven had peripheral blood cytopenia which potentially limits the initiation of antiviral treatment in patients who are otherwise eligible to treatment. However, this study is unable to assess whether or not, peripheral blood cytopenia is associated with higher treatment-related haematological complications or to a lower SVR? Anaemia is the more frequent haematological abnormality potentially limiting eligibility to treatment with pegylated interferon and ribavirin. However, we do not know if pretreatment anaemia is associated with higher rate of treatment-induced anaemia and if it influences SVR. Treatment-induced anaemia with pegylated interferon and ribavirin, associated with variable degrees of myelosuppression and haemolysis, is observed in 15–30% of patients (9–12). In Genotype 1 patients, treatment-induced anaemia with pegylated interferon and ribavirin regimen is associated with increased SVR and early correction by erythropoiesisstimulating agents (ESAs) of early-onset anaemia during the first 8 weeks of treatment increase SVR by avoiding ribavirin dose reduction (13). A recent meta-analysis suggests that administration of ESAs, in case of anaemia during dual therapy, to avoid further ribavirin dose reduction or treatment discontinuation significantly improves SVR (14). In triple therapy with either boceprevir or telaprevir, a two-fold increase of anaemia was observed in phase II and III studies (9–12, 15–18). In cirrhotic patients, anaemia < 10g/dl occurred in 46% of treatment-experienced patients treated with telaprevir compared to 40% in non cirrhotic patients (19). With the boceprevir regimen, anaemia < 10g/dl occurred in 53% of patients with advanced fibrosis compared to 47% in patients with mild to moderate fibrosis (9, 10).