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Threshold for neutropenia in the adjustment of interferon treatment in HCV infection
  Hepatology, April 2003, Volume 37, Number 4. Christophe Renou et al, Hepato-Gastroenterology Unit, Hyers Hospital, Hyers, France
To the editor:
We read with great interest the article by Soza et al. in the November 2002 issue of HEPATOLOGY in which no association was reported to exist between the onset of bacterial infection and neutropenia in chronic hepatitis C patients undergoing combination therapy with interferon alfa and ribavirin. Due to the reversible suppression of bone marrow induced by interferon, along with the inhibition of myelopoiesis and the potential risk for decreased neutrophil counts, patients with pre-existing neutropenia (1,500/mm3) have been excluded from previous large-scale, randomized, therapeutic trials with interferon and ribavirin. In addition, to avoid increasing the risk for infection during the period of antiviral therapy, dose adjustment and the complete discontinuation of interferon generally are recommended when the neutrophil count decreases below 750/mm3 and 500/mm3, respectively. The exact risk for serious infection is therefore not yet known in patients whose neutrophil counts have decreased below these levels when no change in the interferon doses has been made.
The results of the present study fill this gap. This is the first time to our knowledge that a large cohort of chronic hepatitis C patients has been treated by combination therapy without applying criteria as to the neutrophil count before and during the treatment. The baseline neutrophil count was one of the variables studied here, associated with at least one neutrophil count below 1,000/mm3 during treatment. We reported previously that in a small group of 14 post-hepatitis C cirrhosis patients, the onset of severe neutropenia (<750/mm3) during the first 2 months of combination therapy with interferon and ribavirin was caused only by the baseline neutrophil count.5 This finding suggested that post—hepatitis C cirrhosis patients with pre-existing neutropenia and an elevated rate of hepatocellular carcinoma have a high risk for increased neutropenia, which leads to reducing their interferon doses. In this case, these patients may seem unlikely to achieve a sustained virologic response because the response to interferon6 and to combination therapy is known to depend on the dose as well as on the duration of the antiviral treatment. However, similar sustained response rates were obtained whether or not chronic hepatitis C patients developed a significant level of neutropenia when the dose of interferon prescribed remained unchanged.
Although no immediate changes were made in the interferon doses prescribed to our cirrhosis population, none of the 4 patients with severe neutropenia showed any signs of infection during the treatment. Moreover, the intensity of the flu-like symptoms, especially fever, did not increase during the period of severe neutropenia. These data confirm the findings made in the study by Soza et al., in which none of the patients who developed infection had pre-existing neutropenia or levels of less than 750/mm3 during the treatment. It is worth noting that in the latter study the decrease in the lymphocyte counts was less marked in the group with no infection than in the group with infection. In our study, we established that the onset of severe neutropenia was associated simultaneously with a relative lymphocytosis, which might help to explain the absence of infection observed in patients with severe neutropenia during the period of antiviral therapy. In addition, the absence of infection observed here during the severe neutropenia induced by interferon therapy suggested that the neutrophil function was preserved in these patients: to our knowledge this point has not been studied to date.
Based on these preliminary data, it can be concluded that the onset of neutropenia during combination therapy with interferon and ribavirin is not associated with subsequent infection, even in patients with post-hepatitis C cirrhosis. However, changing the dose of interferon affects the likelihood of achieving a sustained virologic response. Careful clinical trials in which a lower neutrophil threshold is adopted in the event of neutropenia are now required with a view to revising the criteria on which dose adjustment and the discontinuation of interferon should be based.