To the Editor:

We wish to raise several issues regarding the recent case report by Hsieh et al.¹ Both the title of the article and its conclusion suggest that rituximab-induced reactivation of hepatitis C virus (HCV) is possible during combination chemotherapy with rituximab. We think it cannot be concluded with certainty whether rituximab alone was associated with HCV reactivation in the case described.

The first reason for the authors’ conclusion is that liver dysfunction did not develop during initial chemotherapy and occurred after combination chemotherapy with rituximab. However, it is known that HCV-infected patients first develop liver dysfunction after the second or later cycles of chemotherapy. Indeed, a previous study of liver dysfunction in HCV-positive patients with diffuse large B-cell lymphoma treated with a cyclophosphamide, vincristine, doxorubicin, and prednisolone–like regimen has shown that the incidence of hepatic toxicity tended to increase with the number of chemotherapy courses.²

Reactivation of viruses such as hepatitis B virus (HBV),³ cytomegalovirus,⁴ and varicella-zoster virus⁵ is considered to be associated with immunosuppression caused by rituximab treatment. Rituximab targets and depletes CD20-positive malignant lymphocytes along with normal CD20-positive B cells, and previous studies have demonstrated rapid depletion of normal B lymphocytes, whereas immunoglobulin levels remain within normal limits until at least 6 months after treatment.⁶ Indeed, HBV reactivation during the fourth to sixth (or between the third and fifth) cycles of rituximab treatment has been reported,³ and one study has documented markedly late HBV reactivation at several months after completion of rituximab treatment.⁷ Therefore we think it is too speculative to conclude that rituximab was responsible for the rapid increase of transaminase levels during the clinical course described.

It is difficult to determine whether liver dysfunction is caused by HCV reactivation or chemotherapy toxicity. In fulminant hepatitis caused by HCV reactivation, the level of HCV RNA has been reported to increase during chemotherapy and dramatically decrease at the onset of severe liver dysfunction.⁸ In fact, we have experienced a case in which the expression of HCV RNA increased during rituximab chemotherapy and dramatically decreased to below the normal limit at the time of severe liver dysfunction.⁹ The changes in serum HCV RNA and transaminase levels described in the latter two reports suggest that the liver dysfunction may have been caused by the spread of HCV in the liver and the resulting immune reaction against HCV-infected hepatocytes. However, for the patient described, the authors provide no data to suggest HCV viral load before and after liver dysfunction.

The authors also consider that a synchronized increase of HCV RNA and transaminases could have accounted for the rituximab-induced HCV reactivation. However, they present no details of HCV RNA levels during the first course of chemotherapy without rituximab, and it is unclear whether the HCV viral load had increased before rituximab administration. A previous study of nine patients with chronic HCV hepatitis has shown that prednisone therapy increased the HCV RNA level in all of them,¹⁰ suggesting that anticancer agents may have induced the increase of HCV RNA. Therefore, we think that, in this particular case, it is necessary to clarify how the HCV RNA level changed during the course of treatment.

Liver dysfunction during rituximab-containing chemotherapy needs additional investigation, given that rituximab-induced HBV reactivation is a significant clinical problem. If rituximab did, in fact induce severe liver dysfunction through HCV reactivation in the present case, this would have important implications for clinical management. Additional detailed information on the association between rituximab infusion and HCV reactivation is therefore required.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.