HCV genotype 2 as a risk factor for reactivation in patients with B‐cell lymphoma undergoing rituximab combination chemotherapy

The majority of CD 20-positive B cell non-Hodgkin lymphoma (NHL) patients with hepatitis C virus (HCV) infection are handled in a similar manner to their HCV-negative counterparts even if the influence of Rituximab against the HCV viral load and liver functions is not well understood. We evaluated five women and five men [five diffuse large B-cell lymphoma (DLBCL), five follicular lymphoma (FL)] with HCV infection out of 98 NHL patients receiving Rituximab in combination with chemotherapy. HCV genotypes were 2a in two patients, 2c in two patients, and 1b in six patients. The six patients with HCV genotype 1b received six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone); a peak of aminotransferase levels [median aspartate transaminase (AST) 146·7 u/l; alanine transaminase (ALT) 183·8 u/l] coincided with the reappearance of B cells, peak serum HCV RNA levels (median 1 043 000 i/u per millilitre) occurred 1–2 weeks before CD20 recovery. Following the reappearance of B cells, HCV RNA levels quickly decreased to the pretreatment viral load (Fig 1A). (A) Changes in serum HCV-RNA and alanine transaminase (ALT) levels in patients with genotype 1 after R-CHOP. (B) Case 1: two weeks after the third cycle, HCV-RNA levels rose to 4 750 000 i/u per millilitre, ALT level abruptly increased to 5 870 u/ml. (C) Case 2: changes of serum HCV-RNA and ALT levels after four cycles of R-CHOP. (D) Case 4: after the third cycle of R-CHOP, HCV-RNA levels increased to 3 680 000 i/u per millilitre while ALT was 1 640 u/l. When B cell recovery occurred, a rapid decrease of HCV-RNA was detected. The results for the HCV genotype 2 positive patient were as follows: Case 1 (genotype 2c, Fig 1B) was a 68-year-old male with DLBCL. Two weeks after the third cycle of R-CHOP, the HCV RNA levels rose to 4 750 000 i/u per millilitre; the AST level abruptly increased to 5870 u/ml, ALT to 5920 u/ml. and the patient died of acute liver failure. Case 2 (genotype 2a, Fig 1C), was a 64-year-old male with DLBCL, after the completion of four cycles of R-CHOP treatment the HCV RNA levels increased to a peak of 1 710 000 i/u per millilitre before the reappearance of B cells, when a rapid decrease of HCV RNA levels was detected (510 000 i/u per millilitre) with mild ALT (165 u/l) and AST (78 u/l) elevation, he subsequently received radiotherapy and achieved a complete remission. Case 3 (genotype 2c) was a 65-year-old female with DLBCL who developed severe ascitis and oedema de-compensation after four cycles of R-CHOP therapy, she died 1 week later due to uncontrolled lymphoma progression. In the last patient (Case 4, genotype 2a, Fig 1D), who had FL, the HCV RNA levels increased gradually to 3 680 000 i/u per millilitre after the third cycle of R-CHOP) before the reappearance of B cells, when a rapid decrease of HCV RNA levels was detected (820 000 i/u per litre). Four weeks later the patient died due to uncontrolled lymphoma progression. Hepatitis C reactivation could be a consequence of the loss of host immune control over the virus (Sheen et al, 1996; Magy et al, 1999; Rumi et al, 2005). Preliminary data are consistent with a significant effect of B cells on the control of HCV viraemia (Lake-Bakaar et al, 2007); after treatment with Rituximab; plasma IgM, which binds circulating HCV, fell by more than 50%, so a rapid increase in the viral load could also reflect a loss of IgM antibodies. Furthermore, several studies have shown that antibody responses to hypervariable region1 (HVR-1) of the HCV envelope glycoprotein E2 are significantly more vigorous in HCV genotype 2-infected subjects in comparison to genotype 1 patients (Coppola et al, 2005; Hiraga et al, 2005). This suggests a stronger antibody immune pressure on the genotype 2 virus and may explain the differences in HCV kinetics among genotypes following B lymphocyte depletion with Rituximab.