Hepatitis B virus reactivation after fludarabine-based regimens for indolent non-Hodgkin's lymphomas: high prevalence of acquired viral genomic mutations.
OBJECTIVE
Chemotherapy can cause hepatitis flare-up through viral reactivation in patients who have had contact with hepatitis viruses. Few data are available on the genotype of the reactivated viruses.


METHODS
In 40 consecutive adult patients with indolent non-Hodgkin's lymphoma (NHL) receiving fludarabine-based front-line chemotherapy, we performed a prospective study on viral hepatitis reactivation and analyzed the genotype of the reactivated viruses. Before chemotherapy, 4 patients were healthy carriers of hepatitis B surface antigen (HBsAg), 2 had HB core antigen antibodies (anti-HBc), 6 anti-HBs and 6 anti-HCV; 22 were seronegative.


RESULTS
Hepatitis flare-up occurred in the 4 HBsAg-positive patients and in 1 anti-HBc-positive patient at a median of 1 month (range 1-4) after chemotherapy, when the CD4/CD8 ratio was still inverted. HBV reactivation was documented in all 5 instances (HBV-DNA 2-8 x 10(6) copies/mL). Two of the 5 patients responded to lamivudine, whereas 1 died of acute liver failure and 2 had persistent severe hepatitis. HBV genome sequencing at hepatitis flare-up showed that deviation from the closest related published sequences was 1.0% and 1.1% in the 2 lamivudine-responsive patients, and 1.5%, 1.8% and 1.7% in the 3 lamivudine-resistant patients. The polymerase open reading frame (ORF) and the HBs ORF of lamivudine-resistant strains contained several novel amino acid substitutions.


CONCLUSIONS
These results suggest that fludarabine treatment of HBV-infected patients is frequently associated with acute hepatitis due to viral reactivation, and that lamivudine may be less effective in this situation than in other settings of immunocompromised hosts because of the emergence of resistant mutant strains.
Picardi
Marco
M
Divisione di Ematologia, II University, Naples, Italy.
Pane
Fabrizio
F
Quintarelli
Concetta
C
De Renzo
Amalia
A
Del Giudice
Annalisa
A
De Divitiis
Bianca
B
Persico
Marcello
M
Ciancia
Rosanna
R
Salvatore
Francesco
F
Rotoli
Bruno
B
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000998:Antiviral Agents / Q000627:therapeutic use; D002353:Carrier State; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D006509:Hepatitis B / Q000150:complications* / Q000188:drug therapy / Q000401:mortality; D006510:Hepatitis B Antibodies / Q000097:blood; D006511:Hepatitis B Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D018937:Hepatitis C Antibodies / Q000097:blood; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use; D017093:Liver Failure / Q000209:etiology; D008228:Lymphoma, Non-Hodgkin / Q000150:complications / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D017385:Sequence Homology; D014740:Vidarabine / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives*; D014775:Virus Activation / Q000187:drug effects
D000998:Antiviral Agents; D006510:Hepatitis B Antibodies; D006511:Hepatitis B Antigens; D018937:Hepatitis C Antibodies; D019259:Lamivudine; D014740:Vidarabine; C024352:fludarabine