Transient restoration of anti-viral T cell responses induced by lamivudine therapy in chronic hepatitis B.
OBJECTIVE
Lamivudine therapy in patients with chronic hepatitis B can induce the recovery of antiviral T cell responses. It is unknown whether the recovery of T cell responsiveness is long-lasting and persists throughout the treatment and whether the elevation of viremia which follows therapy withdrawal can restore a condition of T cell unresponsiveness.


METHODS
Frequency and function of circulating hepatitis B virus (HBV)-specific CD4 and CD8 cells from 12 hepatitis e surface antigen + patients with chronic hepatitis B were studied longitudinally before, during and after lamivudine therapy by intracellular cytokine staining, proliferation and cytotoxicity assays against HBV proteins and peptides. CD4-mediated responses were analyzed in all patients, whereas CD8 cells were studied in 6 HLA-A2+ patients.


RESULTS
HBV-specific CD4 and CD8 reactivity showed a bi-phasic behavior under lamivudine therapy with an early enhancement of T cell frequency and intensity of responses followed by a persistent decline starting from the 5th to 6th month of treatment.


CONCLUSIONS
Since restoration of HBV-specific T cell reactivity is only transient, our study indicates that therapeutic stimulation of HBV-specific T cell responses to complement lamivudine treatment should be done early after the initiation of lamivudine. Moreover, the transient nature of the immune reconstitution may represent a favorable condition for virus reactivation once lamivudine therapy is withdrawn.
Boni
Carolina
C
Divisione Malattie Infettive ed Epatologia, Azienda Ospedaliera di Parma, Via Gramsci 14, 43100 Parma, Italy.
Penna
Amalia
A
Bertoletti
Antonio
A
Lamonaca
Vincenzo
V
Rapti
Irene
I
Missale
Gabriele
G
Pilli
Massimo
M
Urbani
Simona
S
Cavalli
Albertina
A
Cerioni
Simona
S
Panebianco
Ruggero
R
Jenkins
Julian
J
Ferrari
Carlo
C
D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D005260:Female; D006515:Hepatitis B virus / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000188:drug therapy*; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use*; D008297:Male; D008934:Mitogens / Q000494:pharmacology; D010835:Phytohemagglutinins / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000473:pathology; D013745:Tetanus Toxoid / Q000494:pharmacology; D013997:Time Factors
D008934:Mitogens; D010835:Phytohemagglutinins; D018894:Reverse Transcriptase Inhibitors; D013745:Tetanus Toxoid; D019259:Lamivudine