Impact of early viral kinetics on T-cell reactivity during antiviral therapy in chronic hepatitis B.
BACKGROUND
The patterns of hepatitis B viral dynamics during different antiviral therapies and the associated changes in HBV-specific T-cell reactivity are not well defined.


METHODS
We investigated the impact of early viral load decline on virus-specific T-cell reactivity in 30 hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B randomized to monotherapy with adefovir dipivoxil (ADV) or in combination with emtricitabine (ADV/FTC). Viral kinetics were analysed by mathematical modelling. T-cell reactivity to HBV core and/or surface antigens and natural killer T cell frequency were tested longitudinally, baseline to week 48, using EliSPOT assays and/or flow cytometry.


RESULTS
Mathematical modelling of early HBV kinetics identified two subsets of patients: 11 fast responders (undetectable viraemia by week 12; eight on ADV/FTC three on ADV) and 19 slow responders who remained viremic (six on ADV/FTC 13 on ADV). The rate of infected hepatocyte loss was higher in fast than in slow responders (P = 0.0007), and correlated inversely with pre-treatment levels of intrahepatic covalently closed circular HBV DNA. The frequency of HBV core-specific CD4+ T-cells increased significantly only in fast responders, peaking between week 16 and 24, while the HBV surface-specific CD4+ T-cells increased in both subsets. These changes in CD4+ T-cell reactivity were transient however, and no increase in HBV-specific CD8+ T-cells was observed. By week 48, HBeAg seroconversion occurred only in 3/30 (10%) patients.


CONCLUSIONS
Early viraemia clearance facilitates recovery of virus-specific CD4+ T-cell reactivity, but appears insufficient to establish clinically relevant antiviral immunity.
Lau
George K K
GK
Department of Medicine, Queen Mary Hospital, Hong Kong SAR, China. gkkla@netvigator.com
Cooksley
Helen
H
Ribeiro
Ruy M
RM
Powers
Kimberly A
KA
Shudo
Emi
E
Bowden
Scott
S
Hui
Chee-Kin
CK
Anderson
Jane
J
Sorbel
Jeff
J
Mondou
Elsa
E
Rousseau
Franck
F
Lewin
Sharon
S
Perelson
Alan S
AS
Locornini
Stephen
S
Naoumov
Nikolai V
NV
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004279:DNA, Viral / Q000096:biosynthesis / Q000187:drug effects*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D000068679:Emtricitabine; D005260:Female; D006510:Hepatitis B Antibodies / Q000097:blood; D006511:Hepatitis B Antigens / Q000276:immunology; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D022781:Hepatocytes / Q000187:drug effects / Q000821:virology; D006801:Humans; D007111:Immunity, Cellular; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D018448:Models, Immunological; D063065:Organophosphonates / Q000494:pharmacology / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000821:virology; D016896:Treatment Outcome; D019562:Viral Load; D014766:Viremia / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000821:virology; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D004279:DNA, Viral; D006510:Hepatitis B Antibodies; D006511:Hepatitis B Antigens; D063065:Organophosphonates; D003841:Deoxycytidine; D000068679:Emtricitabine; D000225:Adenine; C106812:adefovir dipivoxil