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Progression from immune tolerant to HBeAg-negative
hepatitis B is associated with increased virus sequence
diversity and prevalence of BCP and Precore variants.
Lilly Yuen1, Darren Wong1,2, Margaret Littlejohn1, Julianne Bayliss1,
Gillian Rosenberg1, Kathleen jackson1, Anuj Gaggar3, Kathryn
M. Kitrinos3, Mani Subramanian3, Patrick Marcellin4, Edward
J. Gane7, Henry Lik-Yuen Chan8, Harry L. Janssen6, Maria Buti5,
Scott Bowden1, Tina Sozzi1, Danni Colledge1, Rachel Hammond1,
Rosalind Edwards1, Stephen Locarnini1, Alexander Thompson2,
Peter A. Revill1; 1VIDRL, North Melbourne, VIC, Australia; 2St Vincents
Hospital, Melbourne, VIC, Australia; 3Gilead Sciences, Foster
CIty, CA; 4Hopital Beaujon University of Paris, Clichy, France;
5Liver Unit Vall d”Hebron (Ciberehed) University Hospital, Barcelona,
Spain; 6Toronto Center for Liver Diseases Toronto Western
and General Hospital, Toronto, ON, Canada; 7New Zealand Liver
Transplant Unit Auckland City Hospital, Auckland, New Zealand;
8Chinese University of Hong Kong, Hong Kong, Hong Kong
Background. CHB natural history is characterized by evolution
through multiple phases of host-virus interplay resulting in selection
of HBV variants defective for HBeAg production. Current
understanding suggests a progression from early immune tolerance
(IT), to immune clearance (IC) phase, before late immune
reactivation (IR). We have recently shown that the frequency of
basal core promoter (BCP) and precore (PC) variants, as well
as HBV sequence diversity, are associated with clinical phenotype
at baseline, as well as treatment outcomes in IC patients
who are treated with long-term NA therapy. We have now performed
a detailed cross-sectional analysis of HBV virological
phenotypes comparing patients with IT, IC and IR CHB from
three large randomised controlled studies. Methods. GS-US-
203-0101 evaluated the treatment of tenofovir vs tenofovir
plus emtricitabine in IT persons (HBeAg positive, HBV DNA
>7.28log10 IU/ml and ALT<ULN). GS-US-174-0102 evaluated
tenofovir in IR persons (HBeAg negative, HBV DNA >5log10
copies/ml and ALT >1xULN but <10xULN). GS-US-174-0103
evaluated tenofovir in IC persons (HBeAg positive, HBV DNA
>6log10 copies/ml and ALT >2xULN but <10xULN). Virological
studies included HBV full genome NGS sequencing and
quantitative HBsAg and HBeAg levels (HBV genotypes A to D).
Frequencies of BCP and PC variants were compared to clinical
outcomes using multivariate analysis. Sequence diversity was
analysed using Shannon Entropy. Results. BCP and PC variants
were detected in all phases of disease (IT<IC<IR, Table 1, P <
0.0001). NGS was more sensitive than population sequencing
(PS) for detecting BCP / PC variants in IT, IC, but not IR disease,
where the variants were fixed. Variant frequency differed
by HBV genotype in each CHB phase, with BCP variants more
common in Gt C vs. B and A vs. D, and PC variants more
common in Gt B vs. C and Gt D vs. A. HBV sequence diversity
was highest in HBeAg negative patients and lowest in patients
in the IT phase (Table 1, P<0.001). HBsAg, HBV DNA and
HBeAg levels differed by phase of disease, consistent with the
natural history of CHB: HBsAg (IT>IC>IR), HBV DNA (IT>IC>IR)
and HBeAg (IT>IC), P < 0.05. Conclusions. The progression
from IT – IC – IR disease is characterized by the accumulation
of clinically relevant variants in the BCP and PC regions, as
well as increased HBV sequence diversity.
Table 1
Disclosures:
Anuj Gaggar - Employment: Gilead Sciences, Inc.
Kathryn M. Kitrinos - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Patrick Marcellin - Consulting: Roche, Gilead, BMS, Vertex, Novartis, Janssen,
MSD, Abbvie, Alios BioPharma, Idenix, Akron; Grant/Research Support: Roche,
Gilead, BMS, Novartis, Janssen, MSD, Alios BioPharma; Speaking and Teaching:
Roche, Gilead, BMS, Vertex, Novartis, Janssen, MSD, Boehringer, Pfizer,
Abbvie
Edward J. Gane - Advisory Committees or Review Panels: AbbVie, Janssen,
Gilead Sciences, Achillion, Merck; Speaking and Teaching: AbbVie, Gilead
Sciences, Merck, Alnylam
Henry Lik-Yuen Chan - Advisory Committees or Review Panels: Gilead, Janssen,
Bristol-Myers Squibb, Roche, Novartis Pharmaceutical, Abbvie; Speaking and
Teaching: Echosens
Harry L. Janssen - Consulting: AbbVie, Bristol Myers Squibb, GSK, Gilead Sciences,
Innogenetics, Merck, Medtronic, Novartis, Roche, Janssen, Medimmune,
ISIS Pharmaceuticals, Tekmira; Grant/Research Support: AbbVie, Bristol Myers
Squibb, Gilead Sciences, Innogenetics, Merck, Medtronic, Novartis, Roche,
Janssen, Medimmune
Maria Buti - Advisory Committees or Review Panels: Gilead, Janssen, MSD;
Grant/Research Support: Gilead, Janssen; Speaking and Teaching: Gilead,
Janssen, BMS
Stephen Locarnini - Consulting: Gilead Sciences Inc, Arrowhead Research Corp,
Spring Bank Pharmaceuticals, Inc.; Employment: Melbourne Health
Alexander Thompson - Advisory Committees or Review Panels: Gilead Sciences,
Abbvie, BMS, Merck / MSD; Grant/Research Support: Gilead Sciences, Abbvie,
BMS, Merck / MSD; Speaking and Teaching: Gilead Sciences, Abbvie, BMS,
Merck / MSD, Roche Diagnostics
Peter A. Revill - Grant/Research Support: Gilead Sciences
The following people have nothing to disclose: Lilly Yuen, Darren Wong, Margaret
Littlejohn, Julianne Bayliss, Gillian Rosenberg, Kathleen jackson, Mani
Subramanian, Scott Bowden, Tina Sozzi, Danni Colledge, Rachel Hammond,
Rosalind Edwards
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发表于 2016-10-10 18:37