studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 1029A
Disclosures:
Kazuaki Chayama - Consulting: AbbVie; Grant/Research Support: Ajinomoto,
Astellas, Torii, Tsumura, Aska, Bayer, Zeria, Daiichi Sankyo, Dainippon Sumitomo,
Eisai, Eli Lily, Janssen, Kowa, Mitsubishi Tanabe, MSD, Nippon Kayaku,
Nippon Shinyaku, Otsuka, Roche, Takeda, Toray; Speaking and Teaching:
Ajinomoto, AbbVie, Abott, Astellas, AstraZeneca, Aska, Bayer, BMS, Chugai,
Daiichi Sankyo, Dainippon Sumitomo, Eisai, J & J, Jimro, Miyarisan, MSD, Nihon
Kayaku, Olympus
The following authors have nothing to disclose: Daiki Miki, Hidenori Ochi, C.
Nelson Hayes, Hiromi Abe, Sakura Akamatsu, Atsushi Ono, Takashi Nakahara,
Yizhou Zhang, Keiichi Masaki, Hatsue Fujino, Eisuke Miyaki, Hiromi Kan, Takuro
Uchida, Nobuhiko Hiraga, Masataka Tsuge, Tomokazu Kawaoka, Michio
Imamura, Yoshiiku Kawakami, Hiroshi Aikata
1682
Serial Changes of Th1 and Th17 Cytokines and a SNP
in HLA class II DPB1 Gene Associated with Hepatitis B
Virus Reactivation in Patients Treated with Immunomodulatory
Agents
Hidetaka Matsuda, Tomoyuki Nemoto, Yoshihiko Ozaki, Tatsushi
Naito, Masahiro Ohtani, Katsushi Hiramatsu, Hiroyuki Suto,
Yasunari Nakamoto; Second Department of Internal Medicine,
University of Fukui, Fukui, Japan
BACKGROUND: Hepatitis B virus (HBV) reactivation can be
triggered by various chemotherapies, in which the patients’
immunological status may be suppressive. As the patients’
immunity are influenced by human leukocyte antigen (HLA)
class II mediated interactions between CD4 + helper T cells and
antigen presenting cells, polymorphisms of HLA class II genes
might affect the reactivation of HBV. In this study, we aimed to
assess the cytokine levels reflecting immunosuppressive status
and the candidate single nucleotide polymorphisms (SNPs) of
HLA class II genes associated with the risks of HBV reactivation
in patients treated with immunomodulatory therapies. METH-
ODS: STUDY 1: Five patients with malignant lymphoma (ML)
who undergone R-CHOP or CHOP and achieved complete
remission (CR) in University of Fukui Hospital between 2013
and 2014 were enrolled. The sera collected consecutively from
the subjects were measured for a total of 27 cytokines, chemokines
and growth factors by multiplex cytokine analysis. Immune
profiles after the initiation of chemotherapies were investigated,
and levels of the 27 factors were compared with those
of 20 healthy controls. STUDY 2: A total of 43 patients with
resolved HBV infection treated with immunosuppressive chemotherapies
(e.g. R-CHOP, CHOP, methotrexate, infliximab, and
cyclosporin) during 1999 to 2014 were investigated. All were
followed up for more than 2 years; HBV had reactivated in 10
of the 43 subjects, but not in the other 33. Genotyping of 22
SNPs located within HLA class II DPA1, DPB1, DQA1, DQB1,
and DRB1 genes was conducted by quenching probe PCR
(geneCube). Genotype frequencies of the tested SNPs were
compared between the two groups, whose latently infected
HBV had reactivated and not. RESULTS: STUDY 1: In the tested
patients with ML, serial levels of IL-17, IL-1β, IFN-γ, and G-CSF
at the timing of CR with R-CHOP and CHOP were significantly
decreased in contrast to those of the controls (123.1, 3.7,
96.0, and 194.1 pg/ml vs. 158.2, 6.8, 146.2, and 306.5
pg/ml, respectively; p 22.5% was
significant higher than those with PD-1 expression increasing
≤ 22.5% (46.15% vs 13.64%, P=0.033) from week 12 to
week 24. Interestingly, the patients with both TLR2 expression
< 18% at week 12 and PD-1 expression increasing > 22.5%
from week 12 to week 24 had a significantly higher rate of
virological breakthrough than the patients who met either of
conditions mentioned above (83.33% vs. 9.09%, P=0.002),
and the patients who failed to meet any condition (83.33%
vs. 11.11%, P=0.005). Conclusions Downregulation of TLR2
on CD14 + monocytes and upregulation of PD-1 on CD8 + T cells
correlate with virological breakthrough during the treatment
with Peg IFN alfa-2a after switching them from ETV therapy.
Combination of TLR2 expression < 18% at week 12 and PD-1
expression increasing > 22.5% from week 12 to week 24 has
a high positive predictive value (PPV) for virological breakthrough
in entecavir suppressed CHB patients with sequential
Peg IFN alfa treatment.