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DOUBLE NEGATIVE HBV NUCLEIC ACID (DNA-/RNA-)
PREDICTS OFF-TREATMENT DURABILITY OF NUCLES(T)IDE
ANALOGUE IN A PROSPECTIVE COHORT
Rong Fan1, Bin Zhou1, Min Xu2, Deming Tan3, Junqi Niu4, Hao
Wang5, Hong Ren6, Xinyue Chen7, Maorong Wang8, Qin Ning9,
Guangfeng Shi10, Jifang Sheng11, Hong Tang12, Xuefan Bai13,
Shi Liu1, Fengmin Lu14, Jie Peng15, Jian Sun15, Qing Xie16, Jinlin
Hou15 and Chinese Chronic Hepatitis B Study Consortium, (1)
Nanfang Hospital, Southern Medical University, Guangzhou,
China, (2)8th People’s Hospital, Guangzhou, China, (3)
Xiangya Hospital, Central South University, Changsha, China,
(4)The First Hospital of Jilin University, (5)Peking University
People’s Hospital, Beijing, China, (6)Department of Infectious
Diseases, Institute for Viral Hepatitis, the Key Laboratory of
Molecular Biology for Infectious Diseases, Chinese Ministry
of Education, the Second Affiliated Hospital of Chongqing
Medical University, Chongqing, China, (7)Beijing Youan
Hospital, Capital Medical University, Beijing, China, (8)81st
PLA Hospital, Nanjing, China, (9)Tongji Hospital of Tongji
Medical College, Huazhong University of Science and
Technology, (10)Department of Infectious Diseases, Huashan
Hospital, Fudan University, Shanghai, China, (11)The First
Affiliated Hospital of Medical School of Zhejiang University,
Hangzhou, China, (12)West China Hospital, Chengdu,
China, (13)Tangdu Hospital, Xi’an, China, (14)School of
Basic Medical Sciences, Peking University Health Science
Center, Beijing, China, (15)Department of Infectious Diseases
, Nanfang Hospital, Southern Medical University, (16)
Department of Infectious Diseases, Ruijin Hospital, Shanghai
Jiaotong University School of Medicine
Background: The response durability after nuleos(t)ide
analogue (NAs) discontinuation in chronic hepatitis B (CHB)
was unsatisfactory The aim of this study was to determine
the performance of HBV DNA and HBV RNA as predictors
for durability Methods: The evaluation cohort included 130
HBeAg-positive patients (30 8 ± 6 9 years, 72 3% male)
from a multi-center prospective trial who stopped telbivudinebased
therapy after achieving HBeAg seroconversion and
HBV DNA <300 copies/mL for >48 weeks and were followed
up until clinical relapse occurred As validation, 40 patients
(36 5 ± 9 4 years, 72 5% male) treated with entecavir
or tenofovir before discontinuation were analyzed The
negative HBV DNA at end of treatment (EOT) was strictly
defined as “Target Not detected” by using COBAS Taqman
assay with LLOD of 20 IU/mL. The negative HBV RNA was
defined as both not targeted detection in RT-qPCR with two
different pairs of primers The primary off-treatment outcome
evaluated was clinical relapse, defined as HBV DNA >
2000 IU/mL plus ALT >2 × ULN. The secondary outcomes
included virologic relapse defined as HBV DNA >2000 IU/
mL and HBeAg reversion defined as the reappearance of
HBeAg at two consecutive protocol-defined visits.Results: In
the evaluation cohort, the 4-year cumulative rates of clinical
relapse, virologic relapse and HBeAg reversion were 30 8%,
54 7% and 16 8%, respectively The percentages of patients
with double negative HBV DNA and RNA (DNA-/RNA-),
mono negative HBV DNA (DNA-/RNA+), mono negative HBV
RNA (DNA+/RNA-), and double positive HBV DNA and RNA
(DNA+/RNA+) were 19 7% (25/127), 29 1% (37/127), 6 3%
(8/127) and 44 9% (57/127), respectively Patients with EOT
HBV DNA of “Target Not detected” had significantly lower
cumulative incidence of clinical relapse, than those with either
HBV DNA <20 or >20 IU/mL (20.0% vs. 39.8% vs. 40.0%,
P=0.036). Similarly, patients with negative EOT HBV RNA
level also had significantly lower risk of clinical relapse (15.3%
vs 37 0%, P =0 029) at off-treatment year 4 The multivariate
regression analysis showed that HBV DNA + RNA level at
EOT (either positive vs double negative) was the strongest
independent risk factor for clinical relapse (Hazard ratio [HR],
4.549; 95% confidence interval [CI], 1.089 - 19.002, P =0.038)
and virologic relapse (HR, 11 100; 95% CI, 2 690 - 45 809;
P =0 001), respectively At year 4, patients with EOT double
negative HBV DNA and RNA (DNA-/RNA-) had significantly
lower risk of clinical relapse than those with either positive
HBV DNA or RNA (8.0% [2/25] vs. 31.4% [32/102], P=0.018).
In the validation cohort, the patients with EOT HBV DNA-/
RNA- also had the lowest clinical relapse rate during up to
5.5-year follow-up (15.4% [2/13] vs. 33.3% [9/27], P=0.286).
Conclusion: Double negative HBV nucleic acid (DNA-/RNA-)
at EOT with more rigorous definition is a potent biomarker for
guiding NAs safety discontinuation in CHB HBeAg positive
patients. 作者: StephenW 时间: 2019-10-31 17:25