CONTROL ID: 1424861 |
| PRESENTATION TYPE: Oral or Poster | CURRENT CATEGORY: Hepatitis B | CURRENT DESCRIPTORS: I03. Virology and Diagnostics | TITLE: Quantitative HBsAg Titers in a Multi-Drug Resistance Chronic Hepatitis B cohort on Tenofovir Disoproxil Fumarate Rescue Therapy |
| AUTHORS (FIRST NAME, LAST NAME): Lucy Y. Lim1, 2, Scott Patterson1, Rachel Hammond2, James M. Trauer1, Nadia Warner2, Jacob George3, Simone I. Strasser4, Alice U. Lee5, William Sievert6, Amanda J. Nicoll7, Stuart K. Roberts8, Paul V. Desmond9, Scott Bowden2, Alexander J. Thompson2, 9, Stephen Locarnini2, Peter W. Angus1 | Institutional Author(s): | INSTITUTIONS (ALL): 1. Gastroenterology and Liver Transplant Unit, Austin Hospital, Melbourne, VIC, Australia.
2. Molecular Research and Development, VIDRL, Melbourne, VIC, Australia.
3. Gastroenterology and Hepatology, Westmeade, Sydney, NSW, Australia.
4. AW Morrow Gastroenterology and Liver Centre, RPA, Sydney, NSW, Australia.
5. Gastroenterology, Concord, Sydney, NSW, Australia.
6. Gastroenterology, Monash Medical Centre, Melbourne, VIC, Australia.
7. Gastroenterology, RMH, Melbourne, VIC, Australia.
8. Gastroenterology, The Alfred, Melbourne, VIC, Australia.
9. Gastroenterology, St Vincent's, Melbourne, VIC, Australia. | ABSTRACT BODY: Background: In CHB patients, quantitative hepatitis B surface antigen (QHBsAg) have recently been associated with predicting response to peg-interferon-alfa, including HBsAg seroconversion (SC) & loss or decline. Long-term nucleos(t)ide analogues (NA) suppresses HBV replication in the majority of patients, however very few actually undergo HBsAg SC. The utility of QHBsAg analysis in these patients is poorly understood & the impact of multi-drug resistant (MDR) variants has not been explored.
Aim: To evaluate the QHBsAg decline in a well-characterized cohort of patients with MDR (rtA181T/V) HBV who were treated with >7years with multiple NA, including at least 3 years of tenofovir (TDF).
Methods: TDF109 was an investigator-initiated, prospective, multi-centre, open-label study of the efficacy of TDF rescue therapy in 60 patients who had previously failed lamivudine (LAM) & subsequent adefovir (ADV) add-on or switch therapy. We have previously presented virological outcome at 2 years (Patterson, Gut 2011). All patients have been maintained on TDF in long-term follow-up, now out to 4 years. QHBsAg titers were retrospectively quantified at baseline & every 6 months, expressed as IU/ml (Roche Elecsys). Sub-analysis according to baseline viral load & the type of HBV resistance-associated substitutions present at baseline was then performed.
Results: At baseline, median QHBsAg titer was 5226IU/ml. Baseline QHBsAg positively correlated with HBV DNA levels at baseline, (R = 0.33, p=0.0168). There was a trend for higher baseline QHBsAg levels in HBeAg positive patients (p=0.13). The median HBsAg titers were 2772IU/ml, 2284IU/ml &1819IU/ml at year 1, 2&3 respectively (P<0.0001 for comparison of baseline to year 3). Patients with detectable rtA181T/V variants have a lower QHBsAg at baseline, but more gradual decline in QHBsAg (p=0.002). There was a trend for patients with no detectable resistance changes or LAM resistance HBV Pol at baseline, to have higher baseline QHBsAg, but higher rate of decline in QHBsAg (table).
Conclusion: QHBsAg significantly declined over time achieving QHBsAg <1500 IU/ml in the majority of patients by 3 years, nearing that of the key viral biomarkers of non-replicative CHB. Due to the high genetic barrier of TDF, ongoing therapy would be expected to achieve even lower levels of QHBsAg. | Variables | Number %
(Total n=59) | Median QHBsAg at Baseline | Median QHBsAg at Year 1 | Median QHBsAg at Year 2 | Median QHBsAg at Year 3 | P-value (baseline – year 3) | HBeAg Positive | 66% (39/59) | 8759
Note n = 35 | 3032 | 3450 | 3138 | 0.0027 | HBeAg Negative | 34%
20/59 | 3893
Note n = 17 | 1900 | 1730 | 1289 | 0.0008 | Resistance Changes None Detected | 25% (15) | 15855 | 7768 | 5632 | 4400 | 0.0027 (n=12) | L-Nucleoside (LAM/LdT)
M204I/V | 35% (21) | 7462 | 2225 | 3450 | 2433 | 0.0531 (n=14) | Acyclic phosphonate (ADV)
N236T | 8% (5) | 3912 | 1530 | 862 | 1140 | 0.5468 (n=2) | 181 Containing (LAM/LdT/ADV/TFV)
A181T/V +/-N236T | 30% (18) | 2992 | 2344 | 1664 | 1537 | 0.0020 (n=16) | |
译文:
题目:多重抗药耐药慢性乙肝患者运用富马酸替诺福韦补救疗法的表面抗原定量 |
摘要:背景:最近发现,慢性乙肝患者表面抗原定量与聚乙二醇干扰素-α治疗的应答预期(表面抗原血清学转换和消失/下降)具有相关性。对于大部分病人,长效核苷(酸)类似物可抑制HBV复制,但非常少数能达到表面抗原血清学转换。目前,针对在这些乙肝患者表面抗原定量分析的效用知之甚少,而多重抗药性变异的影响目前尚未探究出来。
目的:评估一个多重抗药耐药(rtA181T/V)特征明显的HBV队列,通过接受多个核苷(酸)类似物药7年以上治疗(其中包括最少3年替诺福韦治疗)后,表面抗原的下降。
方法:TDF109是一项由研究者发起,具有前瞻性、多中心的开放试验:为60位接受拉米夫定治疗失败后加用或改用阿德福韦酯的病人采取替诺福韦补救疗法。之前我们已经介绍了2年期的病毒学性结果。(Patterson,Gut 2011)所有患者坚持替诺福韦长期定期随访,现在是第四年。表面抗原滴度每6个月和在基线回顾性量化,以IU/ml 表达(RocheElecsys)。
根据基线病毒载量及基线显示的HBV耐药性替代类型得出亚分析。
结果:基线时显示,表面抗原滴度定量中位数为5226IU/ml,表面抗原基线与HBVDNA水平基线呈正相关(R= 0.33,P= 0.0168),E抗原阳性患者(p=0.13)的表面抗原基线更高。用药第一、二、三年的表面抗原滴度定量中位数分别为:2772IU/ml,2284IU/ml 及1819IU/ml (P<0.0001,基线对比3年)。检查出rtA181T/V变异的病人,表面抗原定量基线较低,且表面抗原呈现逐步下降趋势(p=0.002)。而没法检查出耐药或基线没有表达出乙型肝炎聚合酶蛋白对拉米夫定耐药的病人,表面抗原定量基线较高,但表面抗原下降速度更快。(表)
结论:大多数接受了3年替诺福韦治疗的患者,表面抗原定量会随着时间的推移而显著下降,达到表面抗原定量下降至<1500 IU/ml,接近到非复制型慢性乙肝的关键病毒学性指标。由于替诺福韦的强基因阻隔作用,接受持续的替诺福韦治疗,或将促使表面抗原滴度水平更低。
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