多重抗药耐药慢性乙肝患者运用替诺福韦补救疗法的S抗原定

ou99334

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。

StephenW

就个人而言，我觉得这些数据非常有意义的：
1。长期使用强效的抗病毒药物可以减少乙肝表面抗原的水平
2。如果这些数据可以被重复证明，长期抗病毒药可以治愈或成功停药？

咬牙硬挺

翻译的真好，做到了信达雅。感谢

StephenW

我觉得下面的研究成果，支持“强效的抗病毒药物的长期使用会降低乙肝表面抗原"这一想法.


[AASLD 2012]CONTROL ID: 1425911
PRESENTATION TYPE: Oral or Poster
CURRENT CATEGORY: Hepatitis B
CURRENT DESCRIPTORS: I03. Virology and Diagnostics
TITLE: Strong decline in HBsAg levels after virological response in a large monocentric therapy cohort: potential to select HBeAg positive chronic hepatitis B patients for finite duration?
AUTHORS (FIRST NAME, LAST NAME): Matthew J. Bruce1, Mary Horner1, Sarah Knighton1, Deepak Joshi1, Phillip M. Harrison1, Kosh Agarwal1, Ivana Carey1
Institutional Author(s):
INSTITUTIONS (ALL): 1. Institute of Liver Studies, Kings College School of Medicine at King's College Hospital, London, United Kingdom.
ABSTRACT BODY: Background and aims: The kinetics of serum HBsAg levels (qHBsAg) decline predict therapy response with interferon in chronic hepatitis B (CHB). However, only limited data are available comparing the effect of different treatment regimens on qHBsAg kinetics. This study compared serum HBsAg and HBVDNA levels kinetics in CHB patients receiving de-novo therapy with either tenofovir (TDF) 245mg/d, entecavir (ETV) 0.5mg/d or lamivudine 100mg/d + adefovir 10 mg/d (LAM+ADV).
Methods: 205 CHB therapy naïve monoinfected patients (75%males,21%HBeAg+, 21%cirrhotic, median age 36y) were treated with TDF (n=50;18%HBeAg+), ETV (n=62;26%HBeAg+) or LAM+ADV (n=93;20%HBeAg+) for minimum 24 months (median 30 months). We quantified qHBsAg (Abbott ARCHITECT®) and HBVDNA in serial serum samples at baseline, months 3 (M3), M6, M12, M18, M24&M30. Proportion of patients achieving HBsAg decline >0.5log10IU/ml (strong decline) and virological response (VR=HBVDNA<20IU/ml) were compared and strong decline was assessed at M6 (early HBsAg response) and after attaining VR for more than 1 year (late HBsAg response). Results are presented as medians.
Results: Baseline HBsAg levels were higher in ETV and TDF patients vs. LAM+ADV (3.75&3.59 vs 3.49,p=0.03), Baseline qHBsAg were higher in HBeAg+ than HBeAg- patients (3.52 vs 3.92,p<0.01) and in patients infected with genotypes A, D and E vs genotypes B/C (3.76 vs 3.26,p<0.01). Kinetics of HBsAg decline was similar in the first year of therapy, but from M18 there was a more rapid HBsAg decline in ETV group (M18:-0.14vs –0.05&–0.01,p=0.04; M24:-0.19vs –0.06&–0.02,p=0.03 and M30:-0.25vs –0.06&–0.02,p=0.01). qHBsAg decrease was greater in HBeAg+ vs. HBeAg- patients (irrespective of therapy) from M18 (M18:-0.53vs –0.02,p=0.01; M24:-0.56vs –0.06,p=0.02 and M30:-0.64vs –0.12, p=0.04), but did not differ in genotypes A, D, E and genotypes B/C infected patients. Early HBsAg strong decline was similar in all groups (2-5%patients). Late HBsAg response was more frequent in TDF and ETV patients than LAM+ADV (year 1:17&15%vs 7% and year 2:18&16%vs 7%,both p<0.05), but HBeAg loss was more frequent in LAM+ADV and TDF groups than ETV (47&33%vs 6%, p=0.03). Patients attainig VR had lower qHBsAg levels (M18:3.39vs 4.16; M24:3.32vs 4.1 and M30:3.25vs 4.17; all p<0.01) than replicating patients.
Conclusions: In this cohort, serum qHBsAg kinetics during therapy was a good predictor of HBeAg loss. However, first line antiviral therapy in CHB with nucleos(t)ide analogues in the first 12 months had similar qHBsAg kinetics between variable therapeutic approaches. A more rapid HBsAg decline was seen in HBeAg+ patients including those in ETV cohort, after M18.
背景与目的：预测治疗反应的动力学血清中HBsAg的水平（qHBsAg）的下降与干扰素在慢性乙型肝炎（CHB）。然而，只有有限的数据是可以比较不同的治疗方案qHBsAg动力学的影响。这项研究比较了血清HBsAg和HBVDNA水平动力学的从头治疗的慢性乙型肝炎患者接受替诺福韦（TDF），恩替卡韦（ETV）0.5毫克/ d或拉米夫定100mg /天245mg /天+阿德福韦10毫克/天（LAM + ADV ）。
方法：205 CHB治疗天真monoinfected患者（75％男性，21％的HBeAg +，21％的肝硬化，中位数年龄36Y）进行处理与TDF（Ň= 50; 18％的HBeAg +），ETV（Ň= 62; ​​26％的HBeAg +）或LAM + ADV（N = 93; 20％的HBeAg +）至少24个月（平均30个月）。我们量化qHBsAg“（雅培ARCHITECT®）和HBVDNA序列在基线血清样本，个月内3（M3），M6，M12，M18，M24和M30。 > 0.5log10IU/ml（大幅下滑）和病毒学应答（VR = HBVDNA <20IU/ml）进行了比较，大幅下滑被评定为M6（早期乙肝表面抗原反应），实现VR超过1年后实现乙肝表面抗原下降的患者比例（晚乙肝表面抗原反应）。结果以中位数。
结果：基线HBsAg水平明显高于ETV和TDF患者对LAM + ADV（3.75，3.59和3.49，P = 0.03），基线qHBsAg较高的HBeAg +低于HBeAg例（3.52比3.92，P <0.01）在患者感染基因型A，D和E与基因型B / C（3.76比3.26，P <0.01）。乙肝表面抗原下降动力学在治疗的第一年，但是从M18有一个更快速的乙肝表面抗原下降，ETV组（M18：0.14vs -0.05和-0.01，P = 0.04; M24-0.19vs -0.06和-0.02，P = 0.03和M30：0.25vs -0.06和-0.02，P = 0.01）。 qHBsAg减少，在HBeAg +和HBeAg的患者（不管治疗与否），M18（M18：0.53vs -0.02，P = 0.01; M24：0.56vs -0.06，P = 0.02和M30：0.64vs -0.12 ，P = 0.04），但并没有不同基因型A，D，E和基因型乙/ C感染的患者。早期乙肝表面抗原大幅下滑，各组（2-5％的患者）。晚乙肝表面抗原的反应是更频繁的TDF和ETV病人的比LAM + ADV（1:17年15％和7％，每年2:18和16％比7％，P均<0.05），但HBeAg消失是更频繁地LAM + ADV TDF组比ETV（47＆33％和6％，P = 0.03）。 attainig VR的患者比复制的患者低qHBsAg（M18：3.39vs 4.16 M24：3.32vs 4.1和M30：3.25vs 4.17，P均<0.01）。
结论：在这个群体中，的血清qHBsAg动力学在治疗过程中是一个很好的预测HBeAg消失。然而，第一线抗病毒药物治疗慢性乙型肝炎的核苷（酸）类似物在首12个月有可变的治疗方法之间的的类似qHBsAg动力学。在HBeAg（+）患者，包括在ETV队列中后，M18看到一个更快速的乙肝表面抗原下降。

hunterpt

to StephenW :

  1.目前 国外是否有服用 替诺福韦 达到 表抗 阴 的 实例？
2.替诺福韦 使用于治疗 HBV 有多少年了？

StephenW

回复 hunterpt 的帖子

1.目前 国外是否有服用 替诺福韦 达到 表抗 阴 的 实例？经过6年的TDF治疗，11％的患者(HBeAg阳性)失去了乙肝表面抗原。
2.替诺福韦 使用于治疗 HBV 有多少年了？2008 FDA 批准治疗
HBV.在临床试验中，当然也有很多年.
最新数据:
AASLD 2012

CONTROL ID: 1423799

PRESENTATION TYPE: Oral or Poster

CURRENT CATEGORY: Hepatitis B

CURRENT DESCRIPTORS: I02. Treatment and Clinical Trials

TITLE: Six Years of Treatment with Tenofovir DF for Chronic Hepatitis B Virus Infection is Safe and Well Tolerated and Associated with Sustained Virological, Biochemical and Serological Responses with no Detectable Resistance

AUTHORS (FIRST NAME, LAST NAME): Patrick  Marcellin1, Maria Buti2, Edward J. Gane3, Naoky Tsai4, William Sievert5, Ira M. Jacobson6, George Germanidis7, John F. Flaherty8, Phillip Dinh8, Kathryn M. Kitrinos8, John G. McHutchison8, Nezam Afdhal9

Institutional Author(s):

INSTITUTIONS (ALL): 1. Hôpital Beaujon, Clichy, France. 2. Hospital General Universitari Vall d’Hebron and Ciberehd, Barcelona, Spain. 3. Auckland City Hospital, Auckland, New Zealand. 4. University of Hawaii at Manoa, Honolulu, CA, United States. 5. Monash University and Monash Medical Centre, Melbourne, VIC, Australia. 6. Weill Cornell Medical College, New York, NY, United States. 7. AHEPA University Hospital, Aristotle University Medical School, Thessaloniki, Greece. 8. Gilead Sciences, Foster City, CA, United States. 9. Beth Israel Deaconess Medical Center, Boston, MA, United States.

ABSTRACT BODY: Background: We previously reported that 5 years of tenofovir DF (TDF) therapy in mostly treatment naïve patients results in sustained virological suppression with no development of resistance and was associated with either the halting or regression of fibrosis in 96% of patients. Here we present 6 year results from these two ongoing 8 year studies (Studies 102 and 103). Methods: After 48 weeks of double-blind comparison of TDF to adefovir dipivoxil, all patients undergoing liver biopsy were eligible to continue open-label TDF. Patients were assessed every 3 months for safety and efficacy with annual resistance surveillance; annual assessments of bone mineral density (BMD) of the spine and hip by DXA were added starting at year 4. Results: In a total 641 patients who were initially randomized and treated, 585 (93%) entered the TDF extension phase, and at Year 6, 466 (73%) remain on study. Efficacy results at Year 6 are shown in the table.  TDF was well tolerated over the 6 year evaluation period.  Less than 2% of patients discontinued TDF due to an adverse event, and ≤1.5% experienced a confirmed renal event (≥0.5 mg/dL increase in serum creatinine from baseline, phosphorus <2 mg/dL, or CrCL <50 mL/min). BMD (T scores) was stable over 2 years of evaluation. No resistance to TDF has been detected through Year 6. Conclusions: In these two trials, TDF remains safe and effective over a 6 year treatment period, with no detectable resistance to TDF; a relatively low rate of renal events and no evidence of clinically relevant bone loss were also observed.

HBeAg-negative Patients (Study 102) N=375 HBeAg-positive Patients (Study 103) N=266 HBV DNA <400 copies/mLa 81% (281/345) 62% (157/251) HBV DNA <400 copies/mLb 99.6% (283/284) 99% (167/169) ALT normalizationb 86% (228/265) 78% (127/162) HBeAg lossb - 50% (82/163) HBeAg seroconversionb - 37% (61/163) HBsAg lossc -d 11% (n=24) HBsAg seroconversionc -d 8% (n=18) aMissing=Failure (LTE-TDF analysis set); bMissing=Excluded (On treatment analysis set); cKaplan-Meier %;dOne HBeAg-negative patient experienced HBsAg loss/seroconversion at Year 5

hunterpt

回复 StephenW 的帖子

thx a lot for ur info.