更新于：2024-12-12

Efavirenz

依非韦伦

更新于：2024-12-12

概要

概要

基本信息

药物类型

小分子化药

别名

(S)-6-chloro-4-(Cyclopropylethynyl)-1,4-dihydro-(S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one、(S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one、6-chloro-4-(2-cyclopropyl-1-ethynyl)-4-trifluoromethyl-(4S)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

+ [18]

靶点

作用机制

RT抑制剂(逆转录酶抑制剂)

治疗领域

免疫系统疾病感染泌尿生殖系统疾病

在研适应症

HIV感染

非在研适应症

获得性免疫缺陷综合征合并感染避孕+ [3]

原研机构

Bristol Myers Squibb Co.

在研机构

Teva Pharmaceuticals Europe BVMerck Sharp & Dohme LLCMerck Sharp & Dohme BV

+ [3]

非在研机构

Merck Sharp & Dohme Corp.

Celgene Corp.

Bristol Myers Squibb Co.

+ [2]

最高研发阶段批准上市

首次获批日期

美国 (1998-09-17),

HIV感染

最高研发阶段(中国)批准上市

特殊审评加速批准 (美国)、孤儿药 (日本)

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结构

分子式C14H9ClF3NO2

InChIKeyXPOQHMRABVBWPR-ZDUSSCGKSA-N

CAS号154598-52-4

关联

260

项与依非韦伦相关的临床试验

CTIS2023-505832-36-01 / Not yet recruitingIIT

OPEN-LABEL EXTENSION STUDY TO ASSESS THE SAFETY AND LONG-TERM EFFECTIVENESS OF ORALLY ADMINISTERED EFAVIRENZ IN PATIENTS DIAGNOSED WITH ADULT OR LATE-ONSET JUVENILE TYPE C NIEMANN-PICK DISEASE WITH COGNITIVE IMPAIRMENT - HUB-NEU-2023-01

开始日期2024-05-16

申办/合作机构

Bellvitge University Hospital

NCT06294561 / Completed临床1期

An Open-label, Two-cycle, Single Sequence, Self-controlled Study Evaluating Effects of Oral Itraconazole or Efavirenz on Pharmacokinetic Profiles of TGRX-326

This is a drug-drug interaction study for TGRX-326 to evaluate the effects of CYP3A inhibitor/inducer drugs on pharmacokinetic profiles of TGRX-326, an ALK inhibitor indicated for treatment of Non-small cell lung cancer.

开始日期2024-03-04

申办/合作机构

深圳市塔吉瑞生物医药有限公司初创企业

CTR20234305 / Completed临床1期

开放、两周期、单序列、自身对照研究设计，评价口服伊曲康唑或依非韦伦对TGRX-326片药代动力学的影响

主要研究目的：评价健康受试者口服CYP3A强抑制剂伊曲康唑和CYP3A中效诱导剂依非韦伦对TGRX-326片药代动力学的影响。次要研究目的：评价健康受试者口服TGRX-326片以及与伊曲康唑、依非韦伦联合用药的安全性。评价TGRX-326片单次给药以及与伊曲康唑合并用药后对健康受试者QTc间期的影响。

开始日期2024-02-28

申办/合作机构

深圳市塔吉瑞生物医药有限公司初创企业

100 项与依非韦伦相关的临床结果

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100 项与依非韦伦相关的转化医学

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100 项与依非韦伦相关的专利（医药）

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5,251

项与依非韦伦相关的文献（医药）

2024-12-10·STATISTICS IN MEDICINE

Causal Inference for Continuous Multiple Time Point Interventions

Article

作者: Díaz, Iván ; Denti, Paolo ; Schomaker, Michael ; McIlleron, Helen

ABSTRACT:

There are limited options to estimate the treatment effects of variables which are continuous and measured at multiple time points, particularly if the true dose–response curve should be estimated as closely as possible. However, these situations may be of relevance: in pharmacology, one may be interested in how outcomes of people living with—and treated for—HIV, such as viral failure, would vary for time‐varying interventions such as different drug concentration trajectories. A challenge for doing causal inference with continuous interventions is that the positivity assumption is typically violated. To address positivity violations, we develop projection functions, which reweigh and redefine the estimand of interest based on functions of the conditional support for the respective interventions. With these functions, we obtain the desired dose–response curve in areas of enough support, and otherwise a meaningful estimand that does not require the positivity assumption. We develop ‐computation type plug‐in estimators for this case. Those are contrasted with g‐computation estimators which are applied to continuous interventions without specifically addressing positivity violations, which we propose to be presented with diagnostics. The ideas are illustrated with longitudinal data from HIV positive children treated with an efavirenz‐based regimen as part of the CHAPAS‐3 trial, which enrolled children years in Zambia/Uganda. Simulations show in which situations a standard g‐computation approach is appropriate, and in which it leads to bias and how the proposed weighted estimation approach then recovers the alternative estimand of interest.

2024-12-01·Lancet Global Health

Cost-effectiveness of viral load testing for transitioning antiretroviral therapy-experienced children to dolutegravir in South Africa: a modelling analysis

Article

作者: Hyle, Emily P ; Davies, Mary-Ann ; Horsfall, Stephanie B ; Collins, Intira Jeannie ; Desmonde, Sophie ; Abrams, Elaine ; Crichton, Siobhan ; Freedberg, Kenneth A ; Ciaranello, Andrea L ; Bacha, Jason ; Penazzato, Martina ; Brenner, Isaac Ravi ; Webb, Karen A ; Flanagan, Clare F ; Neilan, Anne M

BACKGROUND:

For children with HIV on antiretroviral therapy (ART), transitioning to dolutegravir-containing regimens is recommended. The aim of this study was to assess whether introducing viral load testing to inform new nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) for children with HIV and viraemia alongside dolutegravir-based ART is beneficial and of good economic value.

METHODS:

We used the Cost-Effectiveness of Preventing AIDS Complications-Pediatric model to project clinical and cost implications of three strategies among a simulated cohort of South African children aged 8 years with HIV receiving abacavir-lamivudine-efavirenz: (1) continue current ART (no dolutegravir; abacavir-lamivudine-efavirenz); (2) transition all children with HIV to dolutegravir, keeping current NRTIs (dolutegravir; abacavir-lamivudine-dolutegravir); or (3) transition to dolutegravir based on viral load testing (viral load plus dolutegravir), keeping current NRTIs if virologically suppressed (abacavir-lamivudine-dolutegravir, 70% of cohort) or switching abacavir to zidovudine (zidovudine) if viraemic (zidovudine-lamivudine-dolutegravir, 30%). We assumed 50% of children who had viraemia after abacavir-lamivudine exposure had NRTI resistance; with resistance, we assumed zidovudine-lamivudine-dolutegravir was more effective than abacavir-lamivudine-dolutegravir. We designated a strategy as preferred if it was most effective and least costly or had an incremental cost-effectiveness ratio less than half the South African 2020 gross domestic product per capita.

FINDINGS:

Under base-case assumptions, the viral load plus dolutegravir strategy would be the most effective (projected undiscounted life expectancy of 39·72 life-years) and least costly strategy (US$24 600 per person); the no dolutegravir strategy was the least effective (34·49 life-years) and most expensive ($26 480 per person). In sensitivity analyses, the 24-week virological suppression probability and subsequent monthly virological failure risks (ie, late failure) were most influential on cost-effectiveness. Only with a high late-failure risk for zidovudine-lamivudine-dolutegravir (ie, ≥0·3% per month in the base case or >0·5% per month if abacavir also confers low virological suppression probability in the presence of NRTI resistance [65%]) would the dolutegravir strategy become preferred above the viral load plus dolutegravir strategy.

INTERPRETATION:

For programmes transitioning to dolutegravir-based regimens, our model predicted that doing so would be more effective and less costly than continuing current ART regimens, regardless of NRTI choice. Whether viral load testing for children with HIV is necessary to inform NRTI choice depends substantially on the comparative outcomes of abacavir and zidovudine after switching to dolutegravir-containing ART.

FUNDING:

The Eunice Kennedy Shriver Institute for Child Health and Human Development, the National Institute of Allergy and Infectious Diseases, the Massachusetts General Hospital Executive Committee on Research, the Massachusetts General Hospital, and the Medical Research Council.

2024-12-01·Journal of the International AIDS Society

Impact of switching to a dolutegravir‐based regimen on body weight changes: insights from West African adult HIV cohorts

Article

作者: Tiendrebeogo, Thierry ; Ezechi, Oliver ; Ofotokun, Igho ; Minga, Albert ; Malateste, Karen ; Poda, Armel ; Jaquet, Antoine ; Ekouevi, Didier K. ; Lahiri, Cecile D.

Abstract:

Introduction:

Adverse metabolic effects related to dolutegravir (DTG) are increasingly reported as countries are adopting DTG‐based regimens as first‐line antiretroviral therapy (ART), but there is limited data from sub‐Saharan Africa. We explored changes in body weight pre‐ and post‐switch to a DTG‐based regimen and assessed the association between DTG switch and significant weight gain (SWG) defined as a ≥10% increase over a 12‐month period in people living with HIV (PLHIV) on ART in West Africa.

Methods:

We first included all PLHIV followed in the IeDEA West Africa cohorts between January 2017 and June 2021, with a documented switch to DTG during 2019–2021 and in care ≥36 months at the day of switch. Weight change was estimated using a two slope piecewise linear mixed model with change point at the switch date. Secondly, we emulated a sequence of target trials (ETT) based on the observational data, performing pooled logistic regression analysis to compare SWG occurrence between PLHIV who switched to DTG and those who did not.

Results:

We first included 6705 PLHIV from Burkina Faso, Côte d'Ivoire and Nigeria. Their median age at the time of switch was 48 years (IQR: 42–54) with a median follow‐up of 9 years (IQR: 6–12), 63% were female. Most patients switched from efavirenz (EFV)‐based ART (56.6%) and nevirapine (NVP)‐based ART (30.9%). The overall post‐switch annual average weight gain (AAWG) was significantly elevated at 3.07 kg/year [95% CI: 2.33–3.80] compared to the pre‐switch AWG which stood at 0.62 kg/year [95% CI: 0.36–0.88]. The post‐switch AWG was greater in patients previously on EFV and protease inhibitor (PI)‐based ART compared to those on NVP‐based ART. The pooled logistic regression analyses of a sequence of 24 ETT, including 9598 person‐trials, switching to DTG was significantly associated with an SWG (aOR = 2.54; 95% CI = 2.18–2.97).

Conclusions:

In West Africa, a 12‐month DTG exposure was associated with substantial weight gain, especially in PLHIV previously on EFV and PI‐based ARTs. Continuous weight monitoring and metabolic profiling is imperative in HIV cohorts to delineate the long‐term cardiometabolic impact of DTG as patients with, or at elevated risk for cardiovascular diseases might benefit from alternative ART regimens.

项与依非韦伦相关的新闻（医药）

2024-12-05

·医学新视点

如何诊治艾滋病？一文了解2024年中国新指南更新要点

艾滋病，即获得性免疫缺陷综合征（AIDS），其病原体为人类免疫缺陷病毒（HIV），亦称艾滋病病毒。AIDS是影响公众健康的重要公共卫生问题之一。《中国艾滋病诊疗指南（2024版）》重点对抗病毒治疗、全程管理、机会性感染、人类免疫缺陷病毒（HIV）感染合并肿瘤、HIV感染的预防与干预等内容进行了更新，并新增“艾滋病免疫重建不全（INR）”内容，首次提出了“艾滋病脆弱人群”的概念，增加了诊治推荐意见及其推荐证据和推荐强度。新版指南包括流行病学、实验室检测、常见机会性感染、抗病毒治疗、免疫重建炎性综合征、INR、HIV母婴垂直传播阻断及单阳家庭生育等内容。流行病学推荐意见1 对HIV/AIDS患者的配偶和性伴、与HIV/AIDS患者共用注射器的静脉药物依赖者、HIV/AIDS患者所生子女，以及具有疑似HIV感染高危行为和/或临床症状的临床就诊者，医务人员应主动提供HIV相关检测及相应的咨询服务（C1）。实验室检测推荐意见2 HIV筛查试验阳性者需进一步通过补充试验包括抗体补充试验（HIV-1/2抗体确证试验）和核酸补充试验（HIV-1核酸定性和定量检测）来确认HIV感染（A1）。推荐意见3 初治HIV感染者在启动抗反转录病毒治疗（ART）之前应进行基因型耐药检测。新确诊HIV感染者或使用长效卡替拉韦（CAB-LA）进行PrEP后仍感染HIV的患者，如考虑存在HIV对INSTI耐药，则应进行整合酶基因突变检测（C1）。诊断标准推荐意见4 HIV感染的全过程可分3个期，即急性期、无症状期和AIDS期；HIV/AIDS的诊断需结合流行病学史、临床表现和实验室检查结果进行综合分析，慎重做出诊断，并进行临床分期（A1）。常见机会性感染肺孢子菌肺炎（PCP）推荐意见5 PCP的病原治疗首选复方磺胺甲噁唑（SMZ-TMP），甲氧苄啶（TMP）15～20 mg/（kg·d），磺胺甲噁唑（SMZ）75～100 mg/（kg·d），分3～4次用，疗程为21 d；重症患者（PaO2＜70 mm Hg或肺泡-动脉血氧分压差＞35 mm Hg）早期（72 h内）可应用糖皮质激素（泼尼松或静脉用甲泼尼龙）治疗，激素总疗程为21 d（A1）。推荐意见6 CD4+T淋巴细胞计数＜200个/μL的HIV/AIDS患者应使用SMZ-TMP预防PCP，一级预防为1片/天，二级预防2片/天；ART后CD4+T淋巴细胞计数增加到＞200个/μL并持续≥3～6个月可停止预防用药（A1）。结核病推荐意见7 HIV/AIDS患者在每次就诊时均应系统接受结核病筛查，临床上应注意结合病史、结核病典型症状和体征，以及影像学和实验室检查，系统筛查结核病的可能（B1）。推荐意见8 HIV/AIDS患者结核病的治疗原则与普通结核病患者相同，但抗结核药物使用时应注意与抗病毒药物之间的相互作用及配伍禁忌（A1）。推荐意见9 所有合并结核病的HIV/AIDS患者无论CD4+T淋巴细胞计数水平的高低均应尽早接受ART，推荐在抗结核治疗后2周内尽早启动ART。合并耐药结核病，在使用二线抗结核药物后8周内开始ART；对于中枢神经系统结核病患者，通常建议在抗结核后的4～8周启动ART（C1），使用糖皮质激素治疗的AIDS合并结核性脑膜炎的患者，建议在启动抗结核后2周内启动ART（C1）。活动性结核病或非结核分枝杆菌（NTM）感染推荐意见10 HIV/AIDS合并NTM感染主要为鸟分枝杆菌（MAC）感染，确诊MAC病有赖于从患者血液、淋巴结、骨髓及其他无菌组织或体液中培养出MAC（A1）。推荐意见11 MAC病首选病原治疗方案为：克拉霉素500 mg/次，2次/天（或阿奇毒素500 mg/d）+乙胺丁醇15 mg/（kg·d），同时联合应用利福布汀（300～600 mg/d）。严重感染及严重免疫抑制（CD4+T淋巴细胞计数＜50个/μL）患者可加用阿米卡星［10 mg/（kg·d），肌内注射，1次/天］或喹诺酮类抗菌药物如左氧氟沙星或莫西沙星（B1）。疗程通常至少为12个月。抗MAC治疗开始2周后尽快启动ART（B1）。巨细胞病毒（CMV）感染推荐意见12 CMV视网膜炎的确诊有赖于检眼镜检查，治疗可选择更昔洛韦、缬更昔洛韦、膦甲酸钠，疗程为2～3周；局部治疗：玻璃体内注射更昔洛韦或膦甲酸，每周重复1次，疗程到视网膜病变被控制、病变不活动为止（A1）。推荐意见13 不推荐HIV/AIDS患者对CMV感染进行一级预防。二级预防方案推荐首选更昔洛韦（1.0 g，3次/天，口服），在CD4+T淋巴细胞计数＞100个/μL且持续3～6个月以上时可考虑停止二级预防（B1）。弓形虫脑病推荐意见14 弓形虫脑病病原治疗首选乙胺嘧啶（负荷剂量为100 mg，口服，2次/天，此后50～75 mg/d维持）+磺胺嘧啶（1～1.5 g，口服，4次/天），替代治疗：SMZ-TMP（3片，每日3次，口服）联合克林霉素（600 mg/次，静脉给药，每6小时1次）或阿奇霉素（0.5 g/d）。疗程至少为6周（A1）。推荐意见15 对无弓形虫脑病病史但CD4+T淋巴细胞计数＜200个/μL且弓形虫IgG抗体阳性的HIV/AIDS患者应使用SMZ-TMP（2片/次，1次/天）来预防弓形虫脑病（B1）。接受ART后，CD4+T淋巴细胞计数增加到＞200个/μL并持续＞3个月，可停止预防用药（A1）；或ART后CD4+T淋巴细胞计数在100～200个/μL，病毒载量持续低于检测下限3～6个月，也可考虑停止预防用药（B1）。推荐意见16 对既往患过弓形虫脑病者要长期使用乙胺嘧啶（25～50 mg/d）联合磺胺嘧啶（2～4 g/d）预防，直至CD4+T淋巴细胞计数增加到＞200个/μL并持续≥6个月（A1）。一旦CD4+T淋巴细胞计数下降到＜200个/μL，需重启预防用药（C1）。真菌感染推荐意见17 HIV/AIDS合并隐球菌性脑膜炎的病原体治疗分为诱导期、巩固期、维持期3个阶段，诱导期首选两性霉素B［0.5~0.7 mg/(kg·d)］或两性霉素 B 脂质体（L-AMB）［3~4 mg/(kg·d)］+氟胞嘧啶［100 mg/(kg·d)］，诱导期至少4周，巩固期首选氟康唑（600～800 mg/d）治疗至少6周，维持期选择氟康唑（200 mg/d），维持期至少1年，持续至患者通过ART后CD4+T淋巴细胞计数＞100个/μL并持续至少6个月时可停药（A1）。推荐意见18 HIV/AIDS合并隐球菌性脑膜炎诱导期可首选单次L-AMB 10 mg/kg联合使用2周的氟胞嘧啶［100 mg/(kg·d) ］和氟康唑（600~800 mg/d）进行治疗（A1）。推荐意见19 HIV/AIDS合并隐球菌性脑膜炎患者正规抗隐球菌治疗4～6周后启动ART (A1)。推荐意见20 合并隐球菌性抗原血症的HIV/AIDS患者建议给予氟康唑400～800 mg/d口服10周，而后改为200 mg/d口服预防性治疗，总疗程为6～12个月（C1）。推荐意见21 HIV/AIDS合并马尔尼菲篮状菌病诱导期抗真菌治疗方案首选两性霉素B［0.5～0.7 mg/(kg·d) ］或L-AMB［3～5 mg/(kg·d) ］或两性霉素B胆固醇硫酸酯复合物［3~4 mg/(kg·d) ］，静脉滴注2周（A1）；巩固期为口服伊曲康唑或伏立康唑200 mg，每12小时1次，共10周；随后进行二级预防，口服伊曲康唑200 mg，1次/d（B1），至患者通过ART后CD4+T淋巴细胞计数＞100个/μL，并持续至少6个月可停药（B）。一旦CD4+T淋巴细胞计数＜100个/μL，需要重启预防治疗（C1）。抗病毒治疗成人及青少年抗病毒治疗时机与方案 ①成人及青少年启动ART的时机：推荐意见22 所有HIV感染无论CD4+T淋巴细胞水平高低均建议尽早开始ART，以降低发病率和病死率，并预防HIV传播（B1）；有条件患者建议快速启动ART（确诊后7 d内）或确诊当天启动ART（A1）。 ②成人及青少年初始ART方案：推荐意见23 成人初治患者推荐ART方案通常由2种核苷类反转录酶抑制剂（NRTI）类骨干药物联合第三类药物组成，第三类药物可以为整合酶链转移抑制剂（INSTI）或非核苷类反转录酶抑制剂（NNRTI）或者增强型蛋白酶抑制剂（PI，含利托那韦或考比司他）；也可以选用复方单片制剂（STR）（A1）；对于HBV表面抗原（HBsAg）阴性、病毒载量＜5×105拷贝/mL的初治患者可首选多替拉韦/拉米夫定的ART方案（A1）。特殊人群抗病毒治疗儿童：推荐意见24 儿童一旦确诊HIV感染，无论CD4+T淋巴细胞水平高低，均建议立即开始ART（B1）。推荐意见25 儿童初治患者ART方案推荐为2种NRTI类骨干药物联合第三类药物治疗，第三类药物可以为INSTI或NNRTI或者增强型PI（含利托那韦或考比司他）（B1）。合并结核分枝杆菌感染者：推荐意见26 HIV/AIDS合并结核病患者推荐首选ART方案为替诺福韦（齐多夫定）+拉米夫定（恩曲他滨）+依非韦伦或多替拉韦（A1），与利福平合用时，多替拉韦的剂量建议加倍（50 mg，2次/天）（A1）。合并HBV感染者：推荐意见27 HIV/HBV合并感染者不论CD4+T淋巴细胞计数水平如何，均建议尽早启动ART，ART方案中应包含2种具有抗HBV活性的抗病毒药物，ART骨干药物中的核苷类药物推荐选择替诺福韦（或丙酚替诺福韦[TAF]）+拉米夫定（或恩曲他滨）（B1）。合并HCV感染者：推荐意见28 HIV合并HCV感染者应尽早启动ART和积极抗HCV治疗，抗HCV治疗的方案和疗程与单纯HCV感染者相同，应注意与ART药物间的相互作用（A1）。抗病毒治疗监测推荐意见29 启动ART后建议每3～6个月进行病毒学、免疫学和临床情况随访以评价ART的疗效，及时发现抗病毒药物的不良反应及是否出现病毒耐药等，以便及时更换药物而保证ART成功（C1）。药物相互作用推荐意见30 推荐病毒载量检测作为发现和确认抗病毒治疗失败的首选方法（C1）；一旦确认抗病毒治疗失败，则应尽快进行HIV耐药检测（C1）。推荐意见31 病毒出现病毒学失败时应首先评估患者的治疗依从性、药物-药物或药物-食物相互作用，尤其服药依从性是治疗成败的决定因素。ART失败的患者应根据HIV耐药检测结果来进行ART方案调整，方案选择的原则是更换至少2种ART药物，最好选择3种具有抗病毒活性的药物；新的ART方案通常应包括1种具有完全抗病毒活性的增强PI或INSTI或未曾使用过的新的作用机制药物如衣壳抑制剂和FI，或上述药物联合应用（A1）。推荐意见32 低病毒血症（LLV）需评估患者的依从性、耐受性和药物不良反应、药物相互作用（A1）。LLV通常不需要改变治疗方案（B1），但需每3个月监测1次HIV RNA，以评估是否需要调整ART方案（C1）。 IRIS 推荐意见33 HIV感染者接受ART后出现如发热、潜伏感染变成活动性感染、原有感染的加重或恶化等炎症相关表现时，应考虑存在IRIS的可能，但应注意排除由HIV疾病进展、新发感染、HIV相关肿瘤、药物不良反应、治疗失败等情况带来的干扰。临床上应根据IRIS的严重程度，开始或继续治疗相关机会性感染，严重者可短期应用糖皮质激素或非甾体抗炎药（C1）。免疫功能重建不全推荐意见34 接受ART 4年以上，外周血病毒载量低于检测下限（＜50拷贝/mL）超过3年，CD4+T淋巴细胞计数仍持续低于350个/μL，同时排除其他可能导致CD4+T淋巴细胞计数长期低下的原因，需考虑为免疫功能重建不全（B1）。推荐意见35 免疫功能重建不全缺乏明确有效的治疗方法，临床应定期监测，并需根据CD4+T淋巴细胞水平进行机会性感染的预防和NADE的筛查。对于已实现病毒学抑制的患者，不建议为改善免疫重建而随意进行ART调整（B1）。 AIDS相关肿瘤推荐意见36 HIV感染者在随访过程中应注意筛查AIDS定义性肿瘤和非AIDS定义性肿瘤。年龄在25岁以上的女性HIV感染者，建议定期进行宫颈癌的筛查（C1）。所有AIDS合并肿瘤的患者均建议尽早启动ART，需注意抗病毒药物和抗肿瘤药物之间的相互作用，应选用骨髓抑制作用和药物相互作用小的ART方案。提倡MDT模式来为HIV合并肿瘤患者提供标准化诊疗（C1）。 HIV母婴传播阻断及单阳家庭生育抗反转录病毒药物干预推荐意见37 所有感染HIV的孕妇不论其CD4+T淋巴细胞计数多少或疾病临床分期如何，均应尽早终身接受ART（B1）；孕妇ART首选包含多替拉韦或拉替拉韦的三联ART方案（A1）。推荐意见38 HIV感染母亲所生婴儿应在出生后尽早（6 h内）预防性服用抗病毒药物，并根据暴露风险来确定服药方案（B1）。产后喂养指导推荐意见39 HIV阳性孕产妇所生婴儿推荐科学喂养，避免母乳喂养，杜绝混合喂养（A1）；对因不具备人工喂养条件而选择母乳喂养的感染产妇及其家人，要做好充分的咨询和知情，指导其坚持正确的纯母乳喂养，且在整个哺乳期间必须坚持ART，喂养时间不超过6个月（A1）。 HIV暴露前后预防与阻断暴露后预防（PEP）推荐意见40 HIV预防阻断前检测建议进行HIV RNA检测，尤其对既往有阻断用药史的求询者（A1）；在发生HIV暴露后尽可能在最短的时间内（尽可能在2 h内）进行预防性用药，最好在24 h内，但不超过72 h，连续服用28 d（C1）；暴露后阻断方案首选恩曲他滨/替诺福韦（FTC/TDF）或恩曲他滨/丙酚替诺福韦（FTC/TAF）联合INSTI（比克替拉韦[BIC]或多替拉韦或拉替拉韦）的方案（C1）。暴露前预防（PrEP）推荐意见41 实施PrEP前应做好HIV暴露风险评估和医学及适应性评估（C1），PrEP的口服方案有两种，分别为每日服药方案和事件驱动服药方案，药物可选择FTC/TDF（或FTC/TAF）（A1）；不能选择口服药物的可选择长效卡替拉韦（CAB-LA）肌内注射的方案（A1）。 HIV感染的全程管理推荐意见42 所有HIV感染者均推荐按照全程管理的模式来进行管理（C1）。推荐意见43 对于晚发现的HIV感染者尤其是处于HIV感染疾病晚期的患者要进行各种机会性感染的筛查，应将结核病和隐球菌病的筛查作为临床诊疗常规（A1）。推荐意见44 推荐对CD4+T淋巴细胞计数＜200个/μL的HIV感染者开展血清CrAg筛查，阳性者应进行脑脊液检查以排除隐球菌性脑膜炎的可能（B1）。推荐意见45 启动ART之前，建议进行相应的基线检测和评估，这些检测包括：HIV RNA、CD4+T淋巴细胞计数、HIV耐药检测、血常规、尿常规、肝肾功能、血糖、血脂、是否存在合并感染（如病毒性肝炎、隐球菌病、结核病、STI等）的相关检测等（C1）。推荐意见46 需特别关注脆弱人群抗病毒治疗和随访的相关问题，脆弱人群主要包括：年龄超过50岁的老年患者；儿童患者；孕妇；具有多种基础疾病的患者；免疫高度抑制的患者如CD4+T淋巴细胞计数＜50个/μL；ART后免疫功能重建不全的患者。这类患者要更为积极地进行ART，积极治疗基础疾病，注意多学科协作诊治（C1）。推荐意见47 对于ART后病毒得到有效抑制的患者，不建议随意进行治疗方案的调整。优化治疗应当以维持病毒抑制为基础，并且不对未来的药物选择构成威胁。在进行ART方案优化时，应特别注意患者之前是否存在HIV耐药及有无合并HBV或HCV感染的情况（A1）；病毒学抑制且无传播性或获得性HIV耐药史的HIV感染者，通常可以转换为任何首选推荐的初始ART方案并维持病毒学抑制（A1）。推荐意见48 所有HIV感染者均应定期接受CVD风险评估、筛查和预防干预，对于CVD风险高的患者，应相应调整ART方案，同时积极控制相关CVD风险因素如戒烟、血糖、血脂、肥胖和血压等（C1）。推荐意见49 应创造各种条件促进HIV/AIDS患者便利接受各种诊疗服务，确保医疗服务的可持续性（B1）；应对HIV/AIDS患者进行疫苗接种指导（C1）。通信作者北京协和医院李太生感染内科主任，教授，主任医师，博士生导师。中国国家卫生健康委艾滋病专家咨询委员会临床组组长，中华医学会感染性疾病分会副主任委员兼艾滋病学组组长，曾任中华医学会热带病和寄生虫分会主任委员。共发表学术论文200余篇，其中在SCI收录的杂志上发表论文50余篇，被他人引用超过2500次。推荐阅读每月一次，效果可维持11个月！《自然-医学》：三联抗体组合长效抑制HIV 80%的中风可预防！权威指南：降压、降糖、地中海饮食……关注10大要点更新全球约30%的人有脂肪肝！《柳叶刀》子刊：3大危险因素、4类治疗策略 JAMA子刊：结直肠癌肝转移一线治疗，“简化方案”有望成为首选欢迎投稿：学术成果、前沿进展、临床干货等主题均可，点此了解投稿详情。参考资料 [1] 中华医学会感染病学分会艾滋病学组, 中国疾病预防控制中心. 中国艾滋病诊疗指南(2024版)[J]. 协和医学杂志, 2024, 15(6): 1261-1288. DOI: 10.12290/xhyxzz.2024-0766 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。《协和医学杂志》倡导尊重和保护知识产权，欢迎转载、引用，但需取得本平台授权。如您对文章内容及版权存疑，请发送邮件至medj@pumch.cn，我们会与您及时沟通处理。图文内容仅供交流、学习使用，不以盈利为目的；科普内容仅用于大众健康知识普及，读者切勿作为个体诊疗根据，自行处置，以免延误治疗。治病就医相关需求请于北京协和医院APP线上或线下就诊。分享，点赞，在看，传递医学新知

临床结果

2024-11-28

·精准药物

共价药物体外时间依赖性抑制（TDI）数据分析和解读

前言共价药物（Covalent drug）是指在结构中包含反应性的官能团，能与靶蛋白形成共价键，实现与靶蛋白长期结合，从而提供独特的药效学特征。从偶然发现到目标性设计，共价药物在多个疾病领域蓬勃发展，尤其是抗肿瘤领域。自KRAS靶点在癌症中的作用被发现以来，近30年间研究者使用传统药物发现方法一直没有突破这一靶点的不可成药性，而共价抑制剂Sotorasib（Lumakras）和Adagrasib（Krazati）打破了KRAS“不可成药靶点”的魔咒。近年来，多款共价药物成功上市，包括针对EGFR、BTK、KRAS等靶点的抑制剂。细胞色素P450酶（以下简称CYP酶）是体内参与药物代谢最广泛的I相代谢酶，主要位于肝脏，参与约75%的小分子药物代谢。药物对CYP酶的抑制会引起联用药物的暴露量增加或活性代谢产物暴露量减少，造成潜在毒性或影响疗效。抑制评价分为可逆性抑制（Reversible inhibition）和时间依赖性抑制（Time-dependent inhibition, TDI）评价，其中TDI会造成更为严重的药物相互作用（Drug interaction, DDI）。药物本身或其代谢后生成的反应性中间体与CYP酶的共价结合是TDI发生的机理之一，那么共价药物是否一定会发生TDI呢？共价药物的TDI风险比非共价抑制剂更高吗？如何评估TDI风险和解读TDI数据呢？本文分析了29个已上市的共价药物对CYP酶的TDI研究结果，并对体外TDI风险评估的方法和数据解读提供相关建议。上市共价药物对CYP450酶的抑制结果分析据报道，自1947年以来共117种共价药物获批[1]，已上市的共价药物主要涉及抗感染（青霉素、磷霉素）、抗病毒（奈马特韦）和抗肿瘤（奥西替尼、达克替尼）等治疗领域。本文检索了自2000年以来上市的共价药物对CYP酶的体外TDI结果，共整理出29个共价药物的数据，详见文末附表1。其中19个共价药物对至少一种CYP酶表现出TDI，约占65.5%。TDI在7种常见CYP酶的分布汇总如图1，有15个药物对CYP3A存在TDI，约占79%；其次是2C8，5个共价药物对其存在TDI，约占26%；对1A2和2B6存在TDI的共价药物都为3个，占比约16%；有1个共价药物对2C19存在TDI，占比约5%。19个共价药物对2C9和2D6不存在TDI或目前未见报道。图1. 自2000年之后上市的具有TDI的共价药物在常见CYP酶的分布情况一项体外[22]研究评估了14个蛋白激酶抑制剂对CYP2C8和CYP3A的TDI，结果表明经过与NADPH预孵育以后，11个激酶抑制剂对CYP3A的抑制效果增强，3个对CYP2C8的抑制效果增强，（如图2）。其中有8个已被文献报道为CYP3A的TDI抑制剂，另外3个在随后的研究中证实抑制CYP3A的IC50偏移率大于2倍。这14个药物并非共价药物，由此看来，非共价药物尤其是蛋白激酶抑制剂的TDI风险依然不容忽视。对于共价药物和非共价药物，TDI都是需要重点关注的内容。图2. 蛋白激酶抑制剂与NADPH预孵育30min后抑制阿莫地喹N-去乙基化（CYP2C8）和咪达唑仑1'-羟化（CYP3A）的结果。BOSU, bosutinib; BOSU iso, bosutinib isomer 1; CRIZ, crizotinib; DASA, dasatinib; ERLO, erlotinib; GEFI, gefitinib; LEST, lestaurtinib; NILO, nilotinib; PAZO, pazopanib; SARA, saracatinib; SORA, sorafenib; SUNI, sunitinib. [22] 体外TDI风险评估的方法建议监管机构和制药公司已经认识到评估TDI风险的重要性，人用药品技术要求国际协调理事会（ICH）发布的指导原则M12《Drug Interaction Studies》[23]于今年5月21日最终采纳。结合指南推荐，体外评估药物TDI风险的方法总结如下： “ 1 酶活性损失百分比、假一级速率常数kobs和IC50偏移早期药物发现阶段，需要高通量、快速筛选确定CYP酶的TDI潜力，可以通过单一化合物浓度下含和不含NADPH预孵育后损失百分比（%Activity loss），CYP酶活性降低（kobs）或多浓度的化合物含和不含NADPH预孵育后IC50值的偏移(IC50 shift)来判断化合物是否有TDI潜力。 “ 2 TDI抑制的动力学常数测定（kinact、KI）评估CYP酶TDI的重要动力学常数包括最大失活速率常数（kinact）、导致半数最大失活的抑制剂浓度（KI）。采用不同浓度的化合物（至少6个）与酶源（即肝微粒体、肝细胞、重组酶系统）及NADPH进行第1次孵育（至少6个时间点），也称失活孵育；在特定的孵育时间后，将失活孵育混合物加入含有CYP同工酶探针底物的二次孵育当中，反应一定时间后，终止反应，并测量探针底物的代谢产物生成。计算失活后相对于没有抑制剂时所测得的活性的剩余百分比，剩余百分比与失活孵育的时间进行线性拟合作图，得到一系列一级衰减曲线，如图3a，直线斜率的负值即为一个浓度点的表观抑制速率（kobs）。用不同浓度下的表观抑制速率与化合物的浓度进行非线性拟合即可计算得到kinact和KI，如图3b。图3. Verapamil的体外TDI动力学常数测定（kinact和KI）测量kinact和KI的体外实验方法通常不适合早期药物发现项目中的高通量筛选。但从药物发现的角度，较大的kinact值和较小的KI值通常会增加CYP酶失活导致DDI的可能性。因此在临床前药物发现中，也可以通过kinact/KI比值衡量化合物CYP酶失活的效率，对同系列化合物进行排序。案例分享与TDI数据的解读建议 Ritlecitinib是一种共价JAK3酪氨酸激酶抑制剂，主要用于治疗脱发症，尤其是斑秃和非节段型白癜风（NSV）。其共价抑制机制主要通过与JAK3催化域中的半胱氨酸残基（Cys-909）发生不可逆的共价结合来实现。这一残基在其他JAK家族成员中被丝氨酸残基所取代，这使得Ritlecitinib对JAK3具有高度的选择性[24, 25]。 Ritlecitinib在体外肝微粒体TDI评价体系中，被评估为CYP1A2和CYP3A的TDI抑制剂。其中，Ritlecitinib对CYP1A2（以咖啡因底物）代谢活性抑制常数分别是KI为327 μmol/L，kinact为0.0917 min-1。由于在测试的浓度范围内（3-200 μmol/L）未达到抑制饱和，因此无法确定对CYP3A（以咪达唑仑底物）代谢活性的KI或kinact，但kinact/KI估计为0.871 mL/min/μmol[20]。在斑秃患者中，每日一次口服50 mg的Ritlecitinib后最大稳态游离药物浓度（Cmax,u）估计值1.1 μmol/L[20]，结合上述体外TDI参数，根据ICH M12指导原则[23]的基本方法初步评价TDI风险如表1。计算得到Ritlecitinib对CYP1A2的表观一级失活速率常数(Kobs)为0.001517 min-1。Kdeg是酶的表观一级降解速率常数，引用自指导原则，计算（kobs+kdeg）/kdeg的值为6.06，大于1.25，说明需关注Ritlecitinib潜在临床抑制风险。表1. 基本模型预测Ritlecitinib对CYP1A2的TDI风险注：kobs=(kinact*5*Cmax,u)/(KI+5*Cmax,u)，此处计算所使用数据引用自文献[20] 该药物开展了相应的临床DDI研究。Liu[26]等人在健康志愿者中开展的临床研究中发现，咖啡因（CYP1A2底物）与Ritlecitinib联合使用时，咖啡因的AUC和Cmax分别增加了约165%和10%，表明Ritlecitinib是CYP1A2的中等抑制剂，可以增加CYP1A2底物的暴露量。Ritlecitinib与CYP酶底物合用的临床DDI研究结果汇总如表2，Ritlecitinib与咪达唑仑（CYP3A底物）合用导致咪达唑仑的AUC和Cmax分别增加了约169%和81%，而其与Efavirenz（CYP2B6底物）和Tolbutamide（CYP2C底物）合用后，底物的暴露量变化不具有临床意义[27]。在Ritlecitinib药品说明书中，提示与CYP3A和CYP1A2的底物合用时，可能增加不良反应风险，需考虑额外的监测或调整剂量。表2. Ritlecitinib临床与CYP酶底物合用引起的暴露量变化 c: 合用Ritlecitinib相比于单独给药的Cmax和AUCinf的比值。 d: 报告了Efavirenz的AUC0-72。以上结果整理自药品说明书。 TDI数据解读建议药物研发早期可通过单一浓度下的酶活性降低(酶活性损失率%Activity loss或假一级速率常数kobs或多浓度点下IC50偏移(≥1.5)，检测化合物的TDI潜力；如药物具有TDI潜力，可通过体外研究获得TDI的动力学参数kinact、KI，结合人体PK数据，应用模型排除或预测临床TDI风险。结语本文整理的数据表明65%以上的共价药物表现出对CYP酶的TDI，而文献显示非共价药物如蛋白激酶抑制剂的TDI风险同样不容忽视，因此，不论是否为共价药物，均建议在研发早期考察TDI风险。 TDI引起的临床不良反应往往是极其严重的，如米贝拉地尔的撤市，其作为CYP3A的强TDI抑制剂，与其他3A的底物合用会引起严重的毒性反应，严重时导致死亡。对于存在TDI风险的药物，必要时通过体外实验获取抑制动力学参数kinact和KI，结合临床PK数据进行临床DDI风险的评估，如果体外数据和模型无法排除临床抑制风险，则应使用敏感探针底物进行临床DDI研究。药明康德DMPK已经建立了一套专门针对共价药物的药代动力学研究体系，其中包括早期的高通量筛选、共价药物多样化的体内外代谢模型与方法、丰富的体外ADME试验类型、以及14C标记化合物的合成和相应的ADME技术平台，可以支持客户加速共价药物的研发和申报。附表1. 29个共价药物对CYP酶的TDI结果汇总（下滑查看更多） a: 结果引用自药品说明书。 b: 由于测试浓度（3-200 μM）下抑制未被饱和，无法计算准确KI和kinact值。参考文献： [1] Journal of Medicinal Chemistry 2022 65 (8),5886-5901 DOI: 10.1021/acs.jmedchem.1c02134 [2] Suchy D, Łabuzek K, Stadnicki A, Okopień B. Ezetimibe--a new approach in hypercholesterolemia management. 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[12] NDA 209776: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209776Orig1s000PharmR.pdf [13] Report on the Deliberation Results: https://www.pmda.go.jp/files/000240418.pdf [14] Zhang H, Ou YC, Su D, Wang F, Wang L, Sahasranaman S, Tang Z. In vitro investigations into the roles of CYP450 enzymes and drug transporters in the drug interactions of zanubrutinib, a covalent Bruton's tyrosine kinase inhibitor. Pharmacol Res Perspect. 2021 Dec;9(6):e00870. doi: 10.1002/prp2.870. PMID: 34664792; PMCID: PMC8524670. [15] Report on the Deliberation Results: https://www.pmda.go.jp/files/000237315.pdf [16] NDA 214665: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/214665Orig1s000MultidisciplineR.pdf [17] NDA 215301: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/215310Orig1s000MultidisciplineR.pdf [18] KRAZATI 200 mg film-coated tablets: ANNEX I [19] Heather Eng et al, Disposition of Nirmatrelvir, an Orally Bioavailable Inhibitor of SARS-CoV-2 3C-Like Protease, across Animals and Humans; Drug Metab Dispos. 2022 May;50(5):576-590. [20] Litfulo review report; https://www.pmda.go.jp/files/000266925.pdf [21] https://www.ema.europa.eu/en/documents/rmp-summary/skyclarys-epar-risk-management-plan_en.pdf [22] Drug Metab Dispos 42:1202–1209, July 2014, http://dx.doi.org.libproxy1.nus.edu.sg/10.1124/dmd.114.057695 [23] ICH M12《Drug Interaction Studies》 [24] Xu H, Jesson MI, Seneviratne UI, et al. PF-06651600, a dual JAK3/TEC family kinase inhibitor. ACS Chem Biol. 2019;14(6):1235–42. [25] Telliez JB, Dowty ME, Wang L, et al. Discovery of a JAK3- selective inhibitor: functional diferentiation of JAK3-selective inhibition over pan-JAK or JAK1-selective inhibition. ACS Chem Biol. 2016;11(12):3442–51. [26] Liu J, Solan R, Wolk R, et all. Evaluation of the effect of ritlecitinib on the pharmacokinetics of caffeine in healthy participants. Br J Clin Pharmacol. 2023;89:2208–2215. [27] Pfzer Inc. LITFULO™ (ritlecitinib) capsules, for oral use: US prescribing information. 2023. https://www.accessdata.fda.gov/ drugsatfda_docs/label/2023/215830s000lbl.pdf. Accessed 26 Jul 2023. （下滑查看更多）作者：吴文萍，马虹莹，马利萍，周莹，金晶编辑：姜利芳，钱卉娟，陈根富设计：倪德伟，张莹莹声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

上市批准一致性评价医药出海

2024-10-22

·BioSpace

Gilead to Present Latest Research Across Key Liver Disease Indication at the American Association for the Study of Liver Disease (AASLD) Meeting 2024

- Key Insights from Viral Hepatitis, PBC, and MASH/Fibrosis Studies Highlight Gilead’s Ongoing Commitment to Advancing Life-Changing Liver Disease Research - FOSTER CITY, Calif.--(BUSINESS WIRE)--Gilead Sciences, Inc. (Nasdaq: GILD) today announced new research to be presented at The Liver Meeting ® 2024, hosted by the American Association for the Study of Liver Diseases (AASLD) from November 15-19 in San Diego, Calif. More than 40 abstracts will be presented with key data, including 11 abstracts reporting new data on primary biliary cholangitis (PBC). The data will include findings from the RESPONSE trial that demonstrate the efficacy and safety pro Livdelzi ® (seladelpar) in people living with PBC and compensated cirrhosis. Additionally, data will be presented on the effects of Livdelzi on pruritus (chronic itching), a symptom that has significant impact on the quality of life of people living with PBC, along with interim long-term efficacy and safety results from the ongoing ASSURE study. Beyond PBC, Gilead will be presenting an interim analysis of the Phase 3 MYR301 study, which is evaluating people living with hepatitis Delta virus (HDV) who received bulevirtide monotherapy (2 mg for 144 weeks; 10 mg for 144 weeks; or 10 mg for 96 weeks) for chronic HDV and have been off treatment for 48 weeks. The study is evaluating whether or not patients treated with bulevirtide monotherapy for 2-3 years maintained virological and biochemical responses one year after stopping treatment. An additional 144-week analysis of patient-reported outcomes for individuals treated with bulevirtide 2 mg will also be presented, adding to the wealth of long-term data for the treatment for chronic HDV. “We’re excited to share our latest research at The Liver Meeting, as we push the boundaries of what’s possible in liver disease treatment. The breadth of this research reflects Gilead’s unwavering dedication to advancing life-changing science and shaping healthier futures for people living with liver disease,” said Anu Osinusi, Vice President of Clinical Development for Hepatitis, Respiratory and Emerging Viruses, Gilead Sciences. “The depth and range of our data, spanning both viral and inflammatory liver diseases, underscores our commitment to making a meaningful impact at every stage of a person’s journey in liver disease. Our goals go far beyond treatment alone—our work spans awareness, education, screening, diagnosis, and long-term care, all intending to address unmet needs and enhance treatment outcomes.” Gilead will also present hepatitis C virus (HCV) data which will include safety and tolerability outcomes for Epclusa ® (velpatasvir/sofosbuvir) in pregnant individuals with chronic HCV (the STORC study). As a special population that is often excluded from clinical research, these results may help clinicians better support pregnant people living with HCV, which in turn may reduce the risk of transmission to infants. Furthermore, real-world findings from the SVR10K study on HCV will be showcased, demonstrating the effects of direct-acting antivirals against all HCV genotypes across diverse regions. Late-breaking data from a Phase 2a open-label study assessing the safety and efficacy of novel combination therapies for chronic hepatitis B virus (HBV) will also be presented by Gilead. Key Abstracts at AASLD 2024: ID Abstract Title PBC 164 Efficacy and Safety of Seladelpar in Patients with PBC and Compensated Cirrhosis in the Phase 3 Placebo-controlled RESPONSE Trial 167 Attenuation, Near Resolution, and Prevention of Pruritis in Patients with PBC Treated with Seladelpar: A Secondary Analysis of Patterns of Pruritis Change in the RESPONSE Trial 4339 Alkaline Phosphatase Changes with Seladelpar Across Subgroups of Primary Biliary Cholangitis Patients in the RESPONSE Trial 4342 Seladelpar and Reductions in Lipids in Patients with Primary Biliary Cholangitis with and without Statin use in the Phase 3 Placebo-controlled RESPONSE Study 4341 Long-term Safety of Seladelpar 10 mg with up to 5 Years of Treatment in Patients with Primary Biliary Cholangitis Primary sclerosing cholangitis (PSC) 151 Associations Between Biomarkers and Magnetic Resonance Imaging-derived ANALI Score in Patients with Primary Sclerosing Cholangitis: Analysis from the Phase 3 PRIMIS Study HDV 1147 Efficacy and Safety of BLV Monotherapy for Chronic Hepatitis Delta: Post Treatment Results through 48 Weeks after the End of Treatment from an Interim Analysis of a Randomized Phase 3 Study MYR301 1193 Patient-reported Outcomes among Patients with Chronic Hepatitis Delta Treated with Bulevirtide 2 mg: A Long-term Analysis of the Phase 3 MYR301 Trial at 144 Weeks 139 Long-term Bulevirtide Monotherapy in Patients with HDV-related Compensated Cirrhosis: Effectiveness, Safety and Clinical Outcomes from the Retrospective Multicenter European Study (SAVE-D) HCV 222 Safety, Tolerability, and Outcomes of Velpatasvir/Sofosbuvir in Treatment of Chronic Hepatitis C Virus during Pregnancy (STORC) 1455 The SVR10K Study: A Real-world Data with Pangenotypic Direct-acting Antivirals across Multiple Diverse Regions 1476 Hepatitis C Treatment Uptake Differs by Gender among a Commercially Insured Population in the United States HBV 1380 Results from a Phase 2a, Open-label Study to Evaluate the Safety and Efficacy of Novel Combination Therapies Containing VIR-2218, Selgantolimod, and Nivolumab for the Treatment of Chronic Hepatitis B 1252 Effectiveness and Safety of Tenofovir Alafenamide in Chronic Hepatitis B Patients with Suboptimal Response to Antiviral Therapy 1337 Characterization of Changes in Noninvasive Fibrosis Markers over 8 Years of Tenofovir-based Treatment in Chronic Hepatitis B Patients Enrolled in Two Phase 3 Trials Nonalcoholic steatohepatitis (NASH)/Fibrosis 1520 Prospective Validation of the Mediterranean Diet Adherence Screener (MEDAS) for Point-of-care Assessment of Diet Quality in Patients with Metabolic Dysfunction-associated Steatotic Liver Disease For more information, including a complete list of abstract titles being presented at the meeting, please visit the AASLD website . In July 2023, the European Commission (EC) granted full Marketing Authorization (MA) for bulevirtide 2 mg for the treatment of adults with chronic HDV and compensated liver disease. Bulevirtide’s conditional MA license in Great Britain was converted to a full MA in August 2023 and a full MA was granted in Switzerland and Australia in 2024. In regions where it is not approved, including the U.S., bulevirtide 2 mg is an investigational product. In these regions, health authorities have not established the safety and efficacy of bulevirtide. Bulevirtide 10 mg is an investigational product and has not been approved anywhere. Cilofexor and selgantolimod are investigational compounds and are not approved by the FDA or any other regulatory authority; their safety and efficacy have not been established. Please see below for the U.S. Indications and Important Safety Information, including BOXED WARNINGS, for Epclusa and Livdelzi. U.S. Important Safety Information And Indication for EPCLUSA BOXED WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN HCV/HBV COINFECTED PATIENTS Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with EPCLUSA. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals (DAAs) and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported in patients who are HBsAg positive, in patients with serologic evidence of resolved HBV, and also in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV DAAs may be increased in patients taking these other agents. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated. Contraindications If EPCLUSA is used in combination with ribavirin (RBV), all contraindications, warnings and precautions, in particular pregnancy avoidance, and adverse reactions to RBV also apply. Refer to RBV prescribing information. Warnings and Precautions Serious Symptomatic Bradycardia When Coadministered with Amiodarone: Amiodarone is not recommended for use with EPCLUSA due to the risk of symptomatic bradycardia, particularly in patients also taking beta blockers or with underlying cardiac comorbidities and/or with advanced liver disease. A fatal cardiac arrest was reported in a patient taking amiodarone who was coadministered a sofosbuvir containing regimen. In patients without alternative, viable treatment options, cardiac monitoring is recommended. Patients should seek immediate medical evaluation if they develop signs or symptoms of bradycardia. Risk of Reduced Therapeutic Effect Due to Use with P-gp Inducers and/or Moderate to Strong Inducers of CYP2B6, CYP2C8 or CYP3A4 : Rifampin, St. John’s wort and carbamazepine are not recommended for use with EPCLUSA as they may significantly decrease sofosbuvir and/or velpatasvir plasma concentrations. Adverse Reactions The most common adverse reactions (≥10%, all grades) with EPCLUSA in adults and pediatric patients 6 years of age and older were headache and fatigue; and when used with RBV in adults with decompensated cirrhosis were fatigue, anemia, nausea, headache, insomnia and diarrhea. The most common adverse reactions (≥10%, grade 1 or 2) in pediatric patients less than 6 years of age were vomiting and spitting up the drug. Drug Interactions Coadministration of EPCLUSA is not recommended with topotecan due to increased concentrations of topotecan. Coadministration of EPCLUSA is not recommended with proton-pump inhibitors, phenobarbital, phenytoin, rifabutin, rifapentine, efavirenz, and tipranavir/ritonavir due to decreased concentrations of sofosbuvir and/or velpatasvir. Consult the full Prescribing Information for EPCLUSA for more information on potentially significant drug interactions, including clinical comments. Indication EPCLUSA is indicated for the treatment of adult and pediatric patients 3 years of age and older with chronic hepatitis C virus genotype 1, 2, 3, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis and in combination with ribavirin for those with decompensated cirrhosis. U.S. Important Safety Information for LIVDELZI Warnings and Precautions Fractures: Fractures occurred in 4% of LIVDELZI-treated patients compared to no placebo-treated patients. Consider the risk of fracture in the care of patients treated with LIVDELZI and monitor bone health according to current standards of care. Liver Test Abnormalities: LIVDELZI has been associated with dose-related increases in serum transaminase (AST and ALT) levels > 3 x ULN in patients receiving 50 mg and 200 mg once daily (5x and 20x higher than the recommended dosage of 10 mg once daily). Perform baseline clinical and laboratory testing when starting LIVDELZI and monitor thereafter according to routine patient management. Interrupt treatment if the liver tests (ALT, AST, total bilirubin, and/or ALP) worsen, or if the patient develops signs and symptoms of clinical hepatitis (eg, jaundice, right upper quadrant pain, eosinophilia). Consider permanent discontinuation if liver tests worsen after restarting LIVDELZI. Biliary Obstruction: Avoid use of LIVDELZI in patients with complete biliary obstruction. If biliary obstruction is suspected, interrupt LIVDELZI and treat as clinically indicated. Adverse Reactions The most common adverse reactions (≥5%) with LIVDELZI were headache (8%), abdominal pain (7%), nausea (6%), abdominal distension (6%), and dizziness (5%). Drug Interactions OAT3 Inhibitors and Strong CYP2C9 Inhibitors: Avoid coadministration with LIVDELZI due to increased LIVDELZI exposure. Rifampin: Monitor biochemical response (e.g., ALP and bilirubin) when patients initiate rifampin during LIVDELZI treatment. Coadministration may result in delayed or suboptimal biochemical response of LIVDELZI. Dual Moderate CYP2C9 and Moderate-to-Strong CYP3A4 Inhibitors and BCRP Inhibitors (eg, cyclosporine): Monitor closely for adverse effects. Concomitant administration with LIVDELZI may increase LIVDELZI exposure. CYP2C9 Poor Metabolizers Using Moderate-to-Strong CYP3A4 Inhibitors: Monitor more frequently for adverse reactions as concomitant use of a moderate-to-strong CYP3A4 inhibitor in patients who are CYP2C9 poor metabolizers may increase LIVDELZI exposure and risk of LIVDELZI adverse reactions. Bile Acid Sequestrants: Administer LIVDELZI at least 4 hours before or 4 hours after taking a bile acid sequestrant, or at as great an interval as possible. Pregnancy and Lactation Pregnancy: There are insufficient data from human pregnancies exposed to LIVDELZI to allow an assessment of a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Report pregnancies to Gilead Sciences, Inc., at 1-800-445-3235. Lactation: There are no data on the presence of LIVDELZI in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LIVDELZI and any potential adverse effects on the breastfed infant from LIVDELZI. Indication LIVDELZI is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who have an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA. This indication is approved under accelerated approval based on a reduction of ALP. Improvement in survival or prevention of liver decompensation events have not been demonstrated. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). Limitations of Use: Use of Livdelzi is not recommended in patients who have or develop decompensated cirrhosis (e.g., ascites, variceal bleeding, hepatic encephalopathy). About HDV HDV is considered the most aggressive or severe form of viral hepatitis, associated with more rapid progression towards liver-related death and liver cancer in people with HBV. On average, HDV progresses to cirrhosis within 5 years and to liver cancer within 10 years. Nearly 5% of people who have a chronic infection with HBV are estimated to have HDV, equating to 12-15 million people worldwide. The prevalence of HDV infection is largely underestimated due to lack of universal testing of HBV-positive individuals for HDV. About PBC PBC is a rare, chronic inflammatory liver disease primarily affecting women (1 in 1,000 women over the age of 40 or about 130,000 total people in the U.S.). PBC is characterized by impaired bile flow (known as cholestasis) and the accumulation of toxic bile acids in the liver, leading to inflammation and destruction of the bile ducts within the liver and causing increased levels of alkaline phosphatase (ALP), alanine transaminase (ALT) and gamma-glutamyl transferase (GGT), enzymes found primarily in the liver, as well as total bilirubin. The most common symptoms of PBC are pruritus and fatigue, which can be debilitating for some people. Progression of PBC is associated with an increased risk of liver-related mortality. About Gilead Sciences in Liver Disease For decades, Gilead has pioneered the way forward to improve the lives of people living with liver disease around the world. We have helped to transform hepatitis C from a chronic condition into one that can be cured for millions of people. For people living with hepatitis B or D, our focus on advancing our medicines drives hope that today’s research will turn into tomorrow’s cures. Beyond viral hepatitis, we’re working to deliver advanced treatments for people living with PBC. But our commitment doesn’t stop there. Through our ground-breaking science and collaborative partnerships, we strive to create healthier futures for everyone living with liver disease. We are committed to a future without liver disease. About Gilead Sciences Gilead Sciences, Inc. is a biopharmaceutical company that has pursued and achieved breakthroughs in medicine for more than three decades, with the goal of creating a healthier world for all people. The company is committed to advancing innovative medicines to prevent and treat life-threatening diseases, including HIV, viral hepatitis, COVID-19, cancer and inflammation. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, California. Forward-Looking Statements This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including Gilead’s ability to initiate, progress or complete clinical trials or studies within currently anticipated timelines or at all, and the possibility of unfavorable results from ongoing or additional clinical trials or studies, including those involving Epclusa, Hepcludex (bulevirtide), Livdelzi (seladelpar), cilofexor and selgantolimod (such as the ASSURE, RESPONSE, MYR301, STORC and SVR10K studies); uncertainties relating to regulatory applications and related filing and approval timelines, including the risk that the FDA and other regulatory authorities may not approve bulevirtide for the treatment of HDV, and the risk that any such approvals, if granted, may be subject to significant limitations on use or subject to withdrawal or other adverse actions by the applicable regulatory authority; the possibility that Gilead may make a strategic decision to discontinue development of investigational programs for indications that are currently under evaluation and, as a result, these programs may never be successfully commercialized for the indications currently under evaluation; and any assumptions underlying any of the foregoing. These and other risks, uncertainties and factors are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2024, as filed with the U.S. Securities and Exchange Commission. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. The reader is cautioned that any such forward-looking statements are not guarantees of future performance and involve risks and uncertainties and is cautioned not to place undue reliance on these forward-looking statements. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation and disclaims any intent to update any such forward-looking statements. Epclusa, Hepcludex, Livdelzi, Gilead and the Gilead logo are registered trademarks of Gilead Sciences, Inc., or its related companies. For more information about Gilead, please visit the company’s website at , follow Gilead on Twitter (@Gilead Sciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000. Contacts Meaghan Smith, Media public_affairs@gilead.com Jacquie Ross, Investors investor_relations@gilead.com

临床2期临床结果上市批准临床3期

100 项与依非韦伦相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
D00896	依非韦伦	J05AG03	DB00625

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适应症	国家/地区	公司	日期
HIV感染	美国	Bristol Myers Squibb Co.	1998-09-17

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适应症	最高研发状态	国家/地区	公司	日期
结核	临床3期	巴西	Merck Sharp & Dohme Corp.	2015-09-11
结核	临床3期	科特迪瓦	Merck Sharp & Dohme Corp.	2015-09-11
结核	临床3期	法国	Merck Sharp & Dohme Corp.	2015-09-11
结核	临床3期	莫桑比克	Merck Sharp & Dohme Corp.	2015-09-11
结核	临床3期	越南	Merck Sharp & Dohme Corp.	2015-09-11
合并感染	临床2期	-	Abbott Laboratories	2005-07-21
丙型肝炎	临床2期	-	Abbott Laboratories	2005-07-21
获得性免疫缺陷综合征	临床1期	美国	Bristol Myers Squibb Co.	2014-07-01
避孕	临床1期	美国	Bristol Myers Squibb Co.	2007-05-01
肝病	临床1期	美国	Bristol Myers Squibb Co.	2004-11-01

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02777229 (NAMSAL-ANRS-12313, Pubmed \| Open Forum Infect Dis)	临床3期	HIV感染一线	613	Dolutegravir (DTG) 50mg with Tenofovir disoproxil fumarate and Lamivudine (TDF/3TC)	窪願願醖顧獵願蓋獵襯(艱選鏇膚鏇網糧襯顧鏇) = 積膚鏇膚夢遞築簾衊膚顧膚齋艱構廠範餘積網 (繭鹽廠艱夢壓蓋繭製繭 ) 更多	积极	2023-12-01
				Efavirenz 400 mg (EFV400) with Tenofovir disoproxil fumarate and Lamivudine (TDF/3TC)	窪願願醖顧獵願蓋獵襯(艱選鏇膚鏇網糧襯顧鏇) = 鏇鑰鬱窪獵鑰製範廠積顧膚齋艱構廠範餘積網 (繭鹽廠艱夢壓蓋繭製繭 ) 更多
NCT02777229 (NAMSAL ANRS 12313, Pubmed)	临床3期	一线	613	Dolutegravir 50 mg (DTG)	選積窪鏇餘觸糧鏇艱膚(構餘構鬱鬱選餘鑰觸壓) = decreased from 7.2 to 3.0 餘遞膚淵遞鹽壓製窪繭 (簾顧壓鬱築簾顧艱壓艱 ) 更多	积极	2023-11-01
				Low-dose efavirenz (EFV400)
NCT04459598 (CTgov)	临床1期	药物相互作用	32	Efavirenz+Quizartinib (Efavirenz 600 mg + Quizartinib 60 mg)	製壓鑰遞糧繭構觸鏇鹹(糧鬱製製觸顧願範憲獵) = 簾窪壓選觸觸網繭網膚醖蓋廠積獵蓋網襯襯獵 (製齋憲觸鑰壓壓蓋膚範, 選觸積積醖願壓窪壓襯 ~ 憲簾膚獵築艱鏇壓夢顧) 更多	-	2022-06-06
				Quizartinib (Quizartinib 60 mg)	製壓鑰遞糧繭構觸鏇鹹(糧鬱製製觸顧願範憲獵) = 選顧壓製鑰糧鬱觸鑰鬱醖蓋廠積獵蓋網襯襯獵 (製齋憲觸鑰壓壓蓋膚範, 簾範醖餘廠壓夢鬱顧觸 ~ 築蓋夢鑰糧鹽餘艱鏇願) 更多
NCT00964002 (FAVE, CTgov)	临床2期	去势抵抗性前列腺癌 \| 转移性前列腺癌	61	efavirenz	鏇簾鏇壓鬱夢築鏇鏇顧(襯構製遞淵製膚襯蓋憲) = 鹽遞醖構遞構憲願顧餘網淵鹹願選壓窪蓋夢齋 (糧觸製齋衊觸網艱積製, 膚醖選齋簾製觸餘餘鑰 ~ 願鹹醖廠醖範築膚艱醖) 更多	-	2022-05-16
IAS2022	N/A	获得性免疫缺陷综合征	92	Efavirenz-based regimens	獵膚鏇範遞鏇壓淵窪簾(醖鑰淵糧網壓憲襯範構) = 網獵醖夢鑰淵網鬱範鬱淵夢範鏇憲構鹹壓繭壓 (餘積繭糧選夢觸窪蓋餘 ) 更多	-	2022-01-01
				Dolutegravir-based ART	獵膚鏇範遞鏇壓淵窪簾(醖鑰淵糧網壓憲襯範構) = 淵築淵夢遞願遞壓餘選淵夢範鏇憲構鹹壓繭壓 (餘積繭糧選夢觸窪蓋餘 ) 更多
NCT02273765 (Pubmed) 人工标引	临床3期	结核 \| HIV感染	460	Tenofovir Disoproxil Fumarate+lamivudine+raltegravir	蓋簾憲範觸積衊艱鑰憲(憲鹹願廠簾選壓廠製壓) = 淵艱繭蓋鹹獵醖艱壓淵築鏇繭醖遞憲壓鹹繭繭 (艱廠齋繭鹽夢襯窪鏇廠 ) 更多	不佳	2021-06-01
				Tenofovir Disoproxil Fumarate+lamivudine+efavirenz	蓋簾憲範觸積衊艱鑰憲(憲鹹願廠簾選壓廠製壓) = 繭範膚糧製遞觸齋艱廠築鏇繭醖遞憲壓鹹繭繭 (艱廠齋繭鹽夢襯窪鏇廠 ) 更多
NCT01878890 (ESCALE, CTgov)	临床1期	实体瘤 \| 非霍奇金淋巴瘤	25	Efavirenz 600mg (Efavirenz: 600 mg)	選壓積衊衊繭夢願遞壓(願遞鹹選艱淵製簾夢簾) = 鹽膚蓋鹽獵網願廠憲願衊醖衊鏇遞膚醖構壓選 (範遞廠艱壓網膚壓夢鬱, 齋獵願餘構積壓窪積鏇 ~ 積鹽鑰簾範範夢選醖鬱) 更多	-	2021-01-27
				Efavirenz 1200 mg (Efavirenz: 1200 mg)	選壓積衊衊繭夢願遞壓(願遞鹹選艱淵製簾夢簾) = 餘觸廠窪襯憲餘膚鏇積衊醖衊鏇遞膚醖構壓選 (範遞廠艱壓網膚壓夢鬱, 窪範蓋築膚襯鏇醖鹹顧 ~ 鹽壓夢淵獵範餘蓋鑰構) 更多
NCT02777229 (NAMSAL, Pubmed \| Lancet HIV)	临床3期	HIV感染	820	Dolutegravir 50 mg	鹽繭鏇選簾願夢築網築(襯艱繭製網鬱壓淵窪願) = 築積鹽獵獵願獵網網鑰膚齋衊糧餘窪壓鬱築廠 (衊夢艱窪膚鏇壓選鬱鹹 )	积极	2020-10-01
				Efavirenz 400 mg	鹽繭鏇選簾願夢築網築(襯艱繭製網鬱壓淵窪願) = 艱壓鏇膚鏇襯窪衊鹹齋膚齋衊糧餘窪壓鬱築廠 (衊夢艱窪膚鏇壓選鬱鹹 )
EASD2020	N/A	-	-	Palmitate	膚鹹衊蓋窪壓糧鹽鏇膚(夢願夢鬱構遞觸獵顧壓) = 網觸齋選窪艱鬱觸蓋顧壓選鬱鹹襯積襯餘夢鏇 (構窪範糧齋網艱簾構鑰, 0.07)	不佳	2020-09-24
				Efavirenz	膚鹹衊蓋窪壓糧鹽鏇膚(夢願夢鬱構遞觸獵顧壓) = 膚鬱夢簾鏇糧範築築選壓選鬱鹹襯積襯餘夢鏇 (構窪範糧齋網艱簾構鑰, 0.5)
IAS2020	N/A	-	271	TDF/3TC/DTG (TLD)	鏇夢鹽觸襯築蓋夢鬱鹽(憲製齋選衊糧構構簾鬱) = 獵鏇糧醖製蓋夢簾網鏇鏇鹽糧襯糧繭繭鏇簾顧 (觸膚膚餘鹹壓構衊廠鬱 )	-	2020-01-01
				TDF/3TC/EFV (TLE)	鏇夢鹽觸襯築蓋夢鬱鹽(憲製齋選衊糧構構簾鬱) = 鏇衊顧淵廠鬱築餘鏇襯鏇鹽糧襯糧繭繭鏇簾顧 (觸膚膚餘鹹壓構衊廠鬱 )