HIV fusion inhibitors are promising therapeutic agents for AIDS treatment. One fusion inhibitor has been approved as anti-HIV drug, while more of them are in preclinical studies or clinical trials. Highly active fusio...HIV fusion inhibitors are promising therapeutic agents for AIDS treatment. One fusion inhibitor has been approved as anti-HIV drug, while more of them are in preclinical studies or clinical trials. Highly active fusion inhibitors with excellent pharmacokinetic properties are still needed for development of anti-HIV drugs. We found that all-hydrocarbon staples inserted in SC34 EK could not only enhance the inhibitory activity of inhibitors against HIV-1, but also improve protease resistance. Further study revealed that SC34 EK-1 containing a staple was a potent fusion inhibitor with IC;value of 0.04-6.4 nmol/L towards diverse HIV-1 subtypes and half-life value of 112 min against protease hydrolysis. X-ray crystallography studies indicated that introduction of a hydrocarbon staple in SC34 EK could make the amino acid at the interaction surface form perfect conformation to promote inhibitor peptide interacting with target.展开更多
目的系统评价我国HIV/AIDS患者整合酶抑制剂耐药情况。方法从PubMed、Web of Science、Embase、Cochrane Library、中国知网、万方和维普等数据库检索有关HIV/AIDS患者整合酶抑制剂耐药的研究,对符合纳入条件的文献进行质量评价,提取原...目的系统评价我国HIV/AIDS患者整合酶抑制剂耐药情况。方法从PubMed、Web of Science、Embase、Cochrane Library、中国知网、万方和维普等数据库检索有关HIV/AIDS患者整合酶抑制剂耐药的研究,对符合纳入条件的文献进行质量评价,提取原始数据,根据异质性结果选择相应模型进行Meta分析。结果共纳入36项研究,包括15702例研究对象,HIV/AIDS患者整合酶抑制剂整体耐药率为1.3%(95%CI:1.1~1.6)。亚组分析,CRF_01AE、B和CRF07_BC亚型耐药率分别为0.7%(95%CI:0.1~1.2)、1.2%(95%CI:0.6~1.7)和2.5%(95%CI:0.0~4.9);同性性传播人群耐药率为1.3%(95%CI:1.0~1.9),异性性传播人群耐药率为0.9%(95%CI:0.2~1.5);2015-2019年和2020-2022年耐药率均为1.4%。本研究共发现157个整合酶抑制剂耐药突变位点,以E157Q、E138A/K/T和Q148R/H为主,占比分别为21.0%、16.6%和10.2%。结论我国HIV/AIDS患者整合酶抑制剂耐药率处于低水平,CRF07_BC亚型及同性性传播人群耐药率较高。随着整合酶抑制剂药物的应用,应加强耐药监测,为优化治疗方案提供参考。展开更多
Background:Albuvirtide is a once-weekly injectable human immunodeficiency virus(HIV)-1 fusion inhibitor.We present interim data for a phase 3 trial assessing the safety and efficacy of albuvirtide plus lopinavir-riton...Background:Albuvirtide is a once-weekly injectable human immunodeficiency virus(HIV)-1 fusion inhibitor.We present interim data for a phase 3 trial assessing the safety and efficacy of albuvirtide plus lopinavir-ritonavir in HIV-1-infected adults already treated with antiretroviral drugs.Methods:We carried out a 48-week,randomized,controlled,open-label non-inferiority trial at 12 sites in China.Adults on the World Health Organization(WHO)-recommended first-line treatment for>6 months with a plasma viral load>1000 copies/mL were enrolled and randomly assigned(1:1)to receive albuvirtide(once weekly)plus ritonavir-boosted lopinavir(ABT group)or the WHO-recommended second-line treatment(NRTI group).The primary endpoint was the proportion of patients with a plasma viral load below 50 copies/mL at 48 weeks.Non-inferiority was prespecified with a margin of 12%.Results:At the time of analysis,week 24 data were available for 83 and 92 patients,and week 48 data were available for 46 and 50 patients in the albuvirtide and NRTI groups,respectively.At 48 weeks,80.4%of patients in the ABT group and 66.0%of those in the NRTI group had HIV-1 RNA levels below 50 copies/mL,meeting the criteria for non-inferiority.For the per-protocol population,the superiority of albuvirtide over NRTI was demonstrated.The frequency of grade 3 to 4 adverse events was similar in the two groups;the most common adverse events were diarrhea,upper respiratory tract infections,and grade 3 to 4 increases in triglyceride concentration.Renal function was significantly more impaired at 12 weeks in the patients of the NRTI group who received tenofovir disoproxil fumarate than in those of the ABT group.Conclusions:The TALENT study is the first phase 3 trial of an injectable long-acting HIV drug.This interim analysis indicates that once-weekly albuvirtide in combination with ritonavir-boosted lopinavir is well tolerated and non-inferior to the WHO-recommended second-line regimen in patients with first-line treatment failure.Trial registration:ClinicalTrials.gov Identifier:NCT02369965;https://www.clinicaltrials.gov.Chinese Clinical Trial Registry No.ChiCTR-TRC-14004276;http://www.chictr.org.cn/enindex.aspx.展开更多
基金supported by the National Natural Science Foundation of China (No. 21602121)the Natural Science Foundation of Inner Mongolia (No. 2016BS0201)+2 种基金the Inner Mongolia Autonomous Region Higher School Youth scientific Talents Support Project(No. NJYT-17-B22)the Research Funds of Baotou Medical College(Nos. BSJJ201620, BYJJ-YF 201707)Beijing Tongzhou District Science and Technology Project(No. KJ2017CX039-14)
文摘HIV fusion inhibitors are promising therapeutic agents for AIDS treatment. One fusion inhibitor has been approved as anti-HIV drug, while more of them are in preclinical studies or clinical trials. Highly active fusion inhibitors with excellent pharmacokinetic properties are still needed for development of anti-HIV drugs. We found that all-hydrocarbon staples inserted in SC34 EK could not only enhance the inhibitory activity of inhibitors against HIV-1, but also improve protease resistance. Further study revealed that SC34 EK-1 containing a staple was a potent fusion inhibitor with IC;value of 0.04-6.4 nmol/L towards diverse HIV-1 subtypes and half-life value of 112 min against protease hydrolysis. X-ray crystallography studies indicated that introduction of a hydrocarbon staple in SC34 EK could make the amino acid at the interaction surface form perfect conformation to promote inhibitor peptide interacting with target.
文摘目的系统评价我国HIV/AIDS患者整合酶抑制剂耐药情况。方法从PubMed、Web of Science、Embase、Cochrane Library、中国知网、万方和维普等数据库检索有关HIV/AIDS患者整合酶抑制剂耐药的研究,对符合纳入条件的文献进行质量评价,提取原始数据,根据异质性结果选择相应模型进行Meta分析。结果共纳入36项研究,包括15702例研究对象,HIV/AIDS患者整合酶抑制剂整体耐药率为1.3%(95%CI:1.1~1.6)。亚组分析,CRF_01AE、B和CRF07_BC亚型耐药率分别为0.7%(95%CI:0.1~1.2)、1.2%(95%CI:0.6~1.7)和2.5%(95%CI:0.0~4.9);同性性传播人群耐药率为1.3%(95%CI:1.0~1.9),异性性传播人群耐药率为0.9%(95%CI:0.2~1.5);2015-2019年和2020-2022年耐药率均为1.4%。本研究共发现157个整合酶抑制剂耐药突变位点,以E157Q、E138A/K/T和Q148R/H为主,占比分别为21.0%、16.6%和10.2%。结论我国HIV/AIDS患者整合酶抑制剂耐药率处于低水平,CRF07_BC亚型及同性性传播人群耐药率较高。随着整合酶抑制剂药物的应用,应加强耐药监测,为优化治疗方案提供参考。
基金Frontier Biotechnologies Inc.,Ministry of Science and Technology of China(Nos.2013ZX09101001 and 2017ZX09201007)the Beijing Municipal of Science and Technology Major Project(Nos.D141100000314005,D141100000314002,and D161100000416003)+1 种基金the National Natural Science Foundation of China(Nos.81772165,81974303,and 81571973)Beijing Key Laboratory for HIV/AIDS Research(No.BZ0089)。
文摘Background:Albuvirtide is a once-weekly injectable human immunodeficiency virus(HIV)-1 fusion inhibitor.We present interim data for a phase 3 trial assessing the safety and efficacy of albuvirtide plus lopinavir-ritonavir in HIV-1-infected adults already treated with antiretroviral drugs.Methods:We carried out a 48-week,randomized,controlled,open-label non-inferiority trial at 12 sites in China.Adults on the World Health Organization(WHO)-recommended first-line treatment for>6 months with a plasma viral load>1000 copies/mL were enrolled and randomly assigned(1:1)to receive albuvirtide(once weekly)plus ritonavir-boosted lopinavir(ABT group)or the WHO-recommended second-line treatment(NRTI group).The primary endpoint was the proportion of patients with a plasma viral load below 50 copies/mL at 48 weeks.Non-inferiority was prespecified with a margin of 12%.Results:At the time of analysis,week 24 data were available for 83 and 92 patients,and week 48 data were available for 46 and 50 patients in the albuvirtide and NRTI groups,respectively.At 48 weeks,80.4%of patients in the ABT group and 66.0%of those in the NRTI group had HIV-1 RNA levels below 50 copies/mL,meeting the criteria for non-inferiority.For the per-protocol population,the superiority of albuvirtide over NRTI was demonstrated.The frequency of grade 3 to 4 adverse events was similar in the two groups;the most common adverse events were diarrhea,upper respiratory tract infections,and grade 3 to 4 increases in triglyceride concentration.Renal function was significantly more impaired at 12 weeks in the patients of the NRTI group who received tenofovir disoproxil fumarate than in those of the ABT group.Conclusions:The TALENT study is the first phase 3 trial of an injectable long-acting HIV drug.This interim analysis indicates that once-weekly albuvirtide in combination with ritonavir-boosted lopinavir is well tolerated and non-inferior to the WHO-recommended second-line regimen in patients with first-line treatment failure.Trial registration:ClinicalTrials.gov Identifier:NCT02369965;https://www.clinicaltrials.gov.Chinese Clinical Trial Registry No.ChiCTR-TRC-14004276;http://www.chictr.org.cn/enindex.aspx.
