Zidovudine

2024年3月6日，吉利德和默沙东宣布其长效HIV口服组合疗法（Islatravir 和Lenacapavir）的积极结果，在24周时此组合疗法保持了高比率（94.2%）HIV患者的病毒抑制（HIV-1 RNA<50copies/ml），具有成为首款每周一次治疗HIV口服组合疗法的潜力。在此组合疗法中，Islatravir （MK-8591）和Lenacapavir（Sunlenca）分别是默沙东和吉利德研发的抗病毒药物，可在HIV病毒生命周期的不同阶段抑制HIV病毒。其中，默沙东的Islatravir属于核苷逆转录酶抑制剂，可在体内转化成活性的三磷酸核苷衍生物，通过抑制HIV逆转录酶的作用，达到阻碍病毒复制的作用。此前上市的HIV药物多为核苷逆转录酶抑制剂，其中包括齐多夫定、去羟肌苷、扎西他滨等。目前，Islatravir尚处于III临床研究阶段。吉利德的Lenacapavir是一种首创的长效HIV衣壳抑制剂，是全球唯一一款获批上市的每年给药2次的HIV治疗药物。2022年8月Lenacapavir被EMA批准上市，同年12月又被FDA批准上市，用于治疗因耐药性、不耐受或安全问题而无法完全抑制病毒的 HIV-1 患者。Islatravir 和Lenacapavir都是强效HIV药物，半衰期都很长。此次公布的试验结果表明，当两种药物结合在一起时，有明显的病毒抑制效果，或许有望成为HIV患者更好的治疗选择。这次在CROI上公布的II期临床试验，是一项随机、开放标签、活性对照研究（NCT05052996），将正在接受Biktarvy（B/F/TAF）治疗的成人患者随机分为两组，其中试验组（Islatravir 和Lenacapavir组）每周一次口服Islatravir 2mg+Lenacapavir300mg，对照组继续每日口服Biktarvy。先简单介绍一下对照组的药物Biktarvy。Biktarvy由吉利德研发，属于抗反转录病毒治疗（ART），由2种强效核苷类反转录酶抑制剂（NRTI）——恩曲他滨/丙酚替诺福韦（FTC/TAF）与第三代整合酶链转移抑制剂（INSTI）比克替拉韦（BIC）强强联合制成，这三种药品分别作用于HIV生命周期中的反转录和整合过程。Biktarvy于2018年被FDA批准上市，随后很快在中国香港和大陆获批上市。由于病毒抑制效果显著，Biktarvy成为国内外权威艾滋病指南推荐使用的药物，在不到两年的时间里成为全球处方量最大的抗艾滋病药物，销售额一路持续增长。吉利德2023年报披露，Biktarvy年营收达到118.5亿美元。此项II期临床试验的主要终点为24周时HIV患者的病毒抑制（HIV-1 RNA<50copies/ml）。研究结果显示，试验组出现一名受试者在服药的第24周时病毒载量超过50copies/ml，但该名受试者在第30周时表现出有效的病毒抑制；而对照组没有出现受试者病毒载量超过50copies/ml的情况。从次要终点，即第24周时表现出病毒抑制的患者个体比例来看，试验组和对照组均为94.2%，没有明显差异。从不良事件（TRAE）角度分析，对照组没有报告任何1级或2级TRAE，试验组出现的TRAE主要表现为口干和恶心，但两组受试者均未出现与研究药物相关的 3 级或 4 级 TRAE。根据两家公司官方消息，这项开放性标签研究将持续到第48周，相关数据将会在之后的会议上持续公布。相比于给吉利德带来百亿美元营收的Biktarvy，从当前公布的数据来看，新的口服组合疗法的主要优势还是体现在其更长的用药周期上。真实世界中，每天服药常会出现漏服和患者依从性差的问题，同时高频率服药这个行为本身也会增加患者身份暴露概率，更为长效的HIV药物一直是HIV患者的期盼。参考资料1.Groundbreaking Study Shows Promise of Simplified HIV Treatment in Battling AIDS Public Health Threat2.各公司官网封面图来源：123rf版权声明/免责声明本文为团队原创文章。本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。如有任何问题，请与我们联系。衷心感谢!药时代官方网站:www.drugtimes.cn联系方式:电话:13651980212微信:27674131邮箱:contact@drugtimes.cn当年利拉鲁肽没做到的，让司美格鲁肽实现了？这种疾病的治疗方案可能出现大变化！失意之后，这款MASH药物愈挫愈勇...百亿美元市场剧变！RSV疫苗或引起严重自免疾病？点击这里，欣赏更多精彩内容！

Retroviruses are viruses that multiply by incorporating their genes into the genome of a host cell. If the infected cell is a germ cell, the retrovirus can then be passed on to the next generation as an 'endogenous' retrovirus (ERV) and spread as part of the host genome in that host species. In vertebrates, ERVs are ubiquitous and sometimes make up 10 per cent of the host genome. However, most retrovirus integrations are very old, already degraded and therefore inactive -- their initial impact on host health has been minimized by millions of years of evolution. A research team has now discovered a recent case of retrovirus colonization in a rodent from New Guinea, the white-bellied mosaic-tailed rat. Retroviruses are viruses that multiply by incorporating their genes into the genome of a host cell. If the infected cell is a germ cell, the retrovirus can then be passed on to the next generation as an "endogenous" retrovirus (ERV) and spread as part of the host genome in that host species. In vertebrates, ERVs are ubiquitous and sometimes make up 10 per cent of the host genome. However, most retrovirus integrations are very old, already degraded and therefore inactive -- their initial impact on host health has been minimised by millions of years of evolution. A research team led by the Leibniz Institute for Zoo and Wildlife Research (Leibniz-IZW) has now discovered a recent case of retrovirus colonisation in a rodent from New Guinea, the white-bellied mosaic-tailed rat. In a paper in the scientific journal Proceedings of the National Academy of Sciences, they describe this new model of virus integration. The observations on this process will help to improve our understanding how retroviruses rewrite host genomes. Retroviruses, such as the pathogen responsible for AIDS (HIV-1), integrate into the genome of the host cells they infect during their life cycle. When this happens in the germline (egg cells or cells that produce sperm) of the host, the retrovirus can actually become a gene of the host itself. This process is apparently common, as up to 10 percent of the genomes of most vertebrates consist of the remnants of such ancient infections. One of the best studied models of this process is the koala retrovirus (KoRV), which is currently colonising the koala genome. "What happens to the virus and the host during this process of genome colonisation we do not know, as most such events occurred millions of years ago and we only see the leftover 'fossils' of the retrovirus," says Prof Alex Greenwood, head of the Leibniz-IZW Department of Wildlife Diseases. "Nor do we know what the host suffered health-wise during the infection process. The koala retrovirus (KoRV) is one of the few models of this process that occurs in real time and where we can observe the effects of genome colonisation on the host animal." There is now some evidence that KoRV-related viruses are circulating in rodents and bats in Papua New Guinea and Indonesia. A group led by Greenwood and Dr Saba Mottaghinia, former PhD student in Greenwood's department, analysed 278 samples from seven bat and one rodent family endemic to the Australo-Papua region (Australia and New Guinea). They discovered a retrovirus that is currently colonising the genome of an endemic rodent from New Guinea, the white-bellied mosaic-tailed rat (Melomys leucogaster). This is only the second example from the Australo-Papuan region, after KoRV, of a retrovirus that has colonised a genome while retaining a functional viral life cycle. The gibbon ape leukaemia viruses (GALV), a group of viruses discovered in gibbons and woolly monkeys at a research facility in Thailand in the 1960s, are very closely related to KoRV. This is a curious and surprising relationship, as there is a geographical barrier, known as the Wallace lineage, which separates the fauna of Southeast Asia from Indonesia, Papua New Guinea and Australia's fauna. However, there is evidence that the gibbons and woolly monkeys at the research facility in Thailand have been infected with viruses from Papua New Guinea. "The discovery of GALV-like viruses in rodents and bats in Indonesian and Australian rodents and bats from New Guinea suggests that these viruses, and possibly also KoRV, originated in New Guinea," says Greenwood, who initiated the research project funded by the German Research Foundation. The Leibniz-IZW team, together with scientists from the Charité, the Robert Koch Institute, the Max Delbrück Center, the University of Nicosia, California State University Fullerton, the South Australian Museum and Museum Victoria, examined 278 bat and rodent samples from Australia and New Guinea for KoRV and GALV-like viruses. They detected a GALV, the Woolly Monkey Virus (WMV) in a population of the white-bellied mosaic-tailed rat, an endemic rodent from New Guinea. In five of the rats from two New Guinea collection sites, WMV was integrated into the genome at the same location, indicating that it has spread as a gene and not by infection, i.e. it has become part of the genome. However, in other white-bellied mosaic-tailed rat populations the virus was absent -- similar to KoRV in koalas, where all koalas in northern Australia have KoRV in their genome, whereas there are koalas in southern Australia that do not have intact KoRV. The virus, now called the "complete Melomys woolly monkey virus" (cMWMV), was able to infect cell lines, produce new viral progeny, was visible by electron microscopy as viral particles that detached from the cell membrane, and was even sensitive to the antiretroviral drug AZT. "The virus has all the characteristics of an exogenous infectious retrovirus, but is endogenous. It is probably a very recent colonisation event, much younger than KoRV," says Dr Saba Mottaghinia, the lead author of the paper in the Proceedings of the National Academy of Sciences. The results suggest that cMWMV is a new model for retroviral colonisation of the host genome that occurs in real time, as in KoRV, and they also suggest that GALVs like WMV originated in the diverse fauna of New Guinea. The discoveries in New Guinea have certainly not been exhausted. "There are hundreds of mammalian species from this region that have not yet been studied, suggesting that many more viruses and models exist in this region," says Greenwood. The authors dedicate the study to Ken P. Aplin of the South Australian Museum, who sadly passed away during the course of the project.