Long-acting drugs and formulations for the treatment and prevention of HIV infection.
Long-acting drugs and formulations for the treatment and prevention of HIV infection.
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DOI：
10.1016/j.ijantimicag.2020.106220
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发表时间：
2021-01
影响因子：
10.8
通讯作者：
Swindells S
中科院分区：
文献类型：
--
作者：
Flexner C;Owen A;Siccardi M;Swindells S
长效和缓释制剂代表了改善慢性HIV感染的治疗和预防的最重要方法之一。长效小分子和单克隆抗体已在早期和晚期临床试验中显示出有效的抗HIV活性。在漏服剂量后管理毒性和药物浓度下降的策略，以及对当前药物和单克隆抗体的原发性和继发性耐药性是重要的考虑因素。整合酶抑制剂卡替拉韦和非核苷类逆转录酶抑制剂利匹韦林的长效可注射纳米制剂在大型随机III期研究中安全、耐受性良好且有效。这种用于HIV维持治疗的2种药物组合于2020年在加拿大获得监管批准，预计将于2021年在美国获得批准。4′-乙炔基-2-氟-2 ′-脱氧腺苷（islatravir）是一种新型核苷类逆转录酶抑制剂，作为长效口服药物和长效皮下植入剂正在临床开发中。GS-6207是一种新型HIV衣壳抑制剂，每3个月皮下注射一次。广泛中和的单克隆抗体在早期人体试验中具有有效的抗病毒活性;然而，存在大量的基线耐药性，并且如果用作单药治疗，则对这些抗体的耐药性迅速发展。这些抗逆转录病毒方法的局限性包括毒性的管理，以及当这些药物停止使用并且药物浓度随时间缓慢降低时防止耐药性。这些方法似乎对抱怨药丸疲劳的患者和那些经历艾滋病毒相关耻辱的患者特别有吸引力。由于这些制剂被证明是安全的，耐受性良好，经济的，他们可能会获得更广泛的吸引力。
Long acting and extended-release formulations represent one of the most important approaches to improving the treatment and prevention of chronic HIV infection. Long acting small molecules and monoclonal antibodies have demonstrated potent anti-HIV activity in early and late stage clinical trials. Strategies to manage toxicities and falling drug concentrations after missed doses, as well as primary and secondary resistance to current drugs and monoclonal antibodies are important considerations. Long-acting injectable nanoformulations of the integrase inhibitor carbotegravir and the nonnucleoside reverse transcriptase inhibitor rilpivirine were safe, well tolerated, and efficacious in large randomized Phase 3 studies. Regulatory approval for this 2-drug combination for HIV maintenance therapy was granted in Canada in 2020 and is expected in the U.S. during 2021. 4′-ethynyl-2-fluoro-2′-deoxyadenosine (islatravir) is a novel nucleoside reverse transcriptase inhibitor in clinical development as a long acting oral drug and as a long-acting subcutaneous polymer implant. GS-6207 is a novel HIV capsid inhibitor that is injected subcutaneously every 3 months. Broadly neutralizing monoclonal antibodies have potent antiviral activity in early human trials; however, there is substantial baseline resistance, and rapid development of resistance to these antibodies if used as monotherapy. Limitations of these antiretroviral approaches include the management of toxicities, and prevention of drug resistance when these drugs are discontinued and drug concentrations are slowly reduced over time. These approaches appear to be especially attractive for patients complaining of pill fatigue, and for those experiencing HIV-associated stigma. As these formulations are shown to be safe, well-tolerated, and economical, they are likely to gain broader appeal.
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影响因子：
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