Singh Kamal, Sarafianos Stefan G, Sönnerborg Anders
Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65211, USA.
Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA.
Pharmaceuticals (Basel). 2019 Apr 20;12(2):62. doi: 10.3390/ph12020062.
One of the major factors contributing to HIV-1 drug resistance is suboptimal adherence to combination antiretroviral therapy (cART). Currently, recommended cART for HIV-1 treatment is a three-drug combination, whereas the pre-exposure prophylaxis (PrEP) regimens consist of one or two antivirals. Treatment regimens require adherence to a once or twice (in a subset of patients) daily dose. Long-acting formulations such as injections administered monthly could improve adherence and convenience, and thereby have potential to enhance the chances of expected outcomes, although long-lasting drug concentrations can also contribute to clinical issues like adverse events and development of drug resistance. Globally, two long-acting antivirals have been approved, and fifteen are in clinical trials. More than half of investigational long-acting antivirals target HIV-1 reverse transcriptase (HIV-1 RT) and/or integrase (HIV-1 IN). Here, we discuss the status and potential of long-acting inhibitors, including rilpivirine (RPV), dapivirine (DPV), and 4-ethynyl-2-fluoro-2-deoxyadenosine (EFdA; also known as MK-8591), which target RT, and cabotegravir (CAB), which targets IN. The outcomes of various clinical trials appear quite satisfactory, and the future of long-acting HIV-1 regimens appears bright.
导致HIV-1耐药性的主要因素之一是对抗逆转录病毒联合疗法（cART）的依从性欠佳。目前，推荐用于HIV-1治疗的cART是一种三联药物组合，而暴露前预防（PrEP）方案则由一种或两种抗病毒药物组成。治疗方案要求患者坚持每日一次或两次（部分患者）服药。长效制剂，如每月注射一次的药物，可提高依从性和便利性，从而有可能增加实现预期疗效的机会，不过药物浓度长期维持也可能引发不良事件和耐药性等临床问题。在全球范围内，已有两种长效抗病毒药物获批，还有15种正在进行临床试验。超过半数的长效抗病毒药物研究针对HIV-1逆转录酶（HIV-1 RT）和/或整合酶（HIV-1 IN）。在此，我们讨论长效抑制剂的现状和潜力，包括靶向RT的利匹韦林（RPV）、达匹韦林（DPV）和4-乙炔基-2-氟-2-脱氧腺苷（EFdA，也称为MK-8591），以及靶向IN的卡博特韦（CAB）。各项临床试验的结果看起来颇为令人满意，长效HIV-1治疗方案的前景似乎一片光明。
