Jarvis B, Faulds D
Adis International Limited, Auckland, New Zealand.
Drugs. 1998 Jul;56(1):147-67. doi: 10.2165/00003495-199856010-00013.
Nelfinavir is a selective inhibitor of HIV protease, the enzyme responsible for post-translational processing of HIV propeptides. In the presence of the drug, immature, noninfectious virus particles are produced. Nelfinavir in combination with nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors and/or other protease inhibitors profoundly suppresses viral replication. Plasma HIV RNA levels (viral loan) rapidly fall below the limit of detection (LOD; usually 400 or 500 copies/ml in the majority of patients. When used in combination with NRTIs, nelfinavir 1250mg twice daily produced similar results to 3-times-daily nelfinavir at a range of total daily dosages. In an ongoing study > 70% of adults receiving a nelfinavir based combination regimen had plasma HIV RNA levels below the LOD (< 400 copies/ml) after 84 weeks. In addition, 73% of paediatric patients receiving nelfinavir plus at least 1 new NRTI had viral loads below the LOD (< 400 copies/ml) after 34 weeks. Furthermore, CD4+ cell counts generally increased in conjunction with reductions in viral load. Combination therapy with nelfinavir and saquinavir results in higher saquinavir plasma concentrations, make twice-daily administration of saquinavir feasible and may delay the emergence of resistant viral strains. A unique mutation at codon 30 (D30N) of the protease gene confers resistance to nelfinavir, but HIV with D30N mutation remains fully susceptible to indinavir, ritonavir and saquinavir in vitro. Nonetheless, in clinical use, significant cross-resistance is seen with all currently available protease inhibitors. Diarrhoea is the most frequently reported adverse event in patients receiving nelfinavir-based combination therapy and has been reported in up to 32% of nelfinavir recipients in randomised trials. Diarrhoea is generally of mild to moderate severity and does not result in weight loss. Rash, nausea, headache and asthenia were each reported in < or = 5% of patients. Approximately 5% of patients enrolled in an expanded access programme in the US discontinued nelfinavir because of adverse events. Nelfinavir is metabolised by the cytochrome P450 system. Several clinically significant pharmacokinetic drug interactions between nelfinavir and other drugs (i.e. ketoconazole, rifabutin, rifabutin, rifampicin), including other protease inhibitors (i.e. indinavir, ritonavir, saquinavir) have been documented. As with other available protease inhibitors, hyperglycaemia, hyperlipidaemia and abnormal fat distribution have been reported, albeit infrequently, in association with nelfinavir.
Nelfinavir-based combination regimens are well tolerated and produce profound and prolonged suppression of HIV replication in adult and paediatric patients. Hence, nelfinavir is suitable for inclusion in antiretroviral regimens for initial therapy for HIV infection and, alternatively, in regimens for patients unable to tolerate other protease inhibitors.
奈非那韦是一种HIV蛋白酶的选择性抑制剂，HIV蛋白酶是负责HIV前体肽翻译后加工的酶。在药物存在的情况下，会产生未成熟的、无感染性的病毒颗粒。奈非那韦与核苷类逆转录酶抑制剂（NRTIs）、非核苷类逆转录酶抑制剂和/或其他蛋白酶抑制剂联合使用，可显著抑制病毒复制。血浆HIV RNA水平（病毒载量）迅速降至检测下限（LOD；大多数患者通常为400或500拷贝/毫升）以下。当与NRTIs联合使用时，奈非那韦每日两次1250毫克在一系列总日剂量下产生的结果与奈非那韦每日三次相似。在一项正在进行的研究中，超过70%接受基于奈非那韦的联合治疗方案的成年人在84周后血浆HIV RNA水平低于LOD（<400拷贝/毫升）。此外，73%接受奈非那韦加至少1种新NRTI的儿科患者在34周后病毒载量低于LOD（<400拷贝/毫升）。此外，CD4+细胞计数通常随着病毒载量的降低而增加。奈非那韦和沙奎那韦联合治疗可使沙奎那韦血浆浓度升高，使沙奎那韦每日两次给药可行，并可能延缓耐药病毒株的出现。蛋白酶基因第30位密码子（D30N）的独特突变赋予对奈非那韦的耐药性，但带有D30N突变的HIV在体外对茚地那韦、利托那韦和沙奎那韦仍完全敏感。尽管如此，在临床应用中，与所有目前可用的蛋白酶抑制剂均可见明显的交叉耐药性。腹泻是接受基于奈非那韦的联合治疗的患者中最常报告的不良事件，在随机试验中，高达32%的奈非那韦接受者报告有腹泻。腹泻一般为轻度至中度，不会导致体重减轻。皮疹、恶心、头痛和乏力在≤5%的患者中均有报告。在美国一项扩大使用计划中，约5%的患者因不良事件停用了奈非那韦。奈非那韦通过细胞色素P450系统代谢。已记录到奈非那韦与其他药物（即酮康唑、利福布汀、利福布汀、利福平）之间存在几种具有临床意义的药代动力学药物相互作用，包括其他蛋白酶抑制剂（即茚地那韦、利托那韦、沙奎那韦）。与其他可用的蛋白酶抑制剂一样，与奈非那韦相关的高血糖、高脂血症和脂肪分布异常虽报告较少，但也有发生。
基于奈非那韦的联合治疗方案耐受性良好，可在成人和儿科患者中对HIV复制产生深刻且持久的抑制作用。因此，奈非那韦适用于纳入抗逆转录病毒治疗方案，用于HIV感染的初始治疗，或者用于不能耐受其他蛋白酶抑制剂的患者的治疗方案。
