HIV蛋白酶抑制剂的临床应用进展

中国临床药理学与治疗学 ›› 2014, Vol. 19 ›› Issue (10): 1171-1176.

HIV蛋白酶抑制剂的临床应用进展

王昀¹, 江振洲^{1, 2}, 张陆勇^{1, 3}

¹ 江苏省新药筛选中心,中国药科大学,南京 210009,江苏;
² 药物质量与安全预警教育部重点实验室,中国药科大学,南京 210009,江苏;
³ 江苏省药效研究与评价服务中心,中国药科大学,南京 210009,江苏

收稿日期:2013-04-22 修回日期:2014-08-20 出版日期:2014-10-26 发布日期:2014-10-29
通讯作者: 张陆勇,男,教授,博士生导师,研究方向:分子毒理学和肝病研究。E-mail: lyzhang@cpu.edu.cn
作者简介:王昀,女,在读博士,研究方向:分子毒理学。E-mail: gre0602@163.com

Progress in clinical application of HIV protease inhibitors in antiretroviral therapy

WANG Yun¹, JIANG Zhen-zhou^{1, 2}, ZHANG Lu-yong^{1, 3}

¹ Jiangsu Centre for Drug Screening, China Pharmaceutical University, Nanjing 210009, Jiangsu, China;
² Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Nanjing 210009, Jiangsu,China;
³ Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, Jiangsu,China

Received:2013-04-22 Revised:2014-08-20 Online:2014-10-26 Published:2014-10-29

摘要/Abstract

摘要： 自从1996年蛋白酶抑制剂(PI)被使用到高效抗逆转录病毒治疗(HAART)中以来,HIV携带者的发病率和艾滋病患者的死亡率被大大降低。至今经美国FDA批准上市的蛋白酶抑制剂已有11种,其中多种药物被列为美国和欧洲HIV治疗指南的一线治疗方案。然而我国在这方面的报道还不足,因此,本文对HAART,蛋白酶抑制剂的发展史和海外临床应用现状作一综述。

关键词: 艾滋病, HIV, 抗逆转录病毒治疗, 蛋白酶抑制剂

Abstract: The introduction of protease inhibitors (PIs) to highly active antiretroviral therapy (HAART) in 1996 has significantly reduced morbidity and mortality due to HIV infection. Up until now, 11 PIs have been approved by US FDA with several boosted PI regimens recognized as first-line regimens in antiretroviral therapy according to current guidelines. However, reports on HIV PI regimens and their clinical applications are limited in China. Thus, this article will review the history of HAART, the development of PIs and current considerations of PI-based therapy abroad.

Key words: AIDS, HIV, antiretroviral therapy, protease inhibitor

中图分类号:

R978.7

王昀, 江振洲, 张陆勇. HIV蛋白酶抑制剂的临床应用进展[J]. 中国临床药理学与治疗学, 2014, 19(10): 1171-1176.

WANG Yun, JIANG Zhen-zhou, ZHANG Lu-yong. Progress in clinical application of HIV protease inhibitors in antiretroviral therapy[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2014, 19(10): 1171-1176.

参考文献 36

[1]	Joint United Nations Programme on HIV/AIDS (UNAIDS). Global report: UNAIDS report on the global AIDS epidemic2012[S].
[2]	Fischl MA, Richman DD, Grieco MH, et al.The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial[J]. N Engl J Med, 1987, 317(4): 185-191.
[3]	Hammer SM, Katzenstein DA, Hughes MD, et al.A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. AIDS Clinical Trials Group Study 175 Study Team[J]. N Engl J Med, 1996, 335(15): 1081-1090.
[4]	Hammer SM, Squires KE, Hughes MD, et al.A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team[J]. N Engl J Med, 1997, 337(11): 725-733.
[5]	Gulick RM, Mellors JW, Havlir D, et al.Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy[J]. N Engl J Med, 1997, 337(11): 734-739.
[6]	Palella FJ, Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators[J]. N Engl J Med, 1998, 338(13): 853-860.
[7]	US Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. (29 Jan2013, date last accessed).
[8]	Abdel-Rahman HM, Al-karamany GS, El-Koussi NA, et al. HIV protease inhibitors: peptidomimetic drugs and future perspectives[J]. Curr Med Chem, 2002, 9(21): 1905-1922.
[9]	Mathez D, Bagnarelli P, Gorin I, et al.Reductions in viral load and increases in T lymphocyte numbers in treatment-naive patients with advanced HIV-1 infection treated with ritonavir, zidovudine and zalcitabine triple therapy[J]. Antivir Ther, 1997, 2(3): 175-183.
[10]	Cameron DW, Heath-Chiozzi M, Danner S, et al.Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. The Advanced HIV Disease Ritonavir Study Group[J]. Lancet, 1998, 351(9102): 543-549.
[11]	Cuzin L, Allavena C, Morlat P, et al.Boosted protease inhibitor-based or nonnucleoside reverse transcriptase-based HAART: is there a best choice for antiretroviral-naive HIV-1 infected patients[J]? AIDS Rev, 2008, 10(4): 205-211.
[12]	Naggie S,Hicks C.Protease inhibitor-based antiretroviral therapy in treatment-naive HIV-1-infected patients: the evidence behind the options[J]. J Antimicrob Chemother, 2010, 65(6): 1094-1099.
[13]	Walmsley S, Bernstein B, King M, et al.Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection[J]. N Engl J Med, 2002, 346(26): 2039-2046.
[14]	Murphy RL, da Silva BA, Hicks CB, et al. Seven-year efficacy of a lopinavir/ritonavir-based regimen in antiretroviral-naive HIV-1-infected patients[J]. HIV Clin Trials, 2008, 9(1): 1-10.
[15]	Eron J Jr, Yeni P, Gathe J Jr, et al.The KLEAN study of fosamprenavir-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV infection over 48 weeks: a randomised non-inferiority trial[J]. Lancet, 2006, 368(9534): 476-482.
[16]	Ortiz R, Dejesus E, Khanlou H, et al.Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48[J]. AIDS, 2008, 22(12): 1389-1397.
[17]	Molina JM, Andrade-Villanueva J, Echevarria J, et al.Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study[J]. Lancet, 2008, 372(9639): 646-655.
[18]	Staszewski S, Morales-Ramirez J, Tashima KT, et al.Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team[J]. N Engl J Med, 1999, 341(25): 1865-1873.
[19]	van Leeuwen R, Katlama C, Murphy RL, et al. A randomized trial to study first-line combination therapy with or without a protease inhibitor in HIV-1-infected patients[J]. AIDS, 2003, 17(7): 987-999.
[20]	Friedl AC, Ledergerber B, Flepp M, et al.Response to first protease inhibitor- and efavirenz-containing antiretroviral combination therapy. The Swiss HIV Cohort Study[J]. AIDS, 2001, 15(14): 1793-1800.
[21]	Riddler SA, Haubrich R, DiRienzo AG, et al. Class-sparing regimens for initial treatment of HIV-1 infection[J]. N Engl J Med, 2008, 358(20): 2095-2106.
[22]	Hirsch MS, Gunthard HF, Schapiro JM, et al.Antiretroviral drug resistance testing in adult HIV-1 infection: 2008 recommendations of an International AIDS Society-USA panel[J]. Clin Infect Dis, 2008, 47(2): 266-285.
[23]	Haubrich RH, Riddler SA, DiRienzo AG, et al. Metabolic outcomes in a randomized trial of nucleoside, nonnucleoside and protease inhibitor-sparing regimens for initial HIV treatment[J]. AIDS, 2009, 23(9): 1109-1118.
[24]	Pulido F, Matarranz M, Rodriguez-Rivera V, et al.Boosted protease inhibitor monotherapy. What have we learnt after seven years of research[J]? AIDS Rev, 2010, 12(3): 127-134.
[25]	Delfraissy JF, Flandre P, Delaugerre C, et al.Lopinavir/ritonavir monotherapy or plus zidovudine and lamivudine in antiretroviral-naive HIV-infected patients[J]. AIDS, 2008, 22(3): 385-393.
[26]	Clumeck N, Pozniak A, Raffi F, et al.European AIDS Clinical Society (EACS) guidelines for the clinical management and treatment of HIV-infected adults[J]. HIV Med, 2008, 9(2): 65-71.
[27]	Stephan C.Virological efficacy and safety of antiretroviral therapy-switch to atazanavir-based regimen: a review of the literature[J]. Expert Opin Pharmacother, 2012, 13(16): 2355-2367.
[28]	龙亚秋. 艾滋病治疗药物的研究进展[J]. 药学服务与研究, 2007, 7(6):401-407.
[29]	Ruela Correa JC, D'Arcy DM, dos Reis Serra CH, et al. Darunavir: a critical review of its properties, use and drug interactions[J]. Pharmacology, 2012, 90(1/2): 102-109.
[30]	Squires KE, Young B, DeJesus E, et al. ARIES 144 week results: durable virologic suppression in HIV-infected patients simplified to unboosted atazanavir/abacavir/lamivudine[J]. HIV Clin Trials, 2012, 13(5): 233-244.
[31]	Orkin C, DeJesus E, Khanlou H, et al. Final 192-Week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naive patients in the ARTEMIS trial[J]. HIV Med, 2013, 14(1): 49-59.
[32]	Aberg JA, Tebas P, Overton ET,et al.Metabolic effects of darunavir/ritonavir versus atazanavir/ritonavir in treatment-naive, HIV type 1-infected subjects over 48 weeks[J]. AIDS Res Hum Retroviruses, 2012, 28(10): 1184-1195.
[33]	Back D, Sekar V and Hoetelmans RM. Darunavir: pharmacokinetics and drug interactions[J]. Antivir Ther, 2008, 13(1): 1-13.
[34]	Callebaut C, Stray K, Tsai L, et al.In vitro characterization of GS-8374, a novel phosphonate-containing inhibitor of HIV-1 protease with a favorable resistance profile[J]. Antimicrob Agents Chemother, 2011, 55(4): 1366-1376.
[35]	Hruz PW, Yan Q, Tsai L, et al.GS-8374, a novel HIV protease inhibitor, does not alter glucose homeostasis in cultured adipocytes or in a healthy-rodent model system[J]. Antimicrob Agents Chemother, 2011, 55(4): 1377-1382.
[36]	Concert Pharmaceuticals Initiates Phase 1b Clinical Trial of CTP-518, Protease Inhibitor for Treatment of HIV[EB/OL]. http://www.concertpharma.com/CTP518Ph1bStudy.htm (1 June 2013, date last accessed.