Resistance to protease inhibitors

被引:74
作者
Miller, V [1 ]
机构
[1] Goethe Univ Frankfurt, Zentrum Inneren Med, D-60596 Frankfurt, Germany
关键词
protease inhibitor resistance; cross-resistance; cellular resistance; viral fitness; virologic failure;
D O I
10.1097/00126334-200103011-00005
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The availability of protease inhibitors (PIs) and their combination with nucleoside reverse transcriptase inhibitors marked the passage of antiretroviral therapy (ART) from potential for control to effective suppression and thus substantially reduced rates of morbidity and mortality related to HIV. Even so, what was first hoped Co be an immutable HN DNA treatment target has proved to be prone to resistance mutations, with substitutions identified at more than 20 amino acid sites, which reduces PI susceptibility and increases resistance to treatment. The mutation patterns associated with each PI have been defined, and have been observed to occur at one of two locations. at or near the active site, or in the substrate cleavage site. The natural history of PI resistance has been extensively studied, and the genetic and cellular pathways are described in detail in this article. In addition, cross-resistance among PIs is now recognized to be fairly extensive, although the degree of cross-resistance varies with the number of mutations and the variants selected by drug pressure. Thus, it is still possible to salvage a response with another PI after a first regimen with another PI has failed. The extensive basic science and clinical experience with PIs in the tight against HIV are reviewed in this article, which provides data on resistance-mutation profiles, cellular resistance mechanisms, viral fitness studies, and clinical outcome trials with various first-line and subsequent regimens that contain PIs. It is hoped that the information provided will guide, physicians in best using Pls as part of a logical and successful ART strategy.
引用
收藏
页码:S34 / S50
页数:17
相关论文
共 144 条
[1]   An inhibitor of HIV-1 protease modulates proteasome activity, antigen presentation, and T cell responses [J].
André, P ;
Groettrup, M ;
Klenerman, P ;
de Giuli, R ;
Booth, BL ;
Cerundolo, V ;
Bonneville, M ;
Jotereau, F ;
Zinkernagel, RM ;
Lotteau, V .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (22) :13120-13124
[2]   DESIGN OF ENZYME-INHIBITORS USING ITERATIVE PROTEIN CRYSTALLOGRAPHIC ANALYSIS [J].
APPELT, K ;
BACQUET, RJ ;
BARTLETT, CA ;
BOOTH, CLJ ;
FREER, ST ;
FUHRY, MAM ;
GEHRING, MR ;
HERRMANN, SM ;
HOWLAND, EF ;
JANSON, CA ;
JONES, TR ;
KAN, CC ;
KATHARDEKAR, V ;
LEWIS, KK ;
MARZONI, GP ;
MATTHEWS, DA ;
MOHR, C ;
MOOMAW, EW ;
MORSE, CA ;
OATLEY, SJ ;
OGDEN, RC ;
REDDY, MR ;
REICH, SH ;
SCHOETTLIN, WS ;
SMITH, WW ;
VARNEY, MD ;
VILLAFRANCA, JE ;
WARD, RW ;
WEBBER, S ;
WEBBER, SE ;
WELSH, KM ;
WHITE, J .
JOURNAL OF MEDICINAL CHEMISTRY, 1991, 34 (07) :1925-1934
[3]  
ATKINSON B, 2000, 2 FRANKF S CLIN IMPL
[4]   Positive effects of combined antiretroviral therapy on CD4(+) T cell homeostasis and function in advanced HIV disease [J].
Autran, B ;
Carcelain, G ;
Li, TS ;
Blanc, C ;
Mathez, D ;
Tubiana, R ;
Katlama, C ;
Debre, P ;
Leibowitch, J .
SCIENCE, 1997, 277 (5322) :112-116
[5]   Protease inhibitors in patients with HIV disease - Clinically important pharmacokinetic considerations [J].
Barry, M ;
Gibbons, S ;
Back, D ;
Mulcahy, F .
CLINICAL PHARMACOKINETICS, 1997, 32 (03) :194-209
[6]  
BLANCHE S, 2000, 7 C RETR OPP INF SAN
[7]   Resistance to human immunodeficiency virus type 1 protease inhibitors [J].
Boden, D ;
Markowitz, M .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1998, 42 (11) :2775-2783
[8]  
CALVEZ V, 1999, 39 INT C ANT AG CHEM
[9]   In vitro selection and characterization of human immunodeficiency virus type 1 variants with increased resistance to ABT-378, a novel protease inhibitor [J].
Carrillo, A ;
Stewart, KD ;
Sham, HL ;
Norbeck, DW ;
Kohlbrenner, WE ;
Leonard, JM ;
Kempf, DJ ;
Molla, A .
JOURNAL OF VIROLOGY, 1998, 72 (09) :7532-7541
[10]   In vitro and in vivo anticandidal activity of human immunodeficiency virus protease inhibitors [J].
Cassone, A ;
De Bernardis, F ;
Torosantucci, A ;
Tacconelli, E ;
Tumbarello, M ;
Cauda, R .
JOURNAL OF INFECTIOUS DISEASES, 1999, 180 (02) :448-453