Mutation D30N is not preferentially selected by human immunodeficiency virus type I subtype C in the development of resistance to nelfinavir

被引:97
作者
Grossman, Z
Paxinos, EE
Averbuch, D
Maayan, S
Parkin, NT
Engelhard, D
Lorber, M
Istomin, V
Shaked, Y
Mendelson, E
Ram, D
Petropoulos, CJ
Schapiro, JM
机构
[1] Natl HIV Reference Ctr, Cent Virol Lab, Publ Hlth Labs, Tel Hashomer, Israel
[2] Hadassah Med Ctr, IL-91120 Jerusalem, Israel
[3] Rambam Med Ctr, Haifa, Israel
[4] Hillel Jaffe Med Ctr, Hadera, Israel
[5] Natl Hemophilia Ctr, Tel Hashomer, Israel
[6] ViroLogic, San Francisco, CA USA
关键词
D O I
10.1128/AAC.48.6.2159-2165.2004
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Differences in baseline polymorphisms between subtypes may result in development of diverse mutational pathways during antiretroviral treatment. We compared drug resistance in patients with human immunodeficiency virus subtype C (referred to herein as "subtype-C-infected patients") versus subtype-B-infected patients following protease inhibitor (PI) therapy. Genotype, phenotype, and replication capacity (Phenosense; Virologic) were determined. We evaluated 159 subtype-C- and 65 subtype-B-infected patients failing first PI treatment. Following nelfinavir treatment, the unique nelfinavir mutation D30N was substantially less frequent in C (7%) than in B (23%; P = 0.03) while L90M was similar (P < 0.5). Significant differences were found in the rates of M36I (98 and 36%), L63P (35 and 59%), A71V (3 and 32%), V77I (0 and 36%), and I93L (91 and 32%) (0.0001 < P < 0.05) in C and B, respectively. Other mutations were L10I/V, K20R, M46I, V82A/I, I84V, N88D, and N88S. Subtype C samples with mutation D30N showed a 50% inhibitory concentration (IC50) change in susceptibility to nelfinavir only. Other mutations increased IC50 correlates to all PIs. Following accumulation of mutations, replication capacity of the C virus was reduced from 43% +/- 22% to 22% +/- 15% (P = 0.04). We confirmed the selective nature of the D30N mutation in C, and the broader cross-resistance of other common protease inhibitor mutations. The rates at which these mutational pathways develop differ in C and subtype-B-infected patients failing therapy, possibly due to the differential impact of baseline polymorphisms. Because mutation D30N is not preferentially selected in nelfinavir-treated subtype-C-infected patients, as it is in those infected with subtype B, the consideration of using this drug initially to preserve future protease inhibitor options is less relevant for subtype-C-infected patients.
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页码:2159 / 2165
页数:7
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