Sequencing of protease inhibitor therapy: insights from an analysis of HIV phenotypic resistance in patients failing protease inhibitors

Kemper, Carol A.; Witt, Mallory D.; Keiser, Phillip H.; Dubé, Michael P.; Forthal, Donald N.; Leibowitz, Matthew; Smith, Douglas; Rigby, Andrew; Hellmann, Nicholas S.; Lie, Yolanda; Leedom, John M.; Richman, Douglas D.; McCutchan, J. Allen; Haubrich, Richard

doi:10.1097/00002030-200103300-00010

Cited by 39 publications

(14 citation statements)

References 22 publications

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“…A number of studies indicate that cross-resistance is a major obstacle inherent to antiviral therapy with PIs (9,11). This observation should not be a surprise since all the inhibitors were designed to bind to the wild-type enzyme.…”

mentioning

confidence: 99%

Novel bis -Tetrahydrofuranylurethane-Containing Nonpeptidic Protease Inhibitor (PI) UIC-94017 (TMC114) with Potent Activity against Multi-PI-Resistant Human Immunodeficiency Virus In Vitro

Koh

Nakata

Maeda

et al. 2003

Antimicrob Agents Chemother

350

346

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confidence: 99%

Novel bis -Tetrahydrofuranylurethane-Containing Nonpeptidic Protease Inhibitor (PI) UIC-94017 (TMC114) with Potent Activity against Multi-PI-Resistant Human Immunodeficiency Virus In Vitro

Koh

Nakata

Maeda

et al. 2003

Antimicrob Agents Chemother

350

346

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“…This requirement of multiple mutations to overcome the activities of PIs has been referred to as a high genetic barrier to drug resistance (7,16,22). Furthermore, most drug resistance mutations in the protease confer cross-resistance to many PIs, so this resistance should be considered class specific rather than drug specific (10,15,17,27).…”

mentioning

confidence: 99%

Novel Human Immunodeficiency Virus Type 1 Protease Mutations Potentially Involved in Resistance to Protease Inhibitors

Svicher

Ceccherini‐Silberstein

Erba

et al. 2005

Antimicrob Agents Chemother

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Plasma-derived sequences of human immunodeficiency virus type 1 (HIV-1) protease from 1,162 patients (457 drug-naïve patients and 705 patients receiving protease inhibitor [PI]-containing antiretroviral regimens) led to the identification and characterization of 17 novel protease mutations potentially associated with resistance to PIs. Fourteen mutations were positively associated with PIs and significantly correlated in pairs and/or clusters with known PI resistance mutations, suggesting their contribution to PI resistance. In particular, E34Q, K43T, and K55R, which were associated with lopinavir treatment, correlated with mutations associated with lopinavir resistance (E34Q with either L33F or F53L, or K43T with I54A) or clustered with multi-PI resistance mutations (K43T with V82A and I54V or V82A, V32I, and I47V, or K55R with V82A, I54V, and M46I). On the other hand, C95F, which was associated with treatment with saquinavir and indinavir, was highly expressed in clusters with either L90M and I93L or V82A and G48V. K45R and K20T, which were associated with nelfinavir treatment, were specifically associated with D30N and N88D and with L90M, respectively. Structural analysis showed that several correlated positions were within 8 Å of each other, confirming the role of the local environment for interactions among mutations. We also identified three protease mutations (T12A, L63Q, and H69N) whose frequencies significantly decreased in PI-treated patients compared with that in drug-naïve patients. They never showed positive correlations with PI resistance mutations; if anything, H69N showed a negative correlation with the compensatory mutations M36I and L10I. These mutations may prevent the appearance of PI resistance mutations, thus increasing the genetic barrier to PI resistance. Overall, our study contributes to a better definition of protease mutational patterns that regulate PI resistance and strongly suggests that other (novel) mutations beyond those currently known to confer resistance should be taken into account to better predict resistance to antiretroviral drugs.

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“…Another primary mutation associated with NFV is L90M although this substitution occurs less frequently and is commonly associated with several other PIs [85,86]. In terms of secondary mutations, substitutions at amino acid locations 10, 35, 36, 46, 71, 77, and 88 are associated with NFV therapy whereas substitutions at 48, 82, and 84 are not commonly observed despite their exposure to other PI treatments [73,86].…”

Section: Resistance Profilementioning

confidence: 99%

TheFDAApprovedHIV‐1 Protease Inhibitors for Treatment ofHIV/AIDS

Ghosh

Anderson

Mitsuya

2010

Burger's Medicinal Chemistry and Drug Discovery

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Over the past two decades, HIV protease inhibitors have helped revolutionize the treatment of HIV/AIDS transforming this deadly ailment into a more manageable chronic infection. Due to intensive research in the area, a variety of protease inhibitors are now commercially available each of which possesses distinct characteristics and a unique tale of discovery. This manuscript reviews the design and development of the 10 currently available protease inhibitors saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, tipranavir, and darunavir. Special attention is given to the research efforts leading to their discovery and the successes and limitations of these drugs in the clinics. A brief review of the biology associated with the HIV‐1 protease target is provided in addition to a discussion of novel drug candidates currently under investigation.

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Sequencing of protease inhibitor therapy: insights from an analysis of HIV phenotypic resistance in patients failing protease inhibitors

Cited by 39 publications

References 22 publications

Novel bis -Tetrahydrofuranylurethane-Containing Nonpeptidic Protease Inhibitor (PI) UIC-94017 (TMC114) with Potent Activity against Multi-PI-Resistant Human Immunodeficiency Virus In Vitro

Novel bis -Tetrahydrofuranylurethane-Containing Nonpeptidic Protease Inhibitor (PI) UIC-94017 (TMC114) with Potent Activity against Multi-PI-Resistant Human Immunodeficiency Virus In Vitro

Novel Human Immunodeficiency Virus Type 1 Protease Mutations Potentially Involved in Resistance to Protease Inhibitors

TheFDAApprovedHIV‐1 Protease Inhibitors for Treatment ofHIV/AIDS

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