Detection of HIV-1 CXCR4 tropism and resistance in treatment experienced subjects receiving CCR5 antagonist-Vicriviroc
Copyright © 2012 Elsevier B.V. All rights reserved..
BACKGROUND: Vicriviroc (VCV), a small-molecule antagonist of the C-C chemokine receptor 5 (CCR5), blocks HIV's entry into CD4+ cells. Small studies have suggested that resistance to CCR5 antagonists is slow to develop.
OBJECTIVES: To examine resistance to VCV in isolates from treatment experienced patients who experienced virologic failure in two phase 3 trials.
STUDY DESIGN: Genotypic and phenotypic susceptibility to VCV, and other antiretroviral drugs were evaluated at baseline and at defined intervals during the study. In a post hoc analysis, viral tropism at baseline was evaluated using the Trofile-ES assay. Only subjects with R5-tropic virus were included in the analysis. Viral envelope sequencing was performed on samples from subjects with emergent VCV resistance defined using a relative MPI cutoff.
RESULTS: 71/486 subjects treated with VCV for 48 weeks met the protocol-defined virologic failure criteria. 7/71 (10%) had DM/X4 virus at the time of virologic failure; VCV resistance was identified in 4/486 treated subjects (1%). No control subject had detectable DM/X4 virus or VCV resistance at virologic failure. Clonal analysis of envelope sequences from VCV-resistant virus identified 2-5 amino acid substitutions at or near the crown of the V3 loop; however, no signature V3 mutations were identified. Changes outside the V3 loop were also observed in resistant clones; no consistent variant pattern was observed.
CONCLUSIONS: In these trials, use of a sensitive tropism assay and potent antiretroviral drug combinations contributed to the infrequent detection of X4-tropic virus and VCV resistance. Substitutions in the V3 loop were associated with VCV resistance, however, no specific pattern of amino acid changes were sufficient to reliably predict VCV susceptibility.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2012 |
|---|---|
| Erschienen: |
2012 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:55 |
|---|---|
| Enthalten in: |
Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology - 55(2012), 2 vom: 23. Okt., Seite 134-9 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
McNicholas, Paul [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Anti-HIV Agents |
|---|
| Anmerkungen: |
Date Completed 07.01.2013 Date Revised 20.08.2012 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.jcv.2012.06.021 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM219656630 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM219656630 | ||
| 003 | DE-627 | ||
| 005 | 20231224043446.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231224s2012 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.jcv.2012.06.021 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0732.xml |
| 035 | |a (DE-627)NLM219656630 | ||
| 035 | |a (NLM)22824230 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a McNicholas, Paul |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Detection of HIV-1 CXCR4 tropism and resistance in treatment experienced subjects receiving CCR5 antagonist-Vicriviroc |
| 264 | 1 | |c 2012 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 07.01.2013 | ||
| 500 | |a Date Revised 20.08.2012 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2012 Elsevier B.V. All rights reserved. | ||
| 520 | |a BACKGROUND: Vicriviroc (VCV), a small-molecule antagonist of the C-C chemokine receptor 5 (CCR5), blocks HIV's entry into CD4+ cells. Small studies have suggested that resistance to CCR5 antagonists is slow to develop | ||
| 520 | |a OBJECTIVES: To examine resistance to VCV in isolates from treatment experienced patients who experienced virologic failure in two phase 3 trials | ||
| 520 | |a STUDY DESIGN: Genotypic and phenotypic susceptibility to VCV, and other antiretroviral drugs were evaluated at baseline and at defined intervals during the study. In a post hoc analysis, viral tropism at baseline was evaluated using the Trofile-ES assay. Only subjects with R5-tropic virus were included in the analysis. Viral envelope sequencing was performed on samples from subjects with emergent VCV resistance defined using a relative MPI cutoff | ||
| 520 | |a RESULTS: 71/486 subjects treated with VCV for 48 weeks met the protocol-defined virologic failure criteria. 7/71 (10%) had DM/X4 virus at the time of virologic failure; VCV resistance was identified in 4/486 treated subjects (1%). No control subject had detectable DM/X4 virus or VCV resistance at virologic failure. Clonal analysis of envelope sequences from VCV-resistant virus identified 2-5 amino acid substitutions at or near the crown of the V3 loop; however, no signature V3 mutations were identified. Changes outside the V3 loop were also observed in resistant clones; no consistent variant pattern was observed | ||
| 520 | |a CONCLUSIONS: In these trials, use of a sensitive tropism assay and potent antiretroviral drug combinations contributed to the infrequent detection of X4-tropic virus and VCV resistance. Substitutions in the V3 loop were associated with VCV resistance, however, no specific pattern of amino acid changes were sufficient to reliably predict VCV susceptibility | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Anti-HIV Agents |2 NLM | |
| 650 | 7 | |a Piperazines |2 NLM | |
| 650 | 7 | |a Pyrimidines |2 NLM | |
| 650 | 7 | |a RNA, Viral |2 NLM | |
| 650 | 7 | |a env Gene Products, Human Immunodeficiency Virus |2 NLM | |
| 650 | 7 | |a vicriviroc |2 NLM | |
| 650 | 7 | |a TL515DW4QS |2 NLM | |
| 700 | 1 | |a Vilchez, Regis A |e verfasserin |4 aut | |
| 700 | 1 | |a Greaves, Wayne |e verfasserin |4 aut | |
| 700 | 1 | |a Kumar, Sushma |e verfasserin |4 aut | |
| 700 | 1 | |a Onyebuchi, Chinyere |e verfasserin |4 aut | |
| 700 | 1 | |a Black, Todd |e verfasserin |4 aut | |
| 700 | 1 | |a Strizki, Julie M |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology |d 1997 |g 55(2012), 2 vom: 23. Okt., Seite 134-9 |w (DE-627)NLM097223964 |x 1873-5967 |7 nnns |
| 773 | 1 | 8 | |g volume:55 |g year:2012 |g number:2 |g day:23 |g month:10 |g pages:134-9 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.jcv.2012.06.021 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 55 |j 2012 |e 2 |b 23 |c 10 |h 134-9 | ||