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Antiretroviral resistance among HIV-infected persons who have died in British Columbia, in the era of modern antiretroviral therapy.

https://arctichealth.org/en/permalink/ahliterature179504
Source
J Infect Dis. 2004 Jul 15;190(2):285-92
Publication Type
Article
Date
Jul-15-2004
Author
Magdalena A Recsky
Zabrina L Brumme
Keith J Chan
Brian Wynhoven
Benita Yip
Winnie W Y Dong
Katherine V Heath
Julio S G Montaner
Adrian R Levy
Robert S Hogg
P Richard Harrigan
Author Affiliation
British Columbia Centre for Excellence in HIV/AIDS, St. Paul's Hospital, Vancouver, British Columbia, Canada.
Source
J Infect Dis. 2004 Jul 15;190(2):285-92
Date
Jul-15-2004
Language
English
Publication Type
Article
Keywords
Adult
Amino Acid Substitution
Anti-HIV Agents - pharmacology - therapeutic use
Antiretroviral Therapy, Highly Active
British Columbia
Drug Resistance, Multiple, Viral - genetics
Drug Resistance, Viral - genetics
Female
Genotype
HIV - drug effects - genetics - isolation & purification
HIV Infections - drug therapy - mortality - virology
HIV Protease - genetics
HIV Protease Inhibitors - pharmacology - therapeutic use
HIV Reverse Transcriptase - genetics
Humans
Male
Middle Aged
Mutation
Prevalence
Reverse Transcriptase Inhibitors - pharmacology - therapeutic use
Viral Load
Abstract
The prevalence of antiretroviral resistance among persons enrolled in the centralized HIV/AIDS Drug Treatment Program in British Columbia, Canada, who had died between July 1997 and December 2001, was investigated, to determine the degree to which antiretroviral resistance contributed to mortality.
During this period, 637 deaths had occurred. The last plasma sample obtained during therapy was genotyped retrospectively for treated individuals who had died of a nonaccidental cause. Samples with plasma human immunodeficiency virus (HIV) loads /=1, >/=2, or 3 drug classes was observed in 76%, 42%, and 11% of individuals, respectively, in the group of 1220 living individuals experiencing virologic therapy failure, compared with only 44%, 23%, and 5% of individuals, respectively, who had died (P
PubMed ID
15216463 View in PubMed
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CD4-dependent characteristics of coreceptor use and HIV type 1 V3 sequence in a large population of therapy-naive individuals.

https://arctichealth.org/en/permalink/ahliterature159015
Source
AIDS Res Hum Retroviruses. 2008 Feb;24(2):219-28
Publication Type
Article
Date
Feb-2008
Author
Andrew J Low
David Marchant
Chanson J Brumme
Zabrina L Brumme
Winnie Dong
Tobias Sing
Robert S Hogg
Julio S G Montaner
Vikram Gill
Peter K Cheung
P Richard Harrigan
Author Affiliation
B.C. Centre for Excellence in HIV/AIDS, St. Paul's Hospital, Vancouver, British Columbia, Canada.
Source
AIDS Res Hum Retroviruses. 2008 Feb;24(2):219-28
Date
Feb-2008
Language
English
Publication Type
Article
Keywords
British Columbia
CD4 Lymphocyte Count
Cross-Sectional Studies
HIV Envelope Protein gp120 - genetics
HIV Infections - virology
HIV-1 - genetics - isolation & purification - physiology
Humans
Peptide Fragments - genetics
Receptors, CCR5 - metabolism
Receptors, CXCR4 - metabolism
Viral Load
Virus Attachment
Abstract
We investigated the associations between coreceptor use, V3 loop sequence, and CD4 count in a cross-sectional analysis of a large cohort of chronically HIV-infected, treatment-naive patients. HIV coreceptor usage was determined in the last pretherapy plasma sample for 977 individuals initiating HAART in British Columbia, Canada using the Monogram Trofile Tropism assay. Relative light unit (RLU) readouts from the Trofile assay, as well as HIV V3 loop sequence data, were examined as a function of baseline CD4 cell count for 953 (97%) samples with both phenotype and genotype data available. Median CCR5 RLUs were high for both R5 and X4-capable samples, while CXCR4 RLUs were orders of magnitude lower for X4 samples (p
PubMed ID
18240966 View in PubMed
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HIV-1 drug resistance: degree of underestimation by a cross-sectional versus a longitudinal testing approach.

https://arctichealth.org/en/permalink/ahliterature175667
Source
J Infect Dis. 2005 Apr 15;191(8):1325-30
Publication Type
Article
Date
Apr-15-2005
Author
P Richard Harrigan
Brian Wynhoven
Zabrina L Brumme
Chanson J Brumme
Beheroze Sattha
Jennifer C Major
Rafael de la Rosa
Julio S G Montaner
Author Affiliation
British Columbia Centre for Excellence in HIV/AIDS, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada. lab@hivnet.ubc.ca
Source
J Infect Dis. 2005 Apr 15;191(8):1325-30
Date
Apr-15-2005
Language
English
Publication Type
Article
Keywords
Bias (epidemiology)
British Columbia
Cross-Sectional Studies
Drug Resistance, Viral - genetics
Genotype
HIV Infections - virology
HIV-1 - genetics - isolation & purification
Humans
Longitudinal Studies
Time Factors
Abstract
Genotyping of human immunodeficiency virus type 1 (HIV-1) for antiretroviral drug resistance is routinely used both in clinical practice, to guide the selection of options for an individual's antiretroviral therapy, and in epidemiological studies, to estimate levels of antiretroviral drug resistance in a patient population. However, reliance on results of a single test can result in an underestimation of antiretroviral drug resistance. In the present study, we quantified the prevalence of resistance-associated mutations found in recent genotypic tests of 1734 HIV-1-infected, treatment-experienced subjects who had at least 3 genotypic tests (n = 11,404 genotypic tests total; median, 5 tests/subject) and compared it with that of resistance-associated mutations ever detected in these subjects between 1996 and 2004. Single-point analyses underestimated antiretroviral drug resistance, particularly for nucleoside analogues, in both individuals and patient populations. For example, the prevalence of resistance-associated mutation M184V/I was 25.5% in the most recent genotypes and 58.8% in available historical genotypes. Our results suggest that analysis of a combined historical genotype rather than of a cross-sectional genotype may lead to more accurate estimates of antiretroviral drug resistance in individual patients and in patient populations.
Notes
Comment In: AIDS. 2005 Dec 2;19(18):2178-916284473
PubMed ID
15776380 View in PubMed
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HIV VprR77Q mutation does not influence clinical response of individuals initiating highly active antiretroviral therapy.

https://arctichealth.org/en/permalink/ahliterature168363
Source
AIDS Res Hum Retroviruses. 2006 Jul;22(7):615-8
Publication Type
Article
Date
Jul-2006
Author
Celia Chui
Peter K Cheung
Chanson J Brumme
Theresa Mo
Zabrina L Brumme
Julio S G Montaner
Andrew D Badley
P Richard Harrigan
Author Affiliation
BC Centre for Excellence in HIV/AIDS, St. Paul's Hospital, Vancouver, British Columbia, Canada.
Source
AIDS Res Hum Retroviruses. 2006 Jul;22(7):615-8
Date
Jul-2006
Language
English
Publication Type
Article
Keywords
Adult
Analysis of Variance
Anti-HIV Agents - therapeutic use
Antiretroviral Therapy, Highly Active
British Columbia
Cross-Sectional Studies
Disease Progression
Female
Genes, vpr - genetics
HIV Infections - drug therapy - genetics
HIV Long-Term Survivors
HIV-1 - genetics
Humans
Male
Mutation
Viral Load
Abstract
VprR77Q has been associated with long-term nonprogressive (LTNP) HIV infection. We wished to investigate the prevalence, clinical correlates, and effect on treatment response of VprR77Q in a cohort of antiretroviral- naïve individuals initiating highly active antiretroviral therapy (HAART). Baseline plasma samples from 728 subjects were genotyped using RT-PCR and direct DNA sequencing. Cox proportional hazards regression was used to model the effects of VprR77Q on virologic and immunologic responses, and survival following initiation of HAART, over a median 4.5 years follow-up. We found that 308 subjects (42.3%) harbored VprR77Q alone or in combination with another amino acid, while 420 (57.7%) harbored an amino acid other than Q. A cross-sectional analysis found no correlation between R77Q and baseline plasma viral load (pVL), CD4 count, diagnosis of AIDS, or sociodemographic characteristics including age, gender, and history of injection drug use (p > 0.1). In multivariate analyses, no significant associations between VprR77Q and initial pVL and CD4 responses to HAART or survival following initiation of treatment were observed (p > 0.1). The high prevalence and the lack of association with pretherapy clinical parameters in this cohort argue against an association of R77Q with LTNP status. These results do not support an association between R77Q and HAART response.
Notes
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PubMed ID
16831085 View in PubMed
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Increasingly successful highly active antiretroviral therapy delays the emergence of new HLA class I-associated escape mutations in HIV-1.

https://arctichealth.org/en/permalink/ahliterature125689
Source
Clin Infect Dis. 2012 Jun;54(11):1652-9
Publication Type
Article
Date
Jun-2012
Author
David J H F Knapp
Zabrina L Brumme
Sheng Yuan Huang
Brian Wynhoven
Winnie W Y Dong
Theresa Mo
P Richard Harrigan
Chanson J Brumme
Author Affiliation
BC Centre for Excellence in HIV/AIDS, Vancouver, Canada.
Source
Clin Infect Dis. 2012 Jun;54(11):1652-9
Date
Jun-2012
Language
English
Publication Type
Article
Keywords
Adult
Antiretroviral Therapy, Highly Active - methods
British Columbia
Epitopes, T-Lymphocyte - genetics - immunology
Female
HIV Infections - drug therapy - immunology - virology
HIV-1 - genetics - immunology
Histocompatibility Antigens Class I - immunology
Humans
Immune Evasion
Male
Mutation
Polymorphism, Genetic
Selection, Genetic
T-Lymphocytes, Cytotoxic - immunology
Viral Load
pol Gene Products, Human Immunodeficiency Virus - genetics - immunology
Abstract
HLA class I-restricted cytotoxic T lymphocytes and highly active antiretroviral therapy (HAART) exert strong selective pressures on human immunodeficiency virus type 1 (HIV-1), leading to escape mutations compromising virologic control. Immune responses continue to shape HIV-1 evolution after HAART initiation, but the extent and rate at which this occurs remain incompletely quantified. Here, we characterize the incidence and clinical correlates of HLA-associated evolution in HIV-1 Pol after HAART initiation in a large, population-based observational cohort.
British Columbia HAART Observational, Medical Evaluation and Research cohort participants with available HLA class I types and longitudinal posttherapy protease/reverse transcriptase sequences were studied (n = 619; median, 5 samples per patient and 5.2 years of follow-up). HLA-associated polymorphisms were defined according to published reference lists. Rates and correlates of immune-mediated HIV-1 evolution were investigated using multivariate Cox proportional hazard models incorporating baseline and time-dependent plasma viral load and CD4 response data.
New HLA-associated escape events were observed in 269 (43%) patients during HAART and occurred at 49 of 63 (78%) investigated immune-associated sites in Pol. In time-dependent analyses adjusting for baseline factors, poorer virologic, but not immunologic, response to HAART was associated with increased risk of immune escape of 1.9-fold per log(10) viral load increment (P
PubMed ID
22460975 View in PubMed
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Molecular and clinical epidemiology of CXCR4-using HIV-1 in a large population of antiretroviral-naive individuals.

https://arctichealth.org/en/permalink/ahliterature174031
Source
J Infect Dis. 2005 Aug 1;192(3):466-74
Publication Type
Article
Date
Aug-1-2005
Author
Zabrina L Brumme
James Goodrich
Howard B Mayer
Chanson J Brumme
Bethany M Henrick
Brian Wynhoven
Jerome J Asselin
Peter K Cheung
Robert S Hogg
Julio S G Montaner
P Richard Harrigan
Author Affiliation
BC Centre for Excellence in HIV/AIDS, St. Paul's Hospital, and Faculty of Medicine, University of British Columbia, Canada.
Source
J Infect Dis. 2005 Aug 1;192(3):466-74
Date
Aug-1-2005
Language
English
Publication Type
Article
Keywords
Adult
Analysis of Variance
Anti-HIV Agents - therapeutic use
British Columbia
CD4 Lymphocyte Count
Female
Genetic Variation
Genotype
HIV Infections - drug therapy - immunology - prevention & control
HIV-1 - genetics
Humans
Male
Middle Aged
Molecular Epidemiology - methods
Multivariate Analysis
Phenotype
Receptors, CXCR4 - genetics
Treatment Outcome
Abstract
We wished to characterize the epidemiological and clinical correlates of CXCR4-using human immunodeficiency virus type 1 (HIV-1) ("X4 variants") in a cross-sectional analysis of a large population of antiretroviral-naive individuals.
HIV-1 coreceptor use was determined in the last pretherapy plasma sample for 1191 individuals initiating triple-combination therapy in British Columbia, Canada. Baseline variables investigated included sociodemographic characteristics, plasma viral load (pVL), CD4 cell count, AIDS diagnosis, HIV-1 V3 loop sequence, and human CCR5 Delta 32 genotype.
Individuals harboring X4 variants (n = 178 of 979 phenotyped samples; 18.2%) displayed a poorer baseline clinical profile than individuals harboring exclusively CCR5-using HIV-1 ("R5 variants") (median pVL, 175,000 vs. 120,000 copies of HIV-1 RNA/mL [P = .0006]; median CD4 cell count, 110 vs. 290 cells/mm(3) [P
PubMed ID
15995960 View in PubMed
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Phylogenetic analysis of population-based and deep sequencing data to identify coevolving sites in the nef gene of HIV-1.

https://arctichealth.org/en/permalink/ahliterature147008
Source
Mol Biol Evol. 2010 Apr;27(4):819-32
Publication Type
Article
Date
Apr-2010
Author
Art F Y Poon
Luke C Swenson
Winnie W Y Dong
Wenjie Deng
Sergei L Kosakovsky Pond
Zabrina L Brumme
James I Mullins
Douglas D Richman
P Richard Harrigan
Simon D W Frost
Author Affiliation
British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada. apoon@cfenet.ubc.ca
Source
Mol Biol Evol. 2010 Apr;27(4):819-32
Date
Apr-2010
Language
English
Publication Type
Article
Keywords
Amino Acid Sequence
British Columbia
Cohort Studies
Evolution, Molecular
HIV Infections - virology
HIV-1 - genetics
Humans
Molecular Sequence Data
Phylogeny
Sequence Alignment
Sequence Analysis, RNA - methods
nef Gene Products, Human Immunodeficiency Virus - chemistry - genetics
Abstract
Rapidly evolving viruses such as HIV-1 display extensive sequence variation in response to host-specific selection, while simultaneously maintaining functions that are critical to replication and infectivity. This apparent conflict between diversifying and purifying selection may be resolved by an abundance of epistatic interactions such that the same functional requirements can be met by highly divergent sequences. We investigate this hypothesis by conducting an extensive characterization of sequence variation in the HIV-1 nef gene that encodes a highly variable multifunctional protein. Population-based sequences were obtained from 686 patients enrolled in the HOMER cohort in British Columbia, Canada, from which the distribution of nonsynonymous substitutions in the phylogeny was reconstructed by maximum likelihood. We used a phylogenetic comparative method on these data to identify putative epistatic interactions between residues. Two interactions (Y120/Q125 and N157/S169) were chosen to further investigate within-host evolution using HIV-1 RNA extractions from plasma samples from eight patients. Clonal sequencing confirmed strong linkage between polymorphisms at these sites in every case. We used massively parallel pyrosequencing (MPP) to reconstruct within-host evolution in these patients. Experimental error associated with MPP was quantified by performing replicates at two different stages of the protocol, which were pooled prior to analysis to reduce this source of variation. Phylogenetic reconstruction from these data revealed correlated substitutions at Y120/Q125 or N157/S169 repeated across multiple lineages in every host, indicating convergent within-host evolution shaped by epistatic interactions.
Notes
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PubMed ID
19955476 View in PubMed
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Predictors of HIV drug-resistance mutations in a large antiretroviral-naive cohort initiating triple antiretroviral therapy.

https://arctichealth.org/en/permalink/ahliterature176736
Source
J Infect Dis. 2005 Feb 1;191(3):339-47
Publication Type
Article
Date
Feb-1-2005
Author
P Richard Harrigan
Robert S Hogg
Winnie W Y Dong
Benita Yip
Brian Wynhoven
Justin Woodward
Chanson J Brumme
Zabrina L Brumme
Theresa Mo
Chris S Alexander
Julio S G Montaner
Author Affiliation
British Columbia Centre for Excellence in HIV/AIDS, and Department of Medicine, University of British Columbia, Vancouver, Canada. lab@hivnet.ubc.ca
Source
J Infect Dis. 2005 Feb 1;191(3):339-47
Date
Feb-1-2005
Language
English
Publication Type
Article
Keywords
Adult
Antiretroviral Therapy, Highly Active
British Columbia - epidemiology
CD4 Lymphocyte Count
Drug Resistance, Viral - genetics
HIV Infections - drug therapy - epidemiology - virology
HIV Protease - genetics
HIV Reverse Transcriptase - genetics
HIV-1 - drug effects - genetics
Humans
Incidence
Multivariate Analysis
Mutation
Patient compliance
Viral Load
Abstract
The objective of this study was to systematically characterize the incidence and determinants of antiretroviral resistance in the HOMER (Highly Active Antiretroviral Therapy [HAART] Observational Medical Evaluation and Research) cohort of 1191 human immunodeficiency virus-infected, antiretroviral-naive adults initiating HAART in British Columbia, Canada.
All plasma samples with plasma virus loads (pVLs) >1000 copies/mL collected during the first 30 months of follow-up were genotyped for drug resistance. The primary outcome measure was time to the first detection of major drug-resistance mutation(s). Cox proportional hazard regression was used to identify factors significantly associated with the detection of drug-resistance mutations.
Drug-resistance mutations were detected in 298 subjects (25%). Factors significantly associated with detection of drug-resistance mutations included high baseline pVL (multivariate hazard ratio [HR], 1.59; P/=95%) refill percentages but with 2 plasma drug concentrations below the steady-state trough concentration minus 1 standard deviation (multivariate HR, 4.57; P
PubMed ID
15633092 View in PubMed
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Prevalence and clinical implications of insertions in the HIV-1 p6Gag N-terminal region in drug-naive individuals initiating antiretroviral therapy.

https://arctichealth.org/en/permalink/ahliterature185444
Source
Antivir Ther. 2003 Apr;8(2):91-6
Publication Type
Article
Date
Apr-2003
Author
Zabrina L Brumme
Keith J Chan
Winnie W Y Dong
Brian Wynhoven
Theresa Mo
Robert S Hogg
Julio S G Montaner
Michael V O'Shaughnessy
P Richard Harrigan
Author Affiliation
BC Centre for Excellence in HIV/AIDS, St Paul's Hospital, Vancouver, British Columbia, Canada.
Source
Antivir Ther. 2003 Apr;8(2):91-6
Date
Apr-2003
Language
English
Publication Type
Article
Keywords
Adult
Anti-HIV Agents - therapeutic use
British Columbia
CD4 Lymphocyte Count
Cohort Studies
Drug Resistance, Viral - genetics
Female
Gene Products, gag - genetics
Genotype
HIV Envelope Protein gp120 - genetics
HIV Infections - drug therapy - epidemiology - pathology
HIV-1 - drug effects - genetics - isolation & purification
Humans
Male
Mutagenesis, Insertional - genetics
Peptide Fragments - genetics
Prevalence
Proportional Hazards Models
Survival Analysis
Viral Load
gag Gene Products, Human Immunodeficiency Virus
Abstract
We assessed the prevalence and clinical impact of insertions within the HIV-1 p6Gag proline-rich (PTAP) region on initial antiretroviral therapy response in 461 HIV-infected, drug-naive individuals initiating therapy in British Columbia, Canada between June 1996 and August 1998. HIV p6Gag insertions were detected by nested RT-PCR of extracted patient plasma followed by direct DNA sequencing. Insertions were observed in 70 of 423 successfully genotyped samples (16.5%). HIV p6Gag insertions were significantly associated with a lower baseline CD4 cell count (P or = 500 copies/ml) or immunological failure (confirmed CD4 count below baseline), as evaluated by Kaplan-Meier methods and Cox proportional hazard regression (P>0.1). The data suggest that HIV p6Gag insertions are not exclusively related to drug resistance and may not influence response to antiretroviral therapy, but may be linked to sequence variations in the HIV envelope.
PubMed ID
12741620 View in PubMed
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9 records – page 1 of 1.