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dc.contributor.authorPoon, Art F. Y.
dc.contributor.authorAldous, Jeannette L.
dc.contributor.authorMathews, W. Christopher
dc.contributor.authorKitahata, Mari
dc.contributor.authorKahn, James S.
dc.contributor.authorSaag, Michael S.
dc.contributor.authorFrost, Simon D. W.
dc.contributor.authorHaubrich, Richard H.
dc.contributor.authorBoswell, Stephen Louis
dc.contributor.authorRodríguez, Benigno
dc.date.accessioned2011-10-20T02:55:08Z
dc.date.issued2011
dc.identifier.citationPoon, Art F. Y., Jeannette L. Aldous, W. Christopher Mathews, Mari Kitahata, James S. Kahn, Michael S. Saag, Simon D. W. Frost, Richard H. Haubrich, Stephen Louis Boswell, and Benigno Rodriguez. 2011. Transmitted Drug Resistance in the CFAR Network of Integrated Clinical Systems Cohort: Prevalence and Effects on Pre-Therapy CD4 and Viral Load. PLoS ONE 6(6): e21189.en_US
dc.identifier.issn1932-6203en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:5266859
dc.description.abstractHuman immunodeficiency virus type 1 (HIV-1) genomes often carry one or more mutations associated with drug resistance upon transmission into a therapy-naïve individual. We assessed the prevalence and clinical significance of transmitted drug resistance (TDR) in chronically-infected therapy-naïve patients enrolled in a multi-center cohort in North America. Pre-therapy clinical significance was quantified by plasma viral load (pVL) and CD4+ cell count (CD4) at baseline. Naïve bulk sequences of HIV-1 protease and reverse transcriptase (RT) were screened for resistance mutations as defined by the World Health Organization surveillance list. The overall prevalence of TDR was 14.2%. We used a Bayesian network to identify co-transmission of TDR mutations in clusters associated with specific drugs or drug classes. Aggregate effects of mutations by drug class were estimated by fitting linear models of pVL and CD4 on weighted sums over TDR mutations according to the Stanford HIV Database algorithm. Transmitted resistance to both classes of reverse transcriptase inhibitors was significantly associated with lower CD4, but had opposing effects on pVL. In contrast, position-specific analyses of TDR mutations revealed substantial effects on CD4 and pVL at several residue positions that were being masked in the aggregate analyses, and significant interaction effects as well. Residue positions in RT with predominant effects on CD4 or pVL (D67 and M184) were re-evaluated in causal models using an inverse probability-weighting scheme to address the problem of confounding by other mutations and demographic or risk factors. We found that causal effect estimates of mutations M184V/I (\(-1.7log_{10}\)pVL) and D67N/G (-2.1\(\sqrt[3]{CD4})\) and (\(+0.4log_{10}\) pVL) were compensated by K103N/S and K219Q/E/N/R. As TDR becomes an increasing dilemma in this modern era of highly-active antiretroviral therapy, these results have immediate significance for the clinical management of HIV-1 infections and our understanding of the ongoing adaptation of HIV-1 to human populations.en_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi://10.1371/journal.pone.0021189en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3118815/pdf/en_US
dash.licenseLAA
dc.subjectHIVen_US
dc.subjectgeneticsen_US
dc.subjectgenetic screensen_US
dc.subjectmicrobiologyen_US
dc.subjectvirologyen_US
dc.subjectmechanisms of resistance and susceptibilityen_US
dc.subjectmedicineen_US
dc.subjectepidemiologyen_US
dc.subjectgenetic epidemiologyen_US
dc.subjectmolecular epidemiologyen_US
dc.subjectinfectious diseasesen_US
dc.subjectviral diseasesen_US
dc.subjectpublic healthen_US
dc.subjectdisease ecologyen_US
dc.titleTransmitted Drug Resistance in the CFAR Network of Integrated Clinical Systems Cohort: Prevalence and Effects on Pre-Therapy CD4 and Viral Loaden_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS ONEen_US
dash.depositing.authorBoswell, Stephen Louis
dc.date.available2011-10-20T02:55:08Z
dash.affiliation.other100175en_US
dc.identifier.doi10.1371/journal.pone.0021189*
dash.authorsorderedfalse
dash.contributor.affiliatedBoswell, Stephen L.


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