HIV-1 reverse transcriptase connection domain mutations: dynamics of emergence and implications for success of combination antiretroviral therapy.

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It was possible to publish this article open access thanks to a Swiss National Licence with the publisher.
Serval ID
serval:BIB_38891425148E
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
HIV-1 reverse transcriptase connection domain mutations: dynamics of emergence and implications for success of combination antiretroviral therapy.
Journal
Clinical Infectious Diseases
Author(s)
von Wyl V., Ehteshami M., Demeter L.M., Bürgisser P., Nijhuis M., Symons J., Yerly S., Böni J., Klimkait T., Schuurman R., Ledergerber B., Götte M., Günthard H.F.
Working group(s)
Swiss HIV Cohort Study
Contributor(s)
Battegay M., Bernasconi E., Böni J., Bucher HC., Bürgisser P., Calmy A., Cattacin S., Cavassini M., Dubs R., Egger M., Elzi L., Fischer M., Flepp M., Fontana A., Francioli P., Furrer H., Fux CA., Gorgievski M., Günthard HF., Hirsch HH., Hirschel B., Hösli I., Kahlert C., Kaiser L., Karrer U., Kind C., Klimkait T., Ledergerber B., Martinetti G., Müller N., Nadal D., Paccaud F., Pantaleo G., Rauch A., Regenass S., Rickenbach M., Rudin C., Schmid P., Schultze D., Schüpbach J., Speck R., de Tejada BM. , Taffé P., Telenti A., Trkola A., Vernazza P., Weber R., Yerly S.
ISSN
1537-6591 (Electronic)
ISSN-L
1058-4838
Publication state
Published
Issued date
2010
Volume
51
Number
5
Pages
620-628
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
BACKGROUND: Factors promoting the emergence of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) connection domain mutations and their effect on antiretroviral therapy (ART) are still largely undetermined. We investigated this matter by analyzing genotypic resistance tests covering 400 amino acid positions in the RT of HIV-1 subtype B viruses and corresponding treatment histories and laboratory measurements.
METHODS: The emergence of connection domain mutations was studied in 334 patients receiving monotherapy or dual therapy with thymidine analogues at the time of the genotypic resistance test. Response to subsequent combination ART (cART) was analyzed using Cox regression for 291 patients receiving unboosted protease inhibitors. Response was defined by ever reaching an HIV RNA level <50 copies/mL during the first cART.
RESULTS: The connection domain mutations N348I, R356K, R358K, A360V, and A371V were more frequently observed in ART-exposed than ART-naive patients, of which only N348I and A360V were nonpolymorphic (with a prevalence of <1.5% in untreated patients). N348I correlated with M184V and predominantly occurred in patients receiving lamivudine and zidovudine concomitantly. A360V was not associated with specific drug combinations and was found to emerge later than M184V or thymidine analogue mutations. Nonpolymorphic connection domain mutations were rarely detected in the absence of established drug resistance mutations in ART-exposed individuals (prevalence, <1%). None of the 5 connection domain mutations associated with treatment showed a statistically significant effect on response to cART.
CONCLUSIONS: Despite their frequent emergence, connection domain mutations did not show large detrimental effects on response to cART. Currently, routine implementation of connection domain sequencing seems unnecessary for developed health care settings.
Keywords
Anti-HIV Agents/administration & dosage, Anti-HIV Agents/therapeutic use, Base Sequence, Drug Resistance, Viral, Drug Therapy, Combination, Genotype, HIV Reverse Transcriptase/genetics, HIV Reverse Transcriptase/metabolism, HIV-1/drug effects, HIV-1/enzymology, Humans, Mutation, Retrospective Studies
Pubmed
Web of science
Open Access
Yes
Create date
25/08/2010 10:55
Last modification date
25/09/2019 7:08
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