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Author, Editor(s)

Author(s):

Lawyer, Glenn
Altmann, André
Thielen, Alex
Zazzi, Maurizio
Sönnerborg, Anders
Lengauer, Thomas

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Not MPG Author(s):

Zazzi, Maurizio
Sönnerborg, Anders

BibTeX cite key*:

Lawyer2011

Title

Title*:

HIV-1 mutational pathways under multidrug therapy

Journal

Journal Title*:

AIDS Research and Therapy

Journal's URL:

http://www.aidsrestherapy.com

Download URL
for the article:

http://www.aidsrestherapy.com/content/8/1/26

Language:

English

Publisher

Publisher's
Name:

BioMed Central

Publisher's URL:

http://www.biomedcentral.com/

Publisher's
Address:

London

ISSN:

1742-6405

Vol, No, pp, Date

Volume*:

8

Number:

1

Publishing Date:

July 2011

Pages*:

1-13

Number of
VG Pages:


Page Start:

26,1

Page End:

26,13

Sequence Number:

26

DOI:

10.1186/1742-6405-8-26

Note, Abstract, ©

Note:


(LaTeX) Abstract:

\textbf{Background} Genotype-derived drug resistance profiles are a valuable asset in HIV-1 therapy decisions. Therapy decisions could be further improved, both in terms of predicting length of current therapy success and in preserving followup therapy options, through better knowledge of mutational pathways- here defined as specific locations on the viral genome which, when mutant, alter the risk that additional specific mutations arise. We limit the search to locations in the reverse transcriptase region of the HIV-1 genome which host resistance mutations to nucleoside (NRTI) and non-nucleoside (NNRTI) reverse transcriptase inhibitors (as listed in the 2008 International AIDS Society report), or which were mutant at therapy start in 5% or more of the therapies studied.

\textbf{Methods} A Cox proportional hazards model was fit to each location with the hazard of a mutation at that location during therapy proportional to the presence/absence of mutations at the remaining locations at therapy start. A pathway from preexisting to occurring mutation was indicated if the covariate was both selected as important via smoothly clipped absolute deviation (a form of regularized regression) and had a small p-value. The Cox model also allowed controlling for non-genetic parameters and potential nuisance factors such as viral resistance and number of previous therapies. Results were based on 1981 therapies given to 1495 distinct patients drawn from the EuResist database.

\textbf{Results} The strongest influence on the hazard of developing NRTI resistance was having more than four previous therapies, not any one existing resistance mutation. Known NRTI resistance pathways were shown, and previously speculated inhibition between the thymidine analog pathways was evidenced. Evidence was found for a number of specific pathways between NRTI and NNRTI resistance sites. A number of common mutations were shown to increase the hazard of developing both NRTI and NNRTI resistance. Viral resistance to the therapy compounds did not materially effect the hazard of mutation in our model.

\textbf{Conclusions} The accuracy of therapy outcome prediction tools may be increased by including the number of previous treatments, and by considering locations in the HIV genome which increase the hazard of developing resistance mutations.

URL for the Abstract:

http://www.aidsrestherapy.com/content/8/1/26

Categories,
Keywords:


HyperLinks / References / URLs:


Copyright Message:


Personal Comments:


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Access Level:

Internal

Correlation

MPG Unit:

Max-Planck-Institut für Informatik



MPG Subunit:

Computational Biology and Applied Algorithmics

Appearance:

MPII WWW Server, MPII FTP Server, MPG publications list, university publications list, working group publication list, Fachbeirat, VG Wort


BibTeX Entry:

@ARTICLE{Lawyer2011,
AUTHOR = {Lawyer, Glenn and Altmann, Andr{\'e} and Thielen, Alex and Zazzi, Maurizio and S{\"o}nnerborg, Anders and Lengauer, Thomas},
TITLE = {{HIV-1} mutational pathways under multidrug therapy},
JOURNAL = {AIDS Research and Therapy},
PUBLISHER = {BioMed Central},
YEAR = {2011},
NUMBER = {1},
VOLUME = {8},
PAGES = {1--13},
ADDRESS = {London},
MONTH = {July},
ISBN = {1742-6405},
DOI = {10.1186/1742-6405-8-26},
}


Entry last modified by Anja Becker, 03/20/2012
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Editor(s)
[Library]
Created
01/10/2012 02:06:11 PM
Revisions
2.
1.
0.

Editor(s)
Anja Becker
Anja Becker
Glenn Lawyer

Edit Dates
20.03.2012 09:46:22
24.02.2012 12:44:21
01/10/2012 02:06:11 PM