hiv-1 mutational pathways under multidrug therapyhiv - 1突变通路在耐多药治疗.pdfVIP

Lawyer et al. AIDS Research and Therapy 2011, 8:26 /content/8/1/26 RESEARCH Open Access HIV-1 mutational pathways under multidrug therapy 1* 2 1 3 4 1 Glenn Lawyer , André Altmann , Alexander Thielen , Maurizio Zazzi , Anders Sönnerborg and Thomas Lengauer Abstract 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. 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 dis