Comparative analysis of HIV type 1 genotypic resistance across antiretroviral trial treatment regimens

From data on HIV-1 genotypes collected from antiretroviral trial participan ts who fail virologically, we describe methods for comparing distributions of acquired HIV-1 mutations across different treatment regimens. Given a de finition of a "mutational distance" that summarizes the genetic change of a subject's virus in a way that captures the resistance cost of exposure to an antiretroviral regimen, these comparative analyses inform about the rela tive treatability of emergent virus by next-line therapy directed to the sa me viral target. The utility of the methods is illustrated by application t o data from AIDS Clinical Trials Group (ACTG) Study 241. We find that patie nts failing zidovudine/didanosine/nevirapine accumulated a 2.41-fold greate r nonnucleoside reverse transcriptase inhibitor (RTI) mutational distance t han patients failing zidovudine/didanosine [95% confidence interval (1.55, 5.26), p< 0.000001], quantitating expectations that adding a nonnucleoside RTI to a double nucleoside regimen may attenuate future effectiveness of no nnucleoside RTI therapy for nucleoside-experienced patients if viremia is n ot suppressed. We also find that persons with extensive prior experience wi th suboptimal nucleoside therapy who were virologically failing zidovudine/ didanosine/nevirapine or zidovudine/ didanosine accumulated a similar nucl eoside RTI mutational distance, implying that the addition of the nonnucleo side RTI did not preserve future nucleoside options.