Increased Resilience to the Development of Drug Resistance with Modern Boosted Protease Inhibitor. Part 5
Of particular interest is the relationship between emergence of resistance, pVL, and adherence stratified by regimen type. The dependence of resistance selection on baseline pVL and patient adherence was markedly decreased for boosted PI–based regimens. The estimated probability of resistance for the worst adherence‐pVL stratum for boosted PI–based regimens was equal to or lower than that observed for any adherence stratum for nonboosted PI–based regimens and was very similar to that of NNRTI‐based regimens for adherence levels <80%. For those patients with a pVL in the <5 log10 copies/mL range, the risk of the development of drug resistance varied greatly depending on the first regimen. Sensitivity analyses.In the central analysis, samples with a pVL <1000 copies/mL were not genotyped and were assumed to not carry resistance mutations. We addressed the impact of this assumption by conducting a sensitivity analysis, eliminating those individuals with viral suppression (pVL < 1000 copies/mL) during the entire follow‐up period ( [23%]). An explanatory logistic regression model was developed for identifying which patient characteristics were the most influential in the development of drug resistance during antiretroviral treatment. The results from the new univariate analyses were consistent with the previous ones, and the multivariate analysis also yielded results similar to those presented before. Based on the multivariate model, we also observed no difference in the odds of the development of key resistance mutations between nonboosted PI–based regimens (reference group) and NNRTI‐based regimens (OR, 1.27 [95% CI, 0.95–1.68]) but greatly reduced odds for boosted PI–based regimens (OR, 0.36 [95% CI, 0.24–0.54]). Similar results were observed regarding associations between resistance and adherence, pVL, CD4 cell count, start of therapy, and history of injection drug use. In addition, we observed a similar reduction in the risk of detecting resistance in those who started HAART during 1999–2001 (OR, 0.79 [95% CI, 0.60–1.05]) or 2002–2004 (OR, 0.43; 0.30–0.63]), compared with those who started HAART during 1996–1998 (reference group). To address the potential impact of transmitted resistance on resistance that develops during therapy, we conducted another sensitivity analysis examining only those 1426 individuals for whom pretherapy genotypes were available and excluding those who exhibited transmitted resistance, leaving a total of 1295 patients. As with the other sensitivity analysis, the results from the new univariate and multivariate analyses yielded similar results as the original. Based on the multivariate model, we observed no difference in the odds of the development of key resistance mutations between nonboosted PI–based regimens (reference group) and NNRTI‐based regimens (OR, 1.24 [95% CI, 0.87–1.77]) but greatly reduced odds for boosted PI–based regimens (OR, 0.44 [95% CI, 0.24–0.83]). Similar results to those of the original analysis were observed regarding associations between resistance and adherence, pVL, CD4 cell count, start of therapy, and history of injection drug use. Once again, we observed a similar reduction in the risk of detecting resistance in those who started HAART during 1999–2001 (OR, 1.01 [95% CI, 0.72–1.44]) or 2002–2004 (OR, 0.46 [95% CI, 0.28–0.79]), compared with those who started HAART during 1996–1998 (reference group).
To address the potential effects of wild‐type virus outgrowth in patients who ceased active therapy, we conducted another sensitivity analysis eliminating the 117 individuals who were not receiving any therapy at the time of resistance detection. Overall, we obtained results similar to those of the original analysis and of other sensitivity analyses. Of particular note, the effect of boosted PIs on the OR for resistance was even greater than that in the original analysis (OR, 0.37 [95% CI, 0.24–0.56]).