Increased Resilience to the Development of Drug Resistance with Modern Boosted Protease Inhibitor
Highly active antiretroviral therapy (HAART) has led to a dramatic decrease in AIDS‐related comorbidity and mortality. However, the success of HAART can be compromised by the development of HIV drug resistance. Antiretroviral resistance is an independent risk factor for virologic failure in HIV‐1–infected populations. Drug‐resistance testing is now widely recommended in HIV therapy monitoring to detect the development of resistance to antiretrovirals and make appropriate regimen changes.
Several individual factors have been associated with the development of HIV‐1 drug resistance during HAART, including incomplete adherence to therapy, high baseline plasma viral load (pVL), and low CD4 cell count. However, there has been limited research on how the simultaneous presence of these factors and their interactions affect the development of antiretroviral resistance. Recent studies have shown that the relationship between adherence and resistance is complex. The accumulation of resistance mutations across all levels of adherence was greater in treatment‐naive individuals beginning HAART than in those who were treatment experienced. The heterogeneity in the relationship between adherence and resistance in antiretroviral‐exposed and ‐naive populations has been explored via computer simulations.
The relationship between adherence and resistance is also dependent on the individual drug classes used in combination therapy, with discrepancies between the adherence‐resistance relationships for nonnucleoside reverse‐transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) being at least partially explained by differences in the replicative capacity of drug‐resistant versus wild‐type virus in the presence of clinically relevant drug levels for each drug, respectively. Recommendations for the optimal application of HAART have varied over time as therapies have evolved to become more convenient and tolerable. One particularly relevant change has been the widespread shift of international guidelines in favor of low‐dose ritonavir as a PI “boosting” agent when PI‐based HAART is used. The use of boosted PIs have led to improved virological suppression, as detailed in clinical trials and cohort studies, as well as improved clinical outcomes in cohort studies in observational settings. However, the impact of boosted PI–based regimens versus nonboosted PI–based and NNRTI‐based regimens on the development of HIV drug resistance mutations remains to be defined in a population‐based setting.
The objective of the present study was to characterize the probability of the development of drug resistance in drug‐naive individuals starting HAART in the modern era, adjusting for the simultaneous effects of adherence, pVL, and initial HAART regimen. We based our analysis on data from a large population‐based cohort of HIV‐1–infected antiretroviral‐naive adults initiating HAART in British Columbia, Canada, between 1 August 1996 and 30 November 2004.