Modern Ritonavir-boosted Protease Inhibitors Demonstrate Increased Resilience against the Emergence of Drug-resistant HIV

Norvir Capsule

It is widely known that highly active antiretroviral therapy (HAART) has led to a dramatic decrease in AIDS-related morbidity and mortality and has improved quality of life for people with HIV. Unfortunately, the success of HAART can be compromised by the development of drug resistance, which is a risk factor for virological failure. Drug resistance testing is now widely recommended in order to detect the emergence of resistance and to make appropriate changes in to antiretroviral regimens.

Several factors have been linked to the development of drug resistance in patients on HAART, including incomplete adherence to therapy, high baseline plasma viral load, and low CD4 cell count.

In addition, data suggest that the relationship between adherence and resistance is also dependent upon the specific drug classes used. There are known discrepancies in the adherence-resistance relationships for non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs), which are partially explained by differences in the replicative capacities of drug-resistant versus wild-type (non-mutated) virus in the presence of clinically relevant drug levels.

HAART guidelines have varied over time as therapies have become more convenient and tolerable. One particularly relevant change has been the widespread shift in favor of using low-dose ritonavir (Norvir) to "boost" levels of other PIs.

Several studies have suggested that boosted PIs may produce better virological suppression and improved clinical outcomes. However, the impact of boosted PI-based regimens versus non-boosted PI-based and NNRTI-based regimens on the emergence of drug resistance has not been well defined in a population-based setting.

The objective of the present study, published in the July 1, 2008 Journal of Infectious Diseases, was to characterize the likelihood of drug resistance developing in treatment-naive individuals starting HAART in the modern era, after adjusting for the adherence, viral load, and initial antiretroviral regimen.

The investigators analyzed data from a large population-based cohort of HIV positive adults initiating HAART in British Columbia, Canada, between August 1996 and November 2004. Of the total study participants, 475 started ritonavir-boosted PI-based regimens, 991 started non-boosted PI-based regimens, and 884 started NNRTI-based regimens. Participants were followed for a median of 4.8 years.

Results

• Patients taking boosted PI-based regimens had greatly reduced odds of developing drug resistance compared with those taking non-boosted PIs (odds ratio [OR] 0.42)

• There was no significant difference in the development of resistance between patients taking non-boosted PI-based regimens and NNRTI-based regimens (OR 1.09).

• Individuals who started HAART more recently (2002-2004) had a lower risk of resistance than those who started HAART in 1996-1998.

Based on these findings, the study authors concluded, "Individuals initiating first HAART with a boosted PI-based regimen had a 2.4-fold lower [odds ratio] for developing HIV drug resistance than did those starting non-boosted PI-based or NNRTI-based HAART, at all adherence levels."

"We found a complex relationship among adherence, first antiretroviral regimen, plasma viral load, and the probability of the development of drug resistance among naive individuals initiating their first HAART regimen," they wrote. "The data show a clear improvement in the populational levels of HIV drug resistance as patients start more modern HAART regimens. More importantly, our results demonstrate increased resilience to the development of drug resistance with modern boosted PI-based HAART."

British Columbia Centre for Excellence in HIV/AIDS; St. Paul's Hospital; University of British Columbia, Vancouver; Simon Fraser University, Burnaby, British Columbia, Canada.

7/04/08

Reference
VD Lima, VS Gill, Benita Yip, and others. Increased resilience to the development of drug resistance with modern boosted protease inhibitor-based highly active antiretroviral therapy. Journal of Infectious Diseases 198(1): 51-58. July 1, 2008.

Abstract