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PI and 3-Class Resistance Drop Sharply in Monogram Database: 2003-2010
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51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 17-20, 2011, Chicago
Mark Mascolini
Among all viral samples in the Monogram database with resistance to at least one drug in the first three antiretroviral classes, the proportion with phenotypic resistance to protease inhibitors (PIs) plunged from 52% in 2003 to 26% in 2010, with most of the drop coming after 2006 [1]. Triple-class resistance also fell significantly from 2003 through 2010, while resistance to nonnucleosides (NNRTIs) and nucleosides (NRTIs) dropped only slightly.
Many factors may contribute to declining resistance rates in countries with a long history of combination antiretroviral therapy, including introduction of antiretrovirals with higher resistance thresholds and unique resistance profiles, wiser antiretroviral planning by HIV clinicians, and better adherence as regimens become simpler and less toxic.
To track changes in resistance rates, researchers at Monogram Biosciences analyzed their hefty database of viral samples submitted for routine resistance testing. They focused on all samples with phenotypic resistance to at least one PI, NNRTI, or NRTI, defined as a fold change in 50% inhibitory concentration at or above the cutoff indicating loss of susceptibility to that antiretroviral.
The analysis included 68,587 phenotypically resistant viral samples collected from 2003 through 2010. In this overall set, prevalence of resistance to PIs slipped from 52% in 2003 to 49% in 2007, then dived to 26% in 2010 (P = 0.02 for 2007-2010 change). Over the same period, prevalence of resistance to NNRTIs dwindled from 70% to 61%, while prevalence of resistance to NRTIs eased from 77% to 70%.
The Monogram team noted that the waning PI resistance rate "coincides . . . with the more recent availability of PIs that are potent, tolerable and select for resistance mutations that confer less cross-resistance among other members of this drug class."
Frequency of resistance mutations associated with first-generation PIs (such as L10I, D30N, M46I/L, G48V, V82A, and L90M) fell over the study period, while rates of mutations linked to new PIs like atazanavir and darunavir (such as V11I, L33F, I50L/V, I54M/L, T74P, and N88S) rose. Frequency of most NRTI mutations fell over time, except for the tenofovir-associated K65R and the abacavir-related Y115F. Rates of NNRTI mutations also dropped, except for L100I, K103N, and P225H.
From 2003 through 2010, the proportion of viral samples with only 1-class resistance rose steadily from 31% to 54% (P = 0.0015), while the proportion with 2-class resistance remained relatively stable, drifting from 40% to 35%. At the same time, the proportion of viral isolates with 3-class resistance dropped significantly from 29% to 11% (P = 0.001).
Among viral samples with 2-class resistance in 2003, 54% had resistance to NNRTIs and NRTIs, 37% had resistance to PIs and NRTIs, and 9% had resistance to NNRTIs and PIs. In 2010 proportions of 2-class resistance were 70% for NNRTIs and NRTIs, 24% for PIs and NRTIs, and 7% for NNRTIs and PIs.
The Monogram team proposed that "the downward trend in 3-class drug resistance since 2007 is driven by the decrease in the fraction of resistant viruses with reduced susceptibility to the PI class."
Reference
1. Paquet AC, Evans M, Petropoulos C, et al. Significant reductions in the prevalence of protease inhibitor and 3-class resistance: recent trends in a large HIV-1 protease/reverse transcriptase database. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 17-20, 2011. Chicago. Abstract H2-800.
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