ICAAC 2011: Declining Prevalence of HIV Triple-class and Protease Inhibitor Resistance

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HIV strains showing resistance to protease inhibitors, or to all 3 of the earliest classes of antiretroviral drugs, have become less common over the past several years, making it easier to construct effective regimens, researchers reported at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2011) last month in Chicago.

Agnes Paquet and colleagues from Monogram Biosciences in South San Francisco surveyed the company's commercial database of blood samples that been submitted for routine phenotypic testing (how well a drug suppresses HIV in vitro) and genotypic testing (genetic sequencing of virus to look for known resistance mutations).

The researchers analyzed phenotypic drug resistance patterns over time, looking at HIV resistance to protease inhibitors (PIs), nucleoside/nucleotide reverse-transcriptase inhibitors (NRTIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs), as well as 1-, 2-, and 3-class resistance.

The researchers determined resistance according to fold-change in IC50, or 50% inhibitory concentration, needed to inhibit viral replication; as resistance emerges, higher dug concentrations are needed to suppress the virus.

A total of 68,587 resistant samples collected between 2003 and 2010 were sorted into groups that had fold-changes greater than a designated cut-off threshold for at least 1 drug in a class.

Results

"A strong trend of decreasing prevalence of PI resistance was observed in [the] Monogram commercial database between 2003 and 2010," the investigators concluded. "This trend was accompanied by a significant reduction in the prevalence of 3-class resistance."

"These results may have important implications for [antiretroviral] selection, clinical trial design, and drug development, they added.

These findings confirm that PIs -- especially when boosted with ritonavir -- have a higher barrier to resistance than NNRTIs.

NRTI resistance remains relatively common, in part because some of these drugs were used suboptimally as monotherapy or dual therapy before the advent of effective combination ART. However, in this study mutations conferring resistance to older NRTIs fell, well resistance to abacavir (Ziagen, also in the Epzicom combination pill) and tenofovir (Viread, also in the Truvada and Atripla pills) rose.

Fortunately, few people are resistant to both PIs and NNRTIs; such individuals may benefit from adding the newer entry inhibitor or integrase inhibitor classes.

Investigator affiliations: Monogram Biosciences, South San Francisco, CA.

10/7/11

Reference

AC Paquet, M Evans, C Petropoulos, 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 2011). Chicago, September 17-20, 2011. Abstract H2-800.