Identification of I50L as the Signature Atazanavir (ATV)-Resistance Mutation in Treatment-Naive HIV-1-infected Patients Receiving ATV-Containing Regimens

Atazanavir (ATV) is a once-daily human immunodeficiency virus (HIV) protease inhibitor (PI) shown to be effective and well tolerated. ATV has a distinct resistance profile relative to other PIs, with susceptibility maintained against 86% of isolates resistant to 1-2 PIs.

Clinical isolates obtained from PI-naive patients designated as experiencing virologic failure while receiving ATV-containing regimens contained a unique isoleucine-to-leucine substitution at amino acid residue 50 (I50L) of the HIV-1 protease.

The I50L substitution, observed in all isolates exhibiting phenotypic resistance to ATV, emerged in a variety of different backgrounds and was most frequently accompanied by A71V, K45R, and/or G73S.

Viruses containing an I50L substitution were growth impaired, displayed ATV-specific resistance, and had increased susceptibilities (</=0.4 of reference strain) to other PIs.

Comparison of viruses bearing I50L with those bearing I50V revealed specific resistance to ATV and amprenavir, respectively, with no evidence of cross-resistance. The unique I50L substitution is the signature mutation for resistance to ATV.

Discussion

Despite the decreased viral fitness resulting from selection of an I50L change, initial results suggest that viruses containing an I50L substitution do not appear to rapidly accumulate additional amino acid changes or become cross-resistant to multiple PIs. Of interest, the I50L substitution has also been observed (at a reduced frequency) in treatment-experienced patients treated with ATV-containing regimens (authors' unpublished data).

 The clinical significance of the observations described here have yet to be determined. It appears that future PI-treatment options would be preserved with the emergence of the I50L substitution, but the clinical relevance of the observed increases in susceptibility to other PIs, and whether continued treatment with ATV might be required to maintain selective pressure for the I50L substitution will need to be defined in future clinical studies.

Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut.

Atazanavir Drug Summary