Background: Cross-resistance is a hallmark of HIV-1 resistance to protease inhibitors (PI). Some protease mutations, however, promote a lesser degree of cross-resistance, while others, like N88S, have been described as able to induce hypersusceptibility (HS) to some PIs. We have examined the extent and mechanisms of HS to PIs in patients having failed PI treatment, using resistance phenotype data from the Narval ANRS088 trial.

Methods: Susceptibility to PIs was measured using a single-cycle recombinant assay based on PCR-amplified gag-protease sequences from plasma. Susceptibility was expressed using a resistance index (RI) calculated as a fold-change in IC90 relative to reference virus NL4-3.  HS was defined as a RI ≤ 0.5.

Results: HS was observed in 36/320 (11%) patients. HS mostly involved amprenavir 22/320 (7%) and ritonavir 18/320 (5.5%). Protease mutations most often found associated with HS involved codon 30, which determined a unique cluster of PI cross-resistance, and codon 88. The results are summarized in the table below.

	30D 88N	30D 88D	30D 88S/T	30N 88N	30N 88D
n	258	9	10	13	30
Median APV RI	3.3	1.0	0.2	0.7	0.8
% APV RI≤0.5	2.3	11.1	60.0	23.1	20.7
Median RTV RI	20.2	12.1	2.3	0.49	0.98
% RTV RI≤0.5	3.1	0	10.0	53.8	13.8
Median NFV RI	17.9	16.6	22.0	24.7	32.8

Conclusion : Hypersusceptibility to amprenavir and ritonavir is a frequent feature of viruses with mutations at codons 30 and/or 88. While HS to amprenavir is mostly promoted by mutations N88S/T, HS to ritonavir is mainly associated with genotypes bearing D30N in the absence of codon 88 mutation.