Evolution of primary protease inhibitor resistance mutations during protease inhibitor salvage therapy

Abstract

In order to track the evolution of primary protease inhibitor (PI) resistance mutations in human immunodeficiency virus type 1 (HIV-1) isolates, baseline and follow-up protease sequences were obtained from patients undergoing salvage PI therapy who presented initially with isolates containing a single primary PI resistance mutation. Among 78 patients meeting study selection criteria, baseline primary PI resistance mutations included L90M (42% of patients), V82A/F/T (27%), D30N (21%), G48V (6%), and I84V (4%). Despite the switching of treatment to a new PI, primary PI resistance mutations present at the baseline persisted in 66 of 78 (85%) patients. D30N persisted less frequently than L90M (50% versus 100%, respectively; P < 0.001) and V82A/F/T (50% versus 81%, respectively; P = 0.05). HIV-1 isolates from 38 (49%) patients failing PI salvage therapy developed new primary PI resistance mutations including L90M, I84V, V82A, and G48V. Common combinations of primary and secondary PI resistance mutations after salvage therapy included mutations at amino acid positions 10, 82, and 46 and/or 54 in 16 patients; 10, 90, and 71 and/or 73 in 14 patients; 10, 73, 84, 90, and 46 and/or 54 in 5 patients; 10, 48, and 82 in 5 patients; and 30, 88 and 90 in 5 patients. In summary, during salvage PI therapy, most HIV-1 isolates with a single primary PI resistance mutation maintained their original mutations, and 49% developed additional primary PI resistance mutations. The persistence of L90M, V82A/F/T, G48V, and I84V during salvage therapy suggests that these mutations play a role in clinical resistance to multiple PIs.

FIG. 1.

Bar graph indicating the extent to which primary protease inhibitor resistance mutations present at baseline (gray bars) were also present following salvage therapy (black bars).

FIG. 2.

Plasma HIV-1 RNA levels (log₁₀ copies per milliliter, means ± standard errors) from 68 of 78 patients, including 29 of 33 presenting with L90M, 19 of 21 presenting with V82A/F/T, 13 of 16 presenting with D30N, 4 of 5 presenting with G48V, and 3 of 3 presenting with I84V. “Presequence” indicates the lowest plasma RNA levels in the year (median, 6 months) before the first sequence. “1st sequence” indicates the RNA levels at the time of the first sequence (i.e., that containing a single primary drug resistance mutation). “Post salvage Rx nadir” indicates the lowest plasma HIV-1 RNA levels between the first and second sequences (median, 6 months after the first sequence). “2nd sequence” indicates the plasma HIV-1 RNA levels at the time of the second sequence.