background:  Recently the L76V mutation in HIV-1 protease has been reported in patients with detectable viral load while receiving lopinavir (LPV)/ritonavir (r). L76V has also been identified as an important mutation contributing to darunavir (DRV)/r resistance. 

Methods:  A database containing protease inhibitor (PI) susceptibility and sequence information (Monogram Biosciences) was queried to identify isolates containing at least 1 PI-resistance-associated mutation (RAM, defined as L23I, L24I, D30N, V32A/I, M46I/L/V, I47A/V, G48A/M/V, I50L/V, I54A/L/M/S/T/V, L76V, V82A/C/F/G/L/M/S/T, I84A/C/V, N88S/T, L90M). The frequency of L76V, and its effect on susceptibility to currently marketed PI either alone or in combination with other PI RAM, was determined. Mixtures were included in frequency estimates but excluded for phenotypic profiling.

Results:  Of 30,276 clinical sequences with at least 1 PI RAM; 948 (3.1%) contained L76V; and only 11 samples (0.03%) had L76V as the sole PI RAM. The majority (757 of 948, 80%) of L76V-containing sequences also had ≥3 PI PRAM. The most common partner mutations in descending order of prevalence occurred at positions M46, I54, V82, and I84. Among isolates that also had phenotypic data available, the presence of L76V further decreased the susceptibility to LPV, DRV, amprenavir (APV), and indinavir (IDV) by 2- to 6-fold compared with samples with similar PI RAM, but without L76V. In contrast, susceptibility to atazanavir (ATV), saquinavir (SQV), tipranavir (TPV), and nelfinavir (NFV) was either similar or increased in the presence of L76V. 

Conclusions:  The L76V mutation was infrequently observed with a prevalence of 3%. Phenotypic data indicates that this mutation, in combination with other PI RAM leads to a decrease in susceptibility to LPV, DRV, IDV, and APV, but not to ATV, SQV, TPV, and NFV. The presence of the L76V mutation should be considered in PI selection.