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Updated: Jun 21, 2026

Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Failure of treatment with first-line lopinavir boosted with ritonavir can be explained by novel resistance pathways
Monique Nijhuis1, Annemarie M J Wensing, Wouter F W Bierman
1Department of Medical Microbiology, Division of General Medicine, Infectious Diseases and Geriatrics, University Medical Center Utrecht, Utrecht, the Netherlands. m.nijhuis@umcutrecht.nl
Background:
Virological failure of first-line antiretroviral therapy based on lopinavir boosted with ritonavir (lopinavir/r) has rarely been associated with resistance in protease. We identified a new genotypic resistance pathway in 3 patients who experienced failure of first-line lopinavir/r treatment.
Methods:
Viral protease and the C-term part of Gag were sequenced. The observed mutations were introduced in a reference strain to investigate impact on protease inhibitor susceptibility and replication capacity.
Results:
A detailed longitudinal analysis demonstrated the selection of the M46I+L76V protease mutations in all 3 patients. The L76V conferred a solitary 3.5-fold increase in one-half the maximal inhibitory concentration to lopinavir but severely hampered viral replication. Addition of M46I, which did not confer any lopinavir resistance on its own, had a dual effect. It partly compensated for the loss in replication capacity and increased the one-half maximal inhibitory concentration to above the lower clinical cutoff (11-fold). Analysis of a large clinical database (>180,000 human immunodeficiency virus [HIV] sequences) demonstrated a significant association (Spearman rho, 0.93) between the increased presence of L76V in clinical samples (0.5% in 2000 to 3.4% in 2006) and lopinavir prescription over time.
Conclusions:
The HIV protease substitution L76V, in combination with M46I, confers clinically relevant levels of lopinavir resistance and represents a novel resistance pathway to first-line lopinavir/r therapy.
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