In HIV pharmacology, dolutegravir (an integrase strand transfer inhibitor) has a higher genetic barrier to resistance compared to first-generation raltegravir because:

• A Dolutegravir binds the integrase active site in a rigid conformation, requiring multiple mutations to displace it ✓
• B Dolutegravir undergoes less hepatic metabolism, maintaining higher plasma concentrations
• C Dolutegravir is a prodrug requiring intracellular phosphorylation for activation
• D Dolutegravir is actively concentrated in lymph node CD4+ cells via organic cation transporter 1

Explanation

Dolutegravir makes more extensive contacts with the catalytic core of HIV integrase including the metal-chelating DDE motif, adopting a flexible binding pose. Single mutations that confer raltegravir resistance (Q148H/K/R, N155H) do not effectively displace dolutegravir due to its flexible aromatic halophenyl moiety and additional binding contacts; 2–3 simultaneous mutations are typically required for significant resistance, making de novo dolutegravir resistance rare in treatment-naive patients.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.