Dolutegravir is preferred over raltegravir in first-line HIV treatment because of its resistance profile. The primary resistance mechanism relevant to this choice is:

• A Dolutegravir acts at a different catalytic site (strand transfer only) while raltegravir inhibits both 3'-processing and strand transfer steps
• B Dolutegravir is a CCR5 co-receptor antagonist in addition to integrase inhibition, providing dual anti-HIV mechanisms
• C Dolutegravir requires a two-step mutational process to develop resistance, unlike raltegravir where a single Q148H/R/K mutation confers high-level resistance ✓
• D Dolutegravir is not a substrate for the integrase resistance polymorphisms encoded by ISTF gene

Explanation

Both raltegravir and dolutegravir are integrase strand transfer inhibitors (INSTIs) that target the integrase enzyme preventing HIV DNA insertion into the host genome. Raltegravir has a low genetic barrier to resistance: a single amino acid substitution at Q148 (H, R, or K) or N155H confers high-level resistance. Dolutegravir (a 2nd-generation INSTI) binds more deeply into the integrase active site with greater flexibility, requiring at least two concurrent mutations (e.g., Q148 + a secondary mutation like G140A/S) to develop meaningful resistance. This high genetic barrier makes virologic failure with dolutegravir without emergence of resistance-associated mutations (RAMs) far more common — consistent with ADVANCE, DRIVE-FORWARD, and GEMINI trials.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.