Dolutegravir is preferred over older integrase inhibitors (raltegravir, elvitegravir) for HIV treatment. The resistance barrier advantage of dolutegravir relates to which mechanism?

• A Dolutegravir inhibits both integrase and protease simultaneously, providing dual-target activity
• B Dolutegravir binds to the Mg2+ cofactors in the integrase active site with a longer residence time ('slow dissociation kinetics'), requiring multiple simultaneous mutations to confer clinical resistance ✓
• C Dolutegravir activates innate immune responses against HIV-infected cells through TLR9 stimulation
• D Dolutegravir is metabolised to a toxic quinone that alkylates HIV reverse transcriptase, providing a secondary mechanism

Explanation

All integrase strand transfer inhibitors (INSTIs) chelate the two Mg2+ ions in the integrase active site. Raltegravir and elvitegravir have rapid drug-receptor dissociation rates (fast 'off rate'), meaning common single mutations (e.g., N155H, Q148H/R/K, Y143C) in integrase significantly reduce residence time, conferring high-level resistance. Dolutegravir binds with much slower dissociation kinetics due to its bicyclic binding mode and additional contacts with the integrase-DNA complex. This slow-off rate means that single mutations cannot easily shorten the residence time sufficiently to confer clinical resistance — two or three simultaneous mutations are typically required, which impose major viral fitness costs. This is the basis of dolutegravir's 'high genetic barrier to resistance'.

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

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