Integrase strand transfer inhibitors (INSTIs — raltegravir, dolutegravir, bictegravir) are now preferred first-line ARV agents. Dolutegravir's advantage over first-generation raltegravir includes:

• A Dolutegravir requires co-administration with ritonavir boosting for therapeutic plasma levels
• B Dolutegravir inhibits HIV entry by binding gp41
• C Dolutegravir is active against all classes of integrase mutations including G140S/Q148H double-mutants equally as well as wild-type
• D Dolutegravir has a higher genetic barrier to resistance — requiring multiple mutations to confer clinical resistance, unlike raltegravir where a single Q148H mutation causes class-level resistance ✓

Explanation

Raltegravir (first-generation INSTI) has a relatively low genetic barrier to resistance — a single primary resistance mutation (Q148H/K/R, Y143R, or N155H) significantly reduces susceptibility. Dolutegravir (second-generation) maintains a higher genetic barrier: a single integrase mutation rarely confers clinical resistance because dolutegravir's slow dissociation rate from integrase-DNA complexes (a feature of the 'metal chelation pharmacophore') means mutations must substantially reduce both binding affinity and increase dissociation to create resistance, typically requiring several mutations simultaneously. Dolutegravir does not require pharmacokinetic boosting with ritonavir/cobicistat.

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

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Written and medically reviewed by the StethoPrep medical team.