Dolutegravir (DTG), an integrase strand transfer inhibitor (INSTI), has a superior resistance barrier compared to first-generation raltegravir. This is because:
- A DTG binds a different allosteric site on integrase, avoiding cross-resistance mutations
- B DTG has a slower dissociation rate from integrase-DNA complexes (longer binding t½), requiring multiple high-fitness mutations for resistance that confer significant viral replication cost ✓
- C DTG has higher plasma protein binding, preventing passage of resistant variants into lymph nodes
- D DTG is not a substrate for efflux pumps on CD4 T-cells unlike raltegravir
Explanation
Dolutegravir binds the HIV integrase-DNA complex at the same active site as raltegravir but with a significantly slower off-rate (dissociation half-life hours vs. minutes). This prolonged residence time means that single mutations (such as N155H or Q148 signature mutations conferring raltegravir resistance) are insufficient to displace DTG — multiple additional compensatory mutations are required. These compound mutations impose a severe fitness cost on the virus. In clinical practice, virological failure on a DTG-based regimen is extremely rare when adherence is maintained, and emerging resistance is uncommon. This has made DTG-based first-line regimens (TLD: TDF/3TC/DTG) the WHO global preferred first-line standard.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.