Laura Waters

The eagerly anticipated late breakers abstracts include dolutegravir PK in children, 1st line dolutegravir/FTC/TAF vs dolutegravir/FTC/TDF vs efavirenz/FTC/TDF 1st line in South Africa, intermittent vs daily ART dosing, dolutegravir/3TC 1st-line & in switch and a novel 2DR of the nucleoside reverse transcriptase translocation inhibitor islatravir with doravirine.

Dolutegravir pharmacokinetics in children weighing 6-20kg will form the basis for imminent FDA/EMA submissions for a lower weight paediatric indication. ADVANCE (published today!) randomised treatment-naïve individuals to the 3 regimens outlined above (n=351/arm). 96W virological efficacy was high (79-87%) & on-treatment analysis revealed 95-96% efficacy in all arms – incredible considering absence of baseline resistance testing & regional pre-ART NNRTI resistance approaching 15%. Dolutegravir+3TC maintained non-inferiority to TDF/FTC+dolutegravir 1st line in GEMINI W96 with no emergent resistance. DTG/3TC efficacy in switch was confirmed in TANGO where it was non-inferior to continued TAF-based ART. Virological failure rates 0.3% and 0.5% on 2DR/3DR, respectively, without emergent resistance. A phase 2 study demonstrated good efficacy of islatravir/doravirine after achieving suppression on the same drugs+3TC, comparable to TDF/3TC/doravirine. ANRS QUATUOR examined continued daily ART vs 4 days a week. Efficacy was high, but in 6 intermittent arm virological failures, 3 failed with 2-class resistance.

Today reassured 2DR sceptics; surely now DTG/3TC will enter the echelons of guidelines-preferred initial ART. Excellent TANGO results support DTG/3TC in switch, but since clinical importance of DNA ‘resistance’ is uncertain, and M184V/I rates were only 1%, DTG/3TC should be avoided in people with known/likely 3TC resistance. There was no emergent resistance on dolutegravir-ART in ADVANCE; as Francois Venter said “even our clinical setting couldn’t break it!”. Intermittent dosing might be an option for some regimens, surely not those with low barriers/short half-life 3rd agents – 2 class resistance is not an acceptable outcome for people on previously stable ART.