Management of drug resistance to integrase inhibitors: results from an international perinatal virtual clinic

Although drug resistance to second-generation integrase inhibitors (INSTIs) is still relatively uncommon, this is a serious risk that needs expert management, usually as part of a multi-disciplinary team (MDT).

Luckily, combinations based on dolutegravir, bictegravir and cabotegravir generally have low rates of virological failure. However, in the context of continued detectable viral load, early mutations associated with drug resistance can quickly lead to high-level phenotypic resistance and cross-resistance to other INSTIs and potentially other drugs in the combination.

A retrospective cohort study looking at the prevalence of emerging INSTI resistance in a perinatal virtual MDT based at Imperial College, London, reported on the outcomes for 114 anonymised cases of virological failure between October 2018 and January 2024.

Resistance sequences were available for 103/114 of the children and adolescents. Of these, 61/103 had a previous record of INSTI use and 19/61 (31%) had mutations associated with INSTI resistance.

Median age in these 19 cases was 11 years (IQR: 6 to 14), weight was 25 kg (IQR: 17 to 50) and BMI (in 13/19 with height) was 19.4 (IQR: 14.6 to 20.8). The median viral load was 84,000 copies/mL (IQR: 2380 to 137,000) with median CD4 of 485 cells/mm³ (IQR: 153 to 805) and 6/19 had current AIDS diagnoses and 14/19 were referred from 2022 onwards.

Other details included 12/19 were from low- or middle-income countries (LMICs), with 4/19 receiving concomitant rifampicin and using dolutegraivr 50 mg twice-daily.

The median number of earlier combinations was three with 9/19 and 4/19 having 3- and 4-class resistance, respectively. Two cases developed on first-line dolutegravir, 17 on second-line or later ART.

The MDT recommended boosted darunavir for all 19 cases, either once- or twice-daily depending on protease inhibitor resistance, plus TDF/XTC (splitting adult tablets to estimate doses for six children). Twice-daily dolutegravir was added when only partial resistance was detected. Two adolescents with 4-class resistance were able to access fostemsavir or ibalizumab (one on each) through compassionate access.

comment

Although these cases are relatively rare, they have been reported in other cohorts, with a higher prevalence of INSTI-related drug resistance compared to adults.

This paper also discusses limited access to paediatric formulations including paediatric darunavir and the challenges of managing viral failure without drug resistance testing, especially in low- and middle-income settings.

This should be routinely included in the development programme for all new HIV drugs, including lenacapavir.