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CROI 2017: Failure of Dolutegravir Monotherapy
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Leading up to this year, some researchers and clinicians had optimistically viewed dolutegravir an invincible ARV, a drug so mighty that it was unlikely to fail, and even more unlikely to be victim to emergent resistance mutations. Two presentations at CROI demonstrated the vulnerability of dolutegravir to failure and to the development of resistance when it is used as monotherapy.

The first was a switch study (DOLUMONO) in which 104 patients on ART with virologic suppression were randomized to switch to dolutegravir monotherapy (50 mg daily) immediately or to continue their current ART for 24 weeks and then switch to dolutegravir monotherapy. Patients had been on ART for a median of 3 years, and had no resistance mutations at baseline. Eight of 96 patients who were treated with monotherapy developed virologic failure. Six of these had resistance data available after failure, and 3 of the 6 had INSTI mutations. The study was discontinued.

The second study was a retrospective analysis of 122 patients from 3 clinics who had been switched from combination ART to dolutegravir monotherapy (50 mg daily), reportedly for what were described as "clinical reasons"; none had a history of integrase inhibitor therapy resulting in virologic failure and INSTI resistance. Unfortunately, 11 study participants (9%) developed virologic failure after switching to dolutegravir, and 9 of them had genotypic INSTI resistance.

Clinical Bottom Line

These studies show us, if proof were needed, that dolutegravir is not exempt from the laws of gravity. Dolutegravir failure, and resistance mutations, may occur if it is not supported appropriately. The results of these studies likely mark the end of dolutegravir monotherapy.

References
Wijting I, Rokx C, Boucher C, et al. Dolutegravir as maintenance monotherapy for HIV-1: a randomized clinical trial. In: Program and abstracts of the 2017 Conference on Retroviruses and Opportunistic Infections; February 13-16, 2017; Seattle. Abstract 451LB.
Blanco JL, Oldenbuettel C, Thomas R, et al. Pathways of resistance in subjects failing dolutegravir monotherapy. In: Program and abstracts of the 2017 Conference on Retroviruses and Opportunistic Infections; February 13-16, 2017; Seattle. Abstract 42.