Dolutegravir is an integrase inhibitor used as a component of preferred antiretroviral therapy (ART). It is available as the individual agent Tivicay® (dolutegravir 50 mg) or as a co-formulated single tablet regimen Triumeq® (abacavir 600 mg/lamivudine 300 mg/dolutegravir 50 mg). Although dolutegravir (DTG) is known for its high genetic barrier to resistance, its durability to maintain virologic suppression had not previously been evaluated. Typically, effective ART consists of 3 antiretrovirals (ARVs) from at least 2 drug classes. Simplification of ART comes with the advantages of reduced costs, toxicity, pill-burden, and potential for drug-drug interactions.
Data presented at the 2017 Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle, Washington, looked to answer this question. The authors hypothesized that DTG monotherapy (DTG 50 mg by mouth daily) was non-inferior to ART in maintaining virologic suppression.1
This multicenter study was performed in the Netherlands and randomized participants in an open label manner. To be eligible for participation in this study, patients had to be on ART with an undetectable HIV
viral load (VL) (< 50 copies/mL) for more than 6 months, good medication compliance, baseline VL < 100,000 copies/mL, lowest CD4 count above 200 cells/mm3
, no baseline resistance or history of virologic failure, and hepatitis B virus immune or be willing to receive vaccination. The primary endpoint was to compare the proportion of study participatns on treatment who achieved an HIV VL less than 200 copies/mL. Secondary endpoints included the proportion of participants achieving an HIV VL less than 200 copies/mL and less than 50 copies/mL in the entire population on DTG-monotherapy (DOLUMONO) at 24 weeks (W24) and 48 weeks (W48).
Of 256 patients on ART, 51 participants were directly switched to DOLUMONO, 53 participants delayed the switch and were continued on ART for 24 weeks, followed by DTG-monotherapy (Con-cART), and 152 participants remained on ART.
One patient discontinued DTG therapy at week 12 due to unspecified adverse effects. At week 24, DOLUMONO (49/50) was non-inferior to Con-cART (50/50) with no integrase (IN) resistance noted in the single case of virologic failure (VF) in the DOLUMONO group.
A total of 96 patients received DTG-monotherapy, where 94 reached W24. Of the evaluable population, 92/94 achieved a VL less than 200 copies/mL. No IN resistance was noted in the 2 participants that developed VF. Seventy-seven out of 96 participants made it to W48 of DTG-monotherapy. In total, 8 participants developed VF and 3 participants were found to have developed IN resistance. In those who experienced VF, patients had been on ART an average of 70 months (range: 21 months – 169 months) prior to switching to DTG-monotherapy. These findings led to premature study discontinuation. Of note, for those who remained on ART for the entire study, VF occurred significantly less (3/152) compared to DTG-monotherapy (8/96) (P
The results from this study demonstrate that although DTG-monotherapy was non-inferior to ART at W24, VF continued to develop after W24 leading to the development of IN resistance in 3 patients. Therefore, the genetic barrier to resistance against DTG was inferior and should not be used as monotherapy for HIV maintenance therapy.
Wijting I, Rokx C, Boucher C, et al. Dolutegravir as maintenance monotherapy for HIV-1: A randomized clinical trial. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 13-16, 2017; Seattle, WA. Abstract 451LB.