As a result of the high risk for virologic failure and for the emergence of integrase strand transfer inhibitor (INSTI) resistance, dolutegravir monotherapy should be avoided as a maintenance strategy in people living with HIV infection (PLWHIV), according to a study published in Clinical Infectious Diseases.1
Dolutegravir, a second-generation INSTI, has a high genetic barrier, overall good tolerance, easy schedule, and few drug-drug interactions.2 Recent studies have shown that some dual regimens based on a boosted protease inhibitor or dolutegravir are virologically noninferior to triple therapy in both maintenance and first-line strategies.3-7 Monotherapy with boosted protease inhibitor, however, has failed to prove noninferiority over prolonged follow-up.8 Moreover, given that dolutegravir has also demonstrated superiority to darunavir, a boosted protease inhibitor with high potency and genetic barrier to resistance,9 dolutegravir looked to be the ideal candidate for maintenance monotherapy exploration.
Therefore, researchers conducted the MONCAY (Monotherapy of Tivicay; ClinicalTrials.gov identifier: NCT02596334) trial to investigate whether dolutegravir monotherapy would maintain virologic suppression in PLWHIV on a successful dolutegravir/abacavir/lamivudine triple therapy.1 In this randomized, open-label, 12% noninferiority margin trial conducted in 9 French academic centers, participants were randomly assigned 1:1 to either dolutegravir (50 mg once daily) or dolutegravir/abacavir/lamivudine (single-tablet regimen) for 48 weeks.
The primary endpoint was the percentage of patients with HIV RNA <50 copies/mL at week 24. Researchers also evaluated the incidence of emergent genotypic resistance to the INSTI class and virologic success at week 48.
Between January 2016 and July 2017, 158 participants who were receiving a dolutegravir/abacavir/lamivudine regimen for a median of 9 months and a plasma HIV RNA <50 copies/mL for more than 12 months were randomly assigned to dolutegravir monotherapy (n=78) or to continue receiving the dolutegravir/abacavir/lamivudine regimen (n=80).
At week 24, dolutegravir monotherapy met noninferiority to the dolutegravir/abacavir/lamivudine regimen. In the intention-to-treat analysis, the percentage of participants with HIV RNA <50 copies/mL in the dolutegravir and dolutegravir/abacavir/lamivudine groups was 93.6% and 96.3% (difference, 2.7%; 95% CI, −5.0 to 10.8), respectively. Sensitivity analyses examining the primary endpoint by modified intention-to-treat analysis and per protocol populations showed similar results. However, 2 participants experienced virologic failure in the dolutegravir group, defined as 2 consecutive HIV RNA >50 copies/mL measurements at least by 14 days apart.
Between week 24 and week 48, 5 additional participants experienced virologic failure, 2 of whom harbored emerging resistance mutation to INSTI.
Overall, 7 participants experienced virologic failure in the dolutegravir monotherapy group, whereas there were no cases of virologic failure in the dolutegravir/abacavir/lamivudine group. Although the mechanism leading to virologic failure during dolutegravir monotherapy is unclear, all 7 participants who experienced virologic failure were rapidly resuppressed after treatment intensification.
Researchers noted the open-label, 12% noninferiority margin, and short follow-up time (24 weeks) as limitations of the study. Moreover, specified markers of viral reservoir, such as HIV DNA, were not part of the inclusion criteria, which may influence the efficacy of maintenance strategies.
“Our study perfectly illustrates that no definitive conclusion or change in clinical practice should be done on short-term results, especially for new combinations and/or less-drug regimens,” stressed the study authors. “Durability of virologic suppression should become an essential prerequisite before changing the paradigm of antiretroviral therapy,” they concluded.
Disclosure: Multiple authors disclosed affiliations with pharmaceutical companies. See the reference for complete disclosure information.
- Hocqueloux L, Raffi F, Prazuck T, et al; MONCAY Study Group. Dolutegravir monotherapy versus dolutegravir/abacavir/lamivudine for virologically suppressed people living with chronic HIV infection: the randomized non-inferiority MONCAY trial [published online January 2, 2019]. Clin Infect Dis. doi: 10.1093/cid/ciy1132
- Kandel CE, Walmsley SL. Dolutegravir – a review of the pharmacology, efficacy, and safety in the treatment of HIV. Drug Des Devel Ther. 2015;9:3547-3555.
- Arribas JR, Girard P-M, Landman R, et al; OLE/RIS-EST13 Study Group. Dual treatment with lopinavir-ritonavir plus lamivudine versus triple treatment with lopinavir-ritonavir plus lamivudine or emtricitabine and a second nucleos(t)ide reverse transcriptase inhibitor for maintenance of HIV-1 viral suppression (OLE): a randomised, open-label, non-inferiority trial. Lancet Infect Dis. 2015;15(7):785-792.
- Perez-Molina JA, Rubio R, Rivero A, et al; GESIDA 7011 Study Group. Dual treatment with atazanavir-ritonavir plus lamivudine versus triple treatment with atazanavir-ritonavir plus two nucleos(t)ides in virologically stable patients with HIV-1 (SALT): 48 week results from a randomised, open-label, non-inferiority trial. Lancet Infect Dis. 2015;15(7):775-784.
- Di Giambenedetto S, Fabbiani M, Quiros Roldan E, et al; Atlas-M Study Group. Treatment simplification to atazanavir/ritonavir + lamivudine versus maintenance of atazanavir/ritonavir + two NRTIs in virologically suppressed HIV-1-infected patients: 48 week results from a randomized trial (ATLAS-M). J Antimicrob Chemother. 2017;72(4):1163-1171.
- Llibre JM, Hung C-C, Brinson C, et al. Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, non-inferiority SWORD-1 and SWORD-2 studies. Lancet. 2018;391(10123):839-849.
- Cahn P, Madero JS, Arribas JR, et al; GEMINI Study Team. Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials. Lancet. 2019;393(10167):143-155.
- Arribas JR, Girard P-M, Paton N, et al. Efficacy of protease inhibitor monotherapy vs. triple therapy: meta-analysis of data from 2303 patients in 13 randomized trials. HIV Med. 2016;17(5):358-367.
- Patel DA, Snedecor SJ, Tang WY, et al. 48-week efficacy and safety of dolutegravir
- relative to commonly used third agents in treatment-naive HIV-1-infected patients: a systematic review and network meta-analysis. PLoS One. 2014;9(9):e105653.