Virologic failure and HIV drug resistance on simplified, dolutegravir-based maintenance therapy: Systematic review and meta-analysis

Abstract

Background: Dolutegravir-containing maintenance therapy is a promising simplification strategy for virologically suppressed HIV-infected individuals. However, most of the available data to inform this strategy come from small, uncontrolled studies. We estimated the proportion of HIV-infected patients experiencing virological failure (VF) and developing drug resistance on dolutegravir (DTG)-based maintenance therapy. Methods: We searched Medline, Embase, Cochrane Central, Web of Science, and conference abstracts for studies assessing VF on DTG-based maintenance therapy. Studies including ≥5 adults with an undetectable viral load on antiretroviral therapy (ART) who switched to a DTG-based mono- or dual therapy were included. Pooled proportions of VF were estimated using random-intercept logistic meta-regression and acquired drug resistance mutations described for each strategy. Results: Of 1719 studies considered, 21 met our selection criteria, including seven interventional and 14 observational studies. Eight studies including 251 patients assessed VF on DTG monotherapy and fourteen studies including 1670 participants VF on dual therapy. The participant’s median age ranged from 43 to 63 years, their median nadir CD4 count from 90 to 399 cells/µl, and 27.6% were female. The proportion of participants experiencing VF on DTG-monotherapy was 3.6% (95% confidence interval [CI] 1.9-6.7) at 24 weeks and 8.9% (95% CI 4.7-16.2) at 48 weeks. Resistance mutations developed in seven (3.6%) participants on DTG-monotherapy. Among patients on dual therapy, ten (0.7%, 95% CI 0.4-1.3) experienced VF by 48 weeks and none developed resistance to DTG. In adjusted analyses, VF at 24 weeks was less likely on dual therapy than on monotherapy (adjusted odds ratio: 0.10, 95% CI 0.03-0.30). Conclusions: Whereas VF is relatively common on DTG maintenance monotherapy, DTG-based dual therapy appears to be a promising simplification strategy for individuals with a suppressed HIV viral load on triple-ART.

Effectiveness and safety of dolutegravir two‐drug regimens in virologically suppressed people living with HIV: a systematic literature review and meta‐analysis of real‐world evidence

“…In addition to the clinical value of DTG forming part of three-drug regimens, several clinical trials and meta-analyses have shown that DTG-containing two-drug ART regimens, particularly the combinations of DTG with lamivudine (3TC) or rilpivirine (RPV), have similar efficacy in achieving and maintaining virological suppression (VS) in PLHIV. This is achieved whilst reducing the number of ART agents and potential risk of drug-drug interactions owing to the simplified regimen compared with triple ART regimens [14,[19][20][21][22][23][24].…”

Impact of scaling up dolutegravir on antiretroviral resistance in South Africa: A modeling study

“…Another limitation of this study is the fact that the MARISA model does not take into account resistance to DTG and uses a simplified representation of NRTI resistance. In the context of the introduction of DTG-based ART, modeling of NRTI resistance is particularly relevant as individuals starting on DTG as a functional monotherapy due to resistance to both NRTI backbones—TDF and 3TC—experience higher risk of treatment failure [ 27 ]. As they are considerably less frequently transmitted [ 28 ] and revert back quickly [ 29 , 30 ], NRTI resistances might primarily be an issue for ART-experienced individuals and more specifically, in patients failing NNRTI-based regimens, who often exhibit high levels of NRTI resistance [ 31 ].…”

The Impact of Scaling up Dolutegravir on Antiretroviral Resistance in South Africa

“…Another limitation of this study is the fact that the MARISA model does not take into account resistances to neither NRTI nor DTG. In the context of the introduction of DTG-based ART, modelling of NRTI resistance is particularly relevant as individuals starting on DTG as a functional monotherapy due to resistance to both NRTI backbones - tenofovir and lamivudine - experience higher risk of treatment failure [25]. As they are considerably less frequently transmitted] [26] and revert back quickly [27, 28], NRTI resistances might primarily be an issue for ART-experienced individuals and more specifically, in patients failing NNRTI-based regimens, who often exhibit high levels of NRTI resistance [29].…”