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.

Multifaceted HIV integrase functionalities and therapeutic strategies for their inhibition

“…Based on rates of virological failure, the use of DTG as a monotherapy for PLHIV is contra-indicated, whereas the evaluation of dual therapy options is ongoing (143) (reviewed in Ref. 144). Current guidelines recommend the use of DTG, BIC, or RAL with two NRTIs for most PLHIV (9,10).…”

Perspectives on the Barrier to Resistance for Dolutegravir + Lamivudine, a Two-Drug Antiretroviral Therapy for HIV-1 Infection

“…44 This conclusion is consistent with a metaanalysis of studies reporting virological failure among virologically suppressed patients switched to DTG-based 2DRs, which demonstrated that the efficacy of DTG-based combination therapies was considerably higher than that of DTG monotherapy. 45 Importantly, >50% of those experiencing virological failure on DTG monotherapy developed resistance, whereas no treatment-emergent resistance was recorded in patients who received DTG-based 2DRs. 45…”

“…45 Importantly, >50% of those experiencing virological failure on DTG monotherapy developed resistance, whereas no treatment-emergent resistance was recorded in patients who received DTG-based 2DRs. 45…”

Continuation of emtricitabine/lamivudine within combination antiretroviral therapy following detection of the M184V/I HIV‐1 resistance mutation

“…There have been promising results for dual‐therapy regimens containing 3TC and either bPIs or dolutegravir both for first‐line ART and for maintenance therapy. The potential vulnerability of these regimens to compromise by the M184V/I mutation is a source of concern, as bPI or dolutegravir monotherapy is known to be suboptimal, although there is some evidence that bPI + 3TC dual maintenance therapy is effective in PLHIV with the previous detection of M184V . Very few people in our data set were switched to monotherapy or dual therapy including 3TC or FTC following the detection of M184V/I, and so we were not able to evaluate 3TC/FTC use in this setting.…”