Virologic outcomes of switching to dolutegravir functional mono- or dual therapy with a non-cytosine nucleoside analog: a retrospective study of treatment-experienced, patients living with HIV

Abstract

Background Dolutegravir (DTG) monotherapy results in virologic failure and the development of DTG resistance. Here, we evaluated virologic outcomes of patients switched to DTG functional mono- or dual therapy with a non-cytosine nucleoside analog (NA). Methods This retrospective, single center study included treatment-experienced patients switched to regimens containing ≥ 2 antiretrovirals between 8/13/13–11/22/14 who were later found to be on DTG functional mono- or dual therapy with a non-cytosine NA based on historical genotypes. Eligible patients were either suppressed or viremic at baseline and had ≥ 2 HIV-1 RNA measurements at least 4 weeks apart following switch. Demographics, laboratory values and clinical parameters were extracted from the charts of all eligible patients during study treatment until 12/31/2018 and were summarized using descriptive statistics. The primary endpoint was the proportion of patients with HIV-1 RNA < 50 copies/mL following switch. Results Of 70 patients switched to DTG functional mono- or dual therapy, 39 were eligible; 19 (49%) were on DTG functional monotherapy and 20 (51%) were on DTG functional dual therapy with a non-cytosine NA. Historical genotypes indicated that all had an M184V/I, and 23 (59%) had an M184V/I and ≥ 1 additional NA mutation. The median duration of follow-up on study treatment was 50 weeks (range 12–244). Following switch, 32/39 (82%) patients achieved or maintained an HIV-1 RNA < 50 copies/mL and 7 (18%) had persistent HIV-1 RNA ≥ 50 copies/mL. Five viremic patients were found to be on functional dual therapy with DTG plus a non-cytosine NA and 2 were on DTG functional monotherapy. Five of these patients had post-switch genotypes ordered as a part of routine clinical care and there was no evidence of treatment-emergent resistance. Five were switched to a different DTG-containing regimen and achieved HIV-1 RNA < 50 copies/mL, 1 was switched to a non-DTG containing regimen and achieved HIV-1 RNA < 50 copies/mL and 1 was lost-to-follow up at week 36. Conclusions In this real-world cohort, the majority of whom had virus with the M184V/I and ≥ 1 additional NA mutation, switching to DTG functional mono-or dual therapy with a non-cytosine NA resulted in persistent HIV-1 RNA ≥ 50 copies/mL in 18%. None with post-switch genotypes developed treatment-emergent resistance.

HIV-1 drug resistance in people on dolutegravir-based ART: Collaborative analysis of cohort studies

“…The strong associations of DTG resistance with DTG monotherapy and NRTI resistance are consistent with previous findings, 10,31,32 but appear to contradict the results from the NADIA trial, which found no evidence that the efficacy of DTG-based ART is affected by resistance to the NRTI backbone.…”

Dolutegravir Monotherapy as Maintenance Strategy: A Meta-Analysis of Individual Participant Data From Randomized Controlled Trials

“…The risk factors associated with DTG-m virological failure (VL) may well apply to dual therapies including dolutegravir plus a second antiretroviral with low genetic barrier to resistance. This concern of “functional dolutegravir monotherapy” is particularly relevant in the context of previous treatment failure with resistance [ 1 , 13–16 , 27 ]. Finally, potential metabolic problems may arise when DTG is combined with tenofovir alafenamide [ 28 , 29 ].…”

HIV drug resistance in various body compartments

“…Using this approach to exclude defective genomes resulted in improved specificity and agreement with previously or concurrently detected mutations in the blood plasma [24,25]. Taken together, the low reproducibility of currently available archived drug resistance testing, the low proportion of intact proviruses in patients who are virologically suppressed and the high success rate of high genetic barrier regimens, such as ritonavir-boosted protease inhibitor-based or dolutegravir-based regimens, even in cases of functional monotherapy [26–28] may explain the limited value of archived drug resistance in predicting or improving clinical outcomes.…”