Editor: A review article recently published in AIDS Research and Human Retroviruses by Boffito et al. discusses the barrier to resistance in the context of the two-drug regimen, dolutegravir+lamivudine (DTG +3TC).1 This review did not discuss a previously reported case of resistance that emerged during DTG +3TC treatment.2 The participant, who was one of three who experienced protocol-defined virologic failure (VF) in the phase 2 AIDS Clinical Trials Group A5353 study, NCT02582684,2 had no antiretroviral drug resistance mutations by bulk sequencing at the time of study entry, and was found to have the M184V mutation in reverse transcriptase (RT) at the time of VF (week 24). To more thoroughly characterize the observation, the study team performed genotypic analysis at earlier time points (weeks 8 and 14), wherein the participant had low-level viremia and low levels of DTG. One of those analyses (week 14) identified R263R/K, a less characterized integrase mutation, along with M184V.
We would also like to share unpublished results from a preplanned A5353 substudy wherein we conducted (1) next-generation sequencing of the full RT, protease and integrase regions (DEEPGEN)3 to investigate whether minority drug-resistant variants contributed to VF on DTG +3TC, and (2) phenotyping to characterize the impact of emergent mutations on viral susceptibility. The results of minority variant testing are shown in Figure 1. In the participant with emergent M184V and R263R/K by population sequencing (Participant A), the minority variant analysis showed that M184V and R263K mutations were not present at study entry. The M184V mutation developed at week 8 then R263K emerged at week 24, along with additional mutations in the RT region. Phenotypic testing showed no significant impact of the R263K mutation on susceptibility to integrase inhibitors, with raltegravir, elvitegravir, bictegravir, and dolutegravir IC50-fold changes of 1.11, 1.59, 1.35, and 1.11, respectively. The viral minority variants found in the other two participants with VF (Participants B and C) are also shown in Figure 1. Neither of these participants had any 3TC or dolutegravir-linked minority variants. No phenotypic resistance was observed to DTG or any integrase inhibitor in Participant B. A phenotypic result could not be obtained on the VF sample from Participant C. Thus, the additional virology work performed on the three participants who experienced VF found no evidence that minority variants contributed to VF on DTG +3TC in A5353.
FIG. 1.
Minority drug-resistant variants detected in participants with virologic failure in AIDS Clinical Trials Group A5353.
VF in A5353 was strongly linked to suboptimal adherence; the three participants with VF had DTG levels below the limit of detection at least once around the time of VF.2 Given the lack of resistance in other clinical trials of DTG +3TC to date, we speculate that resistance emergence in A5353 was due to a critical level of suboptimal adherence that predisposed to selection of drug-resistant viral variants. An uncommon pattern of nonadherence such as intermittent DTG and/or 3TC monotherapy cannot be excluded, since DTG and 3TC were supplied as two separate pills in the study. Interestingly, the large GEMINI studies also used separate DTG and 3TC tablets without resistance emergence.4 Thus, although this case is important, it should be placed in appropriate context since 716 patients were treated with DTG +3TC in the GEMINI trials and none failed with treatment-emergent resistance through 96 weeks. In conclusion, although failure of DTG +3TC with treatment-emergent resistance is possible, it appears to be rare. Recently, the U.S. Food and Drug Administration (FDA) approved DTG +3TC single tablet formulation as a complete regimen for the treatment of HIV-1 infection.
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The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information
Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award numbers UM1 AI068634, UM1 AI068636, and UM1 AI106701. ViiV Healthcare provided the study medications.
References
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