Table 4.

Virological failure (VF) and prevalence of emergent INSTI-associated DRMs in clinical trials of ART-experienced PLWH with virological suppression (VS) receiving a DTG-containing regimen.

Trial	Regions	Population	DTG-Containing Regimen	# PLWH	Weeks	# (%) VF 1	# (%) Undergoing GRT 2	# (%) INSTI DRMs
DTG plus 2 NRTIs
NEAT022 2017, 2019 [75,76] 3	Europe	<50 copies x ≥ 6 months on a boosted PI regimen; no h/o VF or NRTI DRMs	DTG + 2 NRTIs	205	96	5 (2.4%)	3 (1.5%)	0 (0%)
STRIIVING 2017 [77] 3	North America	<50 copies x ≥ 6M on an NNRTI-, boosted PI, or 1st-generation INSTI regimen; no h/o VF	DTG + ABC/3TC	275	48	0 (0%)	0 (0%)	0 (0%)
2SD 2023 [78] 4	Kenya	<50 copies x ≥ 3M on a 2nd-line boosted PI regimen	DTG + 2 NRTIs	397	48	20 (5.0%)	0 (0%)	0 (0%)
DTG plus a second ARV
TANGO 2020, 2022 [82,83]	Europe, North America, Asia, Oceania	<50 copies/mL x ≥ 6 months on a TAF-containing regimen (78% on an INSTI); no h/o of VF or DRMs	DTG/3TC	369	144	1 (0.3%)	0 (0%)	0 (0%)
SALSA 2023 [84]	Europe, North America, South America, Asia, Africa	<50 copies/mL x ≥ 6 months; 40% on an INSTI; no h/o of VF or DRMs	DTG/3TC	246	48	1 (0.4%)	0 (0%)	0 (0%)
DOLAM–Phase B 2021 [85] 5	Spain	<50 copies/mL x ≥ 12 months; 47% on an INSTI; no h/o of VF or DRMs on an XTC- or INSTI-containing regimen	DTG/3TC	131	48	3 (2.3%)	3 (2.3%)	0 (0%)
LAMIDOL 2019 [86]	France	<50 copies/mL x ≥ 24 months; 21% on an INSTI; no h/o of VF or DRMs	DTG/3TC	104	48	1 (1.0%)	1 (1.0%)	0 (0%)
ASPIRE 2018 [87]	United States	<50 copies/mL x ≥ 6 months; 37% on an INSTI; no h/o of VF or DRMs	DTG/3TC	44	24	1 (2.3%)	1 (2.3%)	0 (0%)
ART-PRO 2020, 2021, 2022 [88,89,90]	Spain	<50 copies/mL x ≥ 12 months; 21 had a history of M184VI; single arm pilot trial.	DTG/3TC	41	48	0 (0%)	0 (0%)	0 (0%)
SIMPL’HIV 2020 [91]	Switzerland	<50 copies/mL x ≥ 6 months; 63% on an INSTI; no h/o VF or DRMs;	DTG/FTC	93	48	1 (1.1%)	1 (1.1%)	0 (0%)
SWORD-1 and 2 2018, 2019, 2020 [92,93,94] 5	Europe, North America, Asia, Oceania	<50 copies/mL x ≥ 6 months on a 1st or 2nd ART regimen; 20% on an INSTI; no h/o of VF or DRMs	DTG/RPV	513	144	14 (2.7%)	7 (1.4%)	0 (0%)
DUALIS 2020 [95,96]	Germany	<50 copies/mL x ≥ 6 months receiving boosted DRV + 2 NRTIs; 7% with prior INSTI use; no h/o DTG or DRV DRMs	DTG/DRV/r	131	48	5 (3.8%)	Not reported	0 (0%)
SMILE 2023 [97] 6	Uganda, South Africa, Thailand, Europe, Latin America	Perinatally infected children/adolescents; <50 copies/mL x ≥ 12 months; no h/o DTG or DRV DRMs	DTG/DRV/r	158	48	8 (5.1%)	6 (3.8%)	0 (0%)
DTG monotherapy
DOMONO 2017, 2018, 2019 7	Netherlands	VL < 50 x ≥ 6 months; plasma HIV-1 RNA zenith <105 copies/mL and CD4 count nadir > 200 cells/mm3; 15% INSTI experienced; no h/o VF.	DTG monotherapy	99	48	10 (10.1%)	8 (8.1%)	4 (4.1%)
DOLAM 2018 [118] 8	Spain	VL < 50 x ≥ 12 months; CD4 count nadir > 200 cells/mm3; 17% INSTI experienced; no h/o VF on an INSTI regimen.	DTG monotherapy	31	24	2 (6.5%)	2 (6.5%)	2 (6.5%)
EARLY SIMPLIFIED 2019, 2023 [119,120]	Switzerland	VL < 50 x ≥ 12 months; ART began within 6 months of HIV infection; 60% INSTI experienced; no h/o VF.	DTG monotherapy	68	96	0 (0%)	0 (0%)	0 (0%)
MONCAY 2019 [121] 9	France	VL < 50 x ≥ 12 months and on DTG/ABC/3TC x ≥ 1 month; CD4 count nadir > 100 cells/mm3; no h/o VF on an INSTI regimen.	DTG monotherapy	78	48	7 (9.0%)	7 (9.0%)	2 (2.6%)

¹ VF was defined as a confirmed VL ≥ 50 in each trial except for DOLAM phase B which required a confirmed VL ≥ 50 or a single VL ≥ 1000; LAMIDOL, ASPIRE, and SMILE which required a confirmed VL ≥50, and DOMONO which required a confirmed VL ≥ 200. In STRIIVING, VF did not include individuals who discontinued DTG-containing ART for reasons other than loss of viral efficacy. ² In STRIIVING, no individual met the criteria for GRT which was two consecutive VL ≥ 400. Only one of 20 individuals with VF in 2SD met the criteria for GRT, VL ≥ 200. But this sample could not be successfully amplified. ³ In both NEAT022 and STRIIVING, participants initially randomized to continue their original ART were subsequently offered a deferred switch to the DTG-containing regimen. The number of individuals undergoing deferred switch and their duration of follow-up was not available, although it was noted that none developed emergent INSTI-associated DRMs. ⁴ In 2SD, there were 3 NRTI combinations: TDF/3TC (52%), AZT/3TC (44%), and ABC/3TC (4%). ⁵ In the SWORD trials, there was an immediate switch group of 513 individuals and a late switch group of 477 individuals that switched after one year. Ten (2.0%) of the late switch group experienced VF. Two underwent successful GRT and one was found to have the polymorphic accessory INSTI-resistance mutation V151I. ⁶ In SMILE, the first five participants randomized to the INSTI arm received elvitegravir; the remaining 153 received DTG. Whether any of those with VF had received elvitegravir was not reported. ⁷ The DOMONO trial included a pilot study group of four individuals, an immediate switch group of 50 individuals, and a delayed switch group of 45 individuals. The 10 individuals with VF included 6 in the immediate switch, 2 in the delayed switch, and 2 in the pilot study. All four of those with emergent INSTI DRMs had been INSTI-naïve. One of the eight individuals who underwent GRT was found to have 3′ polypurine tract mutations. This individual did not have DRMs in integrase and was not counted among the four with INSTI DRMs. ⁸ The DOLAM study had two phases. The first phase (phase A, reported in this table) included a monotherapy arm. In phase B, this arm was discontinued. The two individuals in the DOLAM trial reported to have developed INSTI DRMs were INSTI-naïve. ⁹ Among the 7 individuals with VF, 1 had previously received raltegravir. This individual was not reported to develop INSTI DRMs. One individual developing R263K also had a 3′ polypurine tract mutation. Abbreviations: 3TC—lamivudine; ABC—abacavir; ART—antiretroviral therapy; DTG—dolutegravir; DRMs—drug-resistance mutations; DRV/r—ritonavir-boosted darunavir; FTC—emtricitabine; GRT—genotypic resistance testing; INSTI—integrase strand transfer inhibitor; NRTIs—nucleoside/nucleotide reverse transcriptase inhibitors; PI—protease inhibitor; PLWH—people living with HIV; RPV—rilpivirine; TAF—tenofovir alafenamide; TDF—tenofovir disoproxil fumarate; VF—virological failure; VL—virus load (plasma HIV RNA copies/mL) vs.—virological suppression; XTG—3TC or FTC.