Baseline NNRTI resistance linked to poorer response to first-line dolutegravir in the ADVANCE study
Participants with pretreatment NNRTI resistance, receiving dolutegravir (DTG) in ADVANCE, had lower rates of viral suppression at 96 weeks than those without – according to findings reported in the 1 December issue of Nature Communications. 
ADVANCE is an ongoing, three arm, 192-week, phase 3 study, comparing first-line ART with: tenofovir alafenamide (TAF)/emtricitabine (FTC) + DTG, tenofovir disoproxil fumarate (TDF)/FTC + DTG or TDF/FTC/efavirenz (EFV). Week 96 data were presented this year. 
The resistance analyses were conducted with the hypothesis that pre-treatment NNRTI resistance significantly affects efficacy of EFV-containing regimens but has a negligible effect on outcomes for those starting DTG-based therapy.
Of 1053 participants enrolled in ADVANCE, 991 (94%) consented for specimen storage and had pretreatment plasma available; 874 (83%) had successful sequencing.
Among participants included in the resistance analyses, 289 (33%) were randomised to the EFV and 585 (67%) to the DTG arms. All had completed week 96 of the study at the time of the analyses. Participants starting DTG-based regimens had a higher prevalence of pretreatment drug resistance than those starting EFV-based regimens: 16.5 vs 7.4%, p< 0.001. Otherwise, there were no clinical or demographic differences between the two groups.
The investigators found 14% (122/874) of participants with at least one WHO-defined pretreatment drug resistant mutation. Most of the resistance was to NNRTIs, with over 98% (120/122) of participants with pretreatment resistance having at least one NNRTI mutation.
K103N was the most common NNRTI mutation (9%, 81/874). Only 2% (20) of participants had a NRTI mutation. M184V was the most frequent (1%, 12 participants) followed by K65R (1%, 8 participants). Two per cent (18 participants) had at least one NRTI mutation and one NNRTI mutation.
Rates of virologic suppression were significantly lower overall in participants with pretreatment drug resistance than those without: respectively, 65% (73/112) vs 85% (605/713), p< 0.001.
This was similar for those starting EFV- or DTG-based ART: respectively, 60% (12/20) vs 86% (214/248), p = 0.002, and 66% (61/92) vs 84% (391/465), p< 0.001.
In multivariate analysis, adjusted for demographics, clinical factors and adherence, pretreatment drug resistance was a strong predictor of virologic success: AOR 0.38 (95% CI 0.21 to 0.61).
Results were similar when the investigators assessed persistent virologic failure (defined as two consecutive viral loads >200 copies/mL): respectively, 85% (73/86) vs 94% (428/453), p= 0.001 and 68% (13/19) vs 93% (217/233), p < 0.001 for DTG and EFV-based ART.
By contrast, pretreatment drug resistance only had an effect on early virologic response for participants receiving EFV-based but not DTG-based ART. At week 12, the drop in viral load was greater for those without pretreatment drug resistance in the EFV arm but not in the DTG arms: respectively 1.89 vs 2.61 log10 copies/mL, p< 0.001, and 2.76 vs 2.68 log10 copies/mL, p< 0.43 (p=0.001 for interaction between arms).
The investigators wrote that “…the finding that NNRTI resistance appears to ultimately predict treatment failure among individuals initiating DTG-based ART in LMIC was unexpected, and to our knowledge not previously reported in the literature”.
They noted that integrase resistance mutations were not assessed in this study but are generally believed to be rare (<1%) in this region.
They speculated that one explanation for the lack of long-term suppression in participants receiving DTG-based ART might be behavioral – pre-existing EFV mutations could be a linked to earlier undisclosed ART exposure. Previous ART exposure has been associated with treatment failure and predicts virologic failure, even after controlling for pretreatment drug resistance and adherence.
The finding that NNRTI resistance is associated with a reduction in efficacy of DTG-based ART has multiple public health implications.
It means that viral load monitoring remains a priority with DTG-based regimens.
Second- and third-line options will also still be needed and integrase inhibitor resistance testing should be considered.
However, the authors also recommend that these findings need to be validated. Future analyses should also:
- Assess the contribution of pretreatment integrase mutations to outcomes.
- Look at the impact of prior exposure to ART on treatment outcomes.
- Find out whether treatment failure observed on DTG-based ART is associated with emergence of integrase inhibitor mutations.
1. Siedner MJ et al. Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase. Nature Communications. 11, 5922. 1 December 2020 (Open access).
2. Clayden P. ADVANCE 96-week results: dolutegravir weight gain continues, especially in women and when used with TAF – no evidence of a plateau. HTB. 22 July 2020.