Data from randomized clinical trials has demonstrated that 6–10% of virologically suppressed patients switched to DTG monotherapy experienced VF, and of those 29–100% developed INSTI resistance [4–6]. Studies evaluating virologically suppressed patients switched to dual DTG-based therapy with 3TC and RPV demonstrated VF rates of 1–3% and zero patients developed treatment-emergent INSTI resistance [2, 3]. In the case of DTG + RPV, 54% of VFs developed resistance to RPV . In our cohort, 2/19 (11%) treated with DTG functional monotherapy and 5/20 (25%) treated with functional dual therapy with DTG plus a non-cytosine NA experienced VF. Of these, five had post-switch genotypes and none developed treatment emergent INSTI resistance (Table 2).
The most likely reasons for VF in our cohort included suboptimal adherence and the presence of significant baseline resistance. Of non-adherent VFs, two were on functional DTG monotherapy, and three were on DTG + non-cytosine NA. Of those on functional monotherapy, one was on DTG + RPV and had baseline E138E/K which reduces RPV susceptibility . The other was on DTG + ABC/3TC and had baseline M184V/I, L74I, M41L and T215Y, the combination of which severely reduces susceptibility to 3TC and ABC . In both patients, the presence of these baseline RAMs may have contributed to VF.
Among the three non-adherent VFs on functional dual therapy, two were on DTG + ABC and only had baseline M184V/I whereas the other was on DTG + TDF and had baseline M184V/I, M41L and T215Y. In addition to reduced 3TC and emtricitabine susceptibility, the M184V/I mutation is associated with low-level ABC resistance and may have contributed to VF in those on DTG + ABC . In contrast, this mutation is associated with increased TDF susceptibility and the delay of treatment emergent TDF resistance . However, in the patient on DTG + TDF this “hypersensitizing” effect may have been reduced by the presence of baseline M41L and T215Y which in combination are associated with low-to-intermediate-level TDF resistance and may have contributed to VF in this patient . Nonetheless, 32/39 patients in our cohort with similar baseline resistance on functional DTG-based mono-and-dual therapy achieved or maintained virologic suppression suggesting that the primary reason for VF in these patients was likely non-adherence. This is also supported by the fact that 4/5 non-adherent VFs had baseline HIV-1 RNA ≥ 50 copies/mL which likely indicates a history of non-adherence prior to study entry.
Post-switch genotypes were only available for the 5 non-adherent VFs, and 4 of these were obtained on DTG. We observed no treatment-emergent NRTI or INSTI resistance, and 3/5 patients subsequently went on to achieve HIV-1 RNA < 50 copies/mL on a different DCR after discontinuation of the study regimen. One patient achieved HIV-1 RNA < 50 copies/mL on a non-DCR and the other was lost to follow up (Table 1). Though based on a small sample, this observation reinforces the high genetic barrier to resistance of DTG and its forgiveness in the setting of non-adherence, even in patients with pre-existing ARV resistance.
Two VFs were documented as 100% adherent, both were on functional dual therapy; one was on DTG + TDF and the other was on DTG + ABC. Both had baseline M184V/I without additional NRTI mutations. In the patient on DTG + ABC, the reduction in ABC susceptibility conferred by the M184V/I may have contributed to VF. However, in the other on DTG + TDF, this mutation is expected to increase TDF susceptibility and does not fully explain VF development. Baseline mutations may have contributed to VF in these cases; however, it is unknown how accurate their documented adherence patterns were and whether non-adherence may have also played a role.
In 32/39 patients on functional DTG-based mono-and dual therapy, HIV-1 RNA < 50 copies/mL was achieved and maintained throughout the study period. All patients received DCRs with ≥ 3 ARVs, and though baseline resistance testing predicted either functional-mono or, dual therapy, we acknowledge the possibility of partial activity from other ARVs deemed not fully active. This may explain the high virologic response rates observed in our study and the lack of treatment emergent INSTI resistance in those with VF due to “protection” of DTG by these partially active agents.
Limitations of this study include a small sample size, the retrospective nature of the analysis, the lack of control group, possible inaccuracy of documented information, and that data are from a single center in the Southeastern United states. However, this is the first report of outcomes of patients treated with functional DTG-based mono-and-dual therapy from a US cohort and may provide important insight into DTG-based treatment strategies with fewer ARVs.