Virologic Outcomes of Switching to Dolutegravir Functional Monotherapy, or Functional Dual Therapy With Dolutegravir Plus A Non-cytosine Nucleoside Analog: A Retrospective Study of Treatment-Experienced, HIV-1 Infected Patients

Background Dolutegravir (DTG) monotherapy results in unacceptable virologic failure rates and the development of DTG resistance. Here, we evaluated virologic outcomes of patients switched to DTG functional monotherapy, or functional dual therapy with DTG plus a non-cytosine nucleoside analog (NA). Methods This observational study included treatment-experienced patients switched to regimens containing ≥ 3 antiretrovirals later found to be on DTG functional monotherapy, or functional dual therapy with DTG plus 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 four weeks apart following switch. The primary endpoint was the proportion with HIV-1 RNA<50 copies/mL following switch. Results Thirty-nine patients were included, 19 (49%) were found to be on DTG functional monotherapy and 20 (51%) were found to be on functional dual therapy with DTG plus a non-cytosine NA. The median duration of follow-up was 50 weeks (range 12-244). Following switch, 32/39 (82%) patients achieved or maintained an HIV-1 RNA<50 copies/mL. In 7 (18%) patients with persistent HIV-1 RNA ≥ 50 copies/mL, there was no evidence of treatment-emergent resistance among those with post-switch genotypes. 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 monotherapy, or functional dual therapy with DTG plus a non-cytosine NA resulted in persistent HIV-1 RNA ≥ 50 copies/mL in 18%. None with post-switch genotypes developed treatment-emergent resistance.

Switch studies of DTG + RPV demonstrated that 6/11 patients experiencing con rmed virologic withdrawal developed resistance to RPV, but not DTG [2]. Other clinical trials of suppressed patients switched to DTG monotherapy revealed that a high proportion of virologic failures (VFs) developed DTG resistance [4][5][6]. This suggests that these regimens are 'less forgiving' in the setting of imperfect adherence which is more common in real-world scenarios [7]. Data from non-clinical trial settings would be useful to validate the real-world e cacy and barrier to resistance of DTG-based mono-and dual therapy.

Methods
This was a retrospective study to describe virologic outcomes of patients switched to DTG functional monotherapy, or functional dual therapy with DTG plus a non-cytosine nucleoside analog (NA). Eligible patients included all HIV-1 infected patients seen at the Orlando Immunology Center between 8/13/13 − 11/22/14 switched to once-daily DCRs whose historical genotypes predicted that DTG alone or in combination with a non-cytosine NA were the only fully active antiretrovirals (ARVs). Historical genotypes included standard genotypic assays performed 1-9 years (median 7) prior to switch. Eligible patients were either suppressed or viremic at baseline, must have attended at least two clinic visits during the study period and had a minimum of two HIV-1 RNA measurements at least four weeks apart following switch. Patients with the following baseline mutations associated with reduced susceptibility to DTG: T66K, E92Q, G118R, E138 K/A/T, G140 S/A/C, Q148 H/R/K, N155H and R263K [8] were excluded. Informed consent was waived due to the retrospective nature of the study which utilized data collected as a part of routine clinical care.
Demographics, lab values and clinical parameters were extracted from the charts of eligible patients during DCR treatment until 12/31/2018. The primary endpoint was the proportion of patients achieving or maintaining an HIV-1 RNA < 50 copies/mL following switch. Descriptive statistics were calculated for participant baseline demographic and clinical characteristics, virologic outcomes, and discontinuations throughout the study. The Sterling Institutional Review Board (IRB) determined that the study met IRB exemption criteria based on the retrospective nature of the study (Sterling IRB ID 7115).

Discussion
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][5][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 [2]. 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, ve had postswitch 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 signi cant baseline resistance. Of nonadherent 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 [8]. 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 [8]. 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 [8]. In contrast, this mutation is associated with increased TDF susceptibility and the delay of treatment emergent TDF resistance [8]. 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 [8]. 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 treatmentemergent 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 rst 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.