Dolutegravir-based dual maintenance regimens combined with lamivudine/emtricitabine or rilpivirine: risk of virological failure in a real-life setting

Abstract

Background Maintenance ART with dolutegravir-based dual regimens have proved their efficacy among HIV-1-infected subjects in randomized trials. However, real-life data are scarce, with limited populations and follow-up. Objectives We assessed virological failure (VF) and resistance-associated mutations (RAMs) on dolutegravir maintenance regimens in combination with rilpivirine or with lamivudine or emtricitabine (xTC) and analysed the factors associated with VF. Methods Between 2014 and 2018, all HIV-1-infected adults included in the Dat’AIDS cohort and starting dolutegravir/rilpivirine or dolutegravir/xTC as a maintenance dolutegravir-based dual regimen were selected. VF was defined as two consecutive HIV RNA values >50 copies/mL or a single value >400 copies/mL. We compared cumulative genotypes before initiation of a maintenance dolutegravir-based dual regimen with genotype at VF. Results We analysed 1374 subjects (799 on dolutegravir/rilpivirine and 575 on dolutegravir/xTC) with a median follow-up of 20 months (IQR = 11–31) and 19 months (IQR = 11–31), respectively. VF occurred in 3.8% (n = 30) of dolutegravir/rilpivirine subjects and 2.6% (n = 15) of dolutegravir/xTC subjects. Among subjects receiving dolutegravir/rilpivirine, two genotypes harboured emerging RAMs at VF: E138K on NNRTI (n = 1); and E138K+K101E on NNRTI and N155H on INSTI (n = 1). Among subjects receiving dolutegravir/xTC, no new RAM was detected. The only predictive factor of VF on dolutegravir/rilpivirine was the history of failure on an NNRTI-based regimen (adjusted HR = 2.97, 95% CI = 1.28–6.93). No factor was associated with VF on dolutegravir/xTC. Conclusions In this large real-life cohort, dolutegravir/rilpivirine and dolutegravir/xTC sustained virological suppression and were associated with a low rate of VF and RAM emergence. Careful virological screening is essential before switching to dolutegravir/rilpivirine in virologically suppressed patients with a history of NNRTI therapy.

A Comprehensive Literature Review of Treatment-Emergent Integrase Resistance with Dolutegravir-Based Regimens in Real-World Settings

“…In general, INSTI mutations were infrequently detected at VF across studies identified in this review, even in cohorts where individuals had previous VF and/or historical mutations. VF rates ranged from 1% to 60% among the 16 lead studies reporting VF outcomes [33,[36][37][38][39][40][41][42][43]45,46,49,50,53,58,59] for individuals on DTG-based regimens (excluding 8 lead studies with 100% VF rates due to study design [31,32,35,44,48,52,60,62], i.e., resistance analyses in populations failing treatment); of note, the highest rates (50% and 60%) were observed in cohorts with N ≤ 5 [53,58]. These results are consistent with other real-world studies [69][70][71] reporting low VF rates and/or infrequent INSTI RAM development in people receiving DTG-based treatment and reinforce the high barrier to resistance observed in interventional studies in ART-naive and ART-experienced individuals [14][15][16][17][18][19][20][21][22][23][24][25]27,…”

“…The proportions of people living with HIV who experienced VF on DTG-based therapy and developed treatment-emergent integrase mutations by study and regimen are shown in Table 1. While the definition of VF varied, many included 1 or 2 consecutive measurements of "detectable" HIV-1 RNA [31,32], or 1 or 2 consecutive measurements of HIV-1 RNA > or ≥50 copies/mL [33][34][35][36][37][38][39][40][41], >200 copies/mL [40,42,43], >400 copies/mL [37,44], ≥500 copies/mL [41], and/or >1000 copies/mL [45,46] as part of study-defined VF criteria. Many did not explicitly define VF criteria [47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62].…”

“…The French Dat'AIDS multicenter cohort reported INSTI resistance outcomes in treatment-experienced, virologically suppressed individuals who switched to DTG/RPV (n = 799) and DTG + XTC (n = 575; n = 488 [84.9%] with 3TC) between January 2014 and September 2018. Overall, 464 (33.8%) had a history of prior VF [37]. After a median follow-up of ~20 months, VF was reported in 30 (3.8%) individuals receiving DTG/RPV and 15 (2.6%) receiving DTG + XTC.…”

Long-term Evaluation of Residual Viremia in a Clinical Trial of Dolutegravir Plus Lamivudine as Maintenance Treatment for Participants With and Without Prior Lamivudine Resistance

“…Evidence for dolutegravir (DTG) plus lamivudine (3TC) treatment in persons with past 3TC resistance is limited and comes mostly from retrospective cohorts or small prospective studies showing, so far, that past M184V/I mutations do not have a significant negative impact on maintenance of virological suppression and that, when virological failure occurs, it does not involve emerging integrase resistance [ 1–4 ].…”

Changes in Serum Inflammatory Markers in Antiretroviral Therapy–Naive HIV-Infected Patients Starting Dolutegravir/Lamivudine or Tenofovir Alafenamide/Emtricitabine/Bictegravir

“…The availability of effective 2-drug combinations has made it possible to reduce cumulative drug exposure, long-term toxicity, risk of drug–drug interaction, and costs of antiretroviral regimens. 3,4 However, an unsolved question about dual therapies is the risk of an incomplete virological suppression in viral reservoirs, leading to a significant residual viremia and a persistent inflammatory state. In clinical trials, the dual combination dolutegravir/lamivudine has demonstrated a durable and noninferior virological efficacy in comparison with 3- and 4-drug regimens in both antiretroviral therapy–naive and antiretroviral therapy–experienced patients, but data about the anti-inflammatory effects of current dual regimens are still scarce.…”