Efficacy and Safety of Switching to Dolutegravir/Lamivudine Fixed-Dose 2-Drug Regimen vs Continuing a Tenofovir Alafenamide-Based 3- or 4-Drug Regimen for Maintenance of Virologic Suppression in Adults Living With Human Immunodeficiency Virus Type 1: Phase 3, Randomized, Noninferiority TANGO Study

Abstract

Background: The 2-drug regimen dolutegravir (DTG) + lamivudine (3TC) is indicated for treatment-naive adults with human immunodeficiency virus type 1 (HIV-1). We present efficacy and safety of switching to DTG/3TC in virologically suppressed individuals.

Methods: TANGO is an open-label, multicenter, phase 3 study that randomized adults (1:1, stratified by baseline third agent class) with HIV-1 RNA <50 copies/mL to switch to once-daily fixed-dose DTG/3TC or remain on a tenofovir alafenamide (TAF)-based regimen. The primary end point was proportion of participants with HIV-1 RNA ≥50 copies/mL at week 48 (US Food and Drug Administration Snapshot algorithm) in the intention-to-treat-exposed population (4% noninferiority margin).

Results: 743 adults were enrolled; 741 received ≥1 dose of study drug (DTG/3TC, N = 369; TAF-based regimen, N = 372). At week 48, proportion of participants with HIV-1 RNA ≥50 copies/mL receiving DTG/3TC was 0.3% (1/369) vs 0.5% (2/372) with a TAF-based regimen (adjusted treatment difference [95% confidence interval], -0.3 [-1.2 to .7]), meeting noninferiority criteria. No participants receiving DTG/3TC and 1 receiving a TAF-based regimen met confirmed virologic withdrawal criteria, with no emergent resistance at failure. Drug-related grade ≥2 adverse events and withdrawals due to adverse events occurred in 17 (4.6%) and 13 (3.5%) participants with DTG/3TC and 3 (0.8%) and 2 (0.5%) with a TAF-based regimen, respectively.

Conclusions: DTG/3TC was noninferior in maintaining virologic suppression vs a TAF-based regimen at week 48, with no virologic failure or emergent resistance reported with DTG/3TC, supporting it as a simplification strategy for virologically suppressed people with HIV-1.

Clinical trials registration: NCT03446573.

Keywords: 2-drug regimen; integrase strand transfer inhibitor; nucleoside reverse transcriptase inhibitor; simplification; virologic suppression.

Figure 1.

Trial profile. ^aParticipants could have multiple reasons for ineligibility. ^bThe most common reasons for not meeting inclusion criteria or meeting exclusion criteria are listed. All other reasons occurred in <1% of participants. ^cOne participant in the TAF–based regimen group was found to be taking a tenofovir disoproxil fumarate–based regimen at baseline and therefore was excluded from the safety population. ^dProtocol deviations leading to exclusion from the per-protocol population; participants could have had more than 1 reason. Abbreviations: AE, adverse event; ART, antiretroviral therapy; DTG, dolutegravir; HIV-1, human immunodeficiency virus type 1; 3TC, lamivudine; TAF, tenofovir alafenamide.

Figure 2.

A, Virologic outcomes at week 48 in the intention-to-treat–exposed population by US Food and Drug Administration Snapshot algorithm. B, Adjusted treatment differences. ^aOne fatal adverse event unrelated to study treatment occurred (homicide). ^bBased on Cochran-Mantel-Haenszel stratified analysis adjusting for baseline third agent class. Abbreviations: 3TC, lamivudine; AE, adverse event; DTG, dolutegravir; HIV-1, human immunodeficiency virus type 1; TAF, tenofovir alafenamide.

Figure 3.

Proportion of participants with HIV-1 RNA <50 copies/mL at week 48 by subgroup in the intention-to-treat–exposed study population (US Food and Drug Administration Snapshot algorithm). Abbreviations: 3TC, lamivudine; CDC, Centers for Disease Control and Prevention; CI, confidence interval; DTG, dolutegravir; HIV-1, human immunodeficiency virus type 1; INSTI, integrase strand transfer inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor; TAF, tenofovir alafenamide.

Figure 4.

Change from baseline in homeostasis model assessment–insulin resistance (HOMA-IR) in the safety population. Geometric mean ratio and 95% confidence interval for postbaseline values based on a log_e transformation. Change from baseline was calculated using a repeated measures model adjusting for treatment, visit, baseline third agent class, CD4+ cell count (continuous), age (continuous), sex, race, body mass index (continuous), presence of hypertension, log_e-transformed baseline HOMA-IR, treatment-by-visit interaction, and baseline value-by-visit interaction, with visit as the repeated factor. Abbreviations: 3TC, lamivudine; CI, confidence interval; DTG, dolutegravir; TAF, tenofovir alafenamide.

Figure 5.

Change from baseline at week 48 in renal biomarkers. ^aEstimated mean change from baseline at week 48 in each group calculated from mixed model repeated measures adjusting for treatment, visit, baseline third agent class, CD4+ cell count (continuous), age (continuous), sex, race, body mass index (continuous), presence of diabetes mellitus, presence of hypertension, baseline biomarker (continuous), treatment-by-visit interaction, and baseline value-by-visit interaction, with visit as the repeated factor. ^bBased on estimated geometric means ratio of week 48 vs baseline. Based on the same model as plasma/serum markers except adjusting for log_e-transformed baseline biomarker (continuous). *P < .001. Abbreviations: 3TC, lamivudine; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration equation; DTG, dolutegravir; eGFR, estimated glomerular filtration rate; TAF, tenofovir alafenamide.

Figure 6.

Change from baseline in serum or plasma lipids at week 48. ^an = number of participants with nonmissing fasting lipid data at baseline and week 48, removing those with lipid-modifying agent administered at baseline (lipid data collected after initiation of a lipid-modifying agent were censored and a last observation carried forward method was applied so that the last available fasted, on-treatment lipid value before initiation of a lipid-modifying agent was used). ^bPercent change from baseline based on adjusted ratio (week 48 to baseline) in each group calculated from a repeated measures model applied to change from baseline in log_e-transformed data adjusting for the following: treatment, visit, baseline third agent class, CD4+ cell count (continuous), log_e-transformed baseline value (continuous), treatment-by-visit interaction, and baseline value-by-visit interaction, with visit as the repeated factor. *P = .017. **P < .001. Abbreviations: 3TC, lamivudine; DTG, dolutegravir; HDL, high-density lipoprotein; LDL, low-density lipoprotein; TAF, tenofovir alafenamide.