Efficacy and Safety of Switching to Dolutegravir/Lamivudine Versus Continuing a Tenofovir Alafenamide-Based 3- or 4-Drug Regimen for Maintenance of Virologic Suppression in Adults Living With Human Immunodeficiency Virus Type 1: Results Through Week 144 From the Phase 3, Noninferiority TANGO Randomized Trial

Abstract

Background: Switching to dolutegravir/lamivudine (DTG/3TC) was noninferior to continuing tenofovir alafenamide (TAF)-based regimens for maintaining virologic suppression at week 48 of the TANGO study. Here we present week 144 outcomes (efficacy, safety, weight, and biomarkers).

Methods: TANGO is a randomized (1:1, stratified by baseline third agent class), open-label, noninferiority phase 3 study. Virologically suppressed (>6 months) adults with human immunodeficiency virus type 1 (HIV-1) switched to once-daily DTG/3TC or continued TAF-based regimens.

Results: A total of 741 participants received study treatment (DTG/3TC, n = 369; TAF-based regimen, n = 372). At week 144, the proportion of participants with an HIV-1 RNA level ≥50 copies/mL (primary end point, Snapshot; intention-to-treat-exposed population) after switching to DTG/3TC was 0.3% (1 of 369) versus 1.3% (5 of 372) for those continuing TAF-based regimens, demonstrating noninferiority (adjusted treatment difference, -1.1 [95% confidence interval, -2.4 to .2), with DTG/3TC favored in the per-protocol analysis (adjusted treatment difference, -1.1 [-2.3 to -.0]; P = .04). Few participants met confirmed virologic withdrawal criteria (none in the DTG/3TC and 3 in the TAF-based regimen group), with no resistance observed. Drug-related adverse events were more frequent with DTG/3TC (15%; leading to discontinuation in 4%) than TAF-based regimens (5%; leading to discontinuation in 1%) through week 144, but rates were comparable after week 48 (4%; leading to discontinuation in 1% in both groups). Changes from baseline in lipid values generally favored DTG/3TC; no clinical impact on renal function and comparable changes in inflammatory and bone biomarkers across groups were observed.

Conclusions: Switching to DTG/3TC demonstrated noninferior and durable efficacy compared with continuing TAF-based regimens in treatment-experienced adults with HIV-1, with good safety and tolerability, and no resistance through 144 weeks.

Trial registration: ClinicalTrials.gov NCT03446573.

Keywords: 2-drug regimen; dolutegravir/lamivudine; durable; integrase strand transfer inhibitor; treatment-experienced.

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. ^cOf 919 screened participants, 543 (59%) had historical genotypic reports, 9 (2%) of whom were excluded because of major nucleoside reverse-transcriptase inhibitor (NRTI) resistance: 1 had M41L and D67N, 2 had M41L, and the remaining 6 each had a single mutation identified as M184I, K65R, K219E, K219Q, D67N, or L210W (post hoc analysis). ^dOne participant in the tenofovir alafenamide (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. ^eForty-four participants had missing week 96 human immunodeficiency virus type 1 (HIV-1) RNA data owing to the coronavirus disease 2019 pandemic (ie, discontinued or unable to attend week 96 site visit because of the pandemic). ^fProtocol deviations leading to exclusion from the per-protocol population; participants could have had ≥1 reason. Abbreviations: AEs, adverse events; ART, antiretroviral therapy; DTG/3TC, dolutegravir/lamivudine.

Figure 2.

A, Virologic outcomes at weeks 96 and 144 in the intention-to-treat–exposed (ITT-E) population by the US Food and Drug Administration Snapshot algorithm. B, Adjusted treatment differences (dolutegravir/lamivudine [DTG/3TC] group value − tenofovir alafenamide [TAF] group value), based on Cochran-Mantel-Haenszel stratified analysis, with adjustment for baseline third agent class. Abbreviation: HIV-1, human immunodeficiency virus type 1.

Figure 3.

Proportion of participants with human immunodeficiency virus type 1 (HIV-1) RNA levels <50 copies/mL by subgroup in the intention-to-treat–exposed population by US Food and Drug Administration Snapshot algorithm at week 144. ^aThe study population was stratified by baseline third agent class (protease inhibitor [PI], integrase strand transfer inhibitor [INSTI], or nonnucleoside reverse-transcriptase inhibitor [NNRTI]). ^bIn all 8 Snapshot nonresponders receiving dolutegravir/lamivudine (DTG/3TC) with a baseline CD4⁺ cell count <350/µL, Snapshot nonresponse occurred for nonvirologic reasons. ^cAdjusted difference for overall population (DTG/3TC − tenofovir alafenamide [TAF]–based regimen) and 95% confidence intervals (CIs) are based on a stratified analysis (adjusting for baseline third agent class) using Cochran-Mantel-Haenszel weights (meeting noninferiority based on −8% margin); unadjusted differences for subgroups represent proportion on DTG/3TC − proportion on TAF-based regimen.

Figure 4.

Summary of adverse events (AEs) after week 48. Abbreviations: DTG/3TC, dolutegravir/lamivudine; TAF, tenofovir alafenamide.

Figure 5.

Change from baseline in homeostasis model of assessment–insulin resistance (HOMA-IR) in the safety population through week 144. The change from baseline was calculated using 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 hypertension, log_e-transformed baseline HOMA-IR (continuous), treatment-by-visit interaction, and baseline value-by-visit interaction, with visit as the repeated factor. Abbreviations: CI, confidence interval; DTG/3TC, dolutegravir/lamivudine; TAF, tenofovir alafenamide.

Figure 6.

Change from baseline in fasting lipids at week 144 (A) and at weeks 96 and 144 (B) by National Cholesterol Education Program (NCEP) category. ^aNumber of participants with nonmissing fasting lipid data at baseline and week 144, excluding 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). Use of lipid-modifying agents at baseline was similar between treatment groups (dolutegravir/lamivudine [DTG/3TC], 13%; tenofovir alafenamide [TAF]–based regimen, 15%). ^bPercentage change from baseline based on adjusted ratio (week 144 to baseline) in each group calculated from mixed-model repeated measures applied to change from baseline in log_e-transformed data adjusting for treatment, visit, baseline third agent class, age (continuous), body mass index (continuous), race, 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. ^cNumbers of participants with nonmissing fasting lipid data at baseline and study week (week 96: DTG/3TC, n = 238; TAF- based regimen, n = 213; week 144: DTG/3TC, n = 243; TAF-based regimen, n = 230), excluding participants 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). ^dNCEP categories at weeks 96 and 144 versus baseline. Abbreviations: CI, confidence interval; HDL, high-density lipoprotein; LDL, low-density lipoprotein; NA, not applicable; TC, total cholesterol; TGL, triglycerides.