INTRODUCTION

Dolutegravir (DTG)/lamivudine (3TC) is a 2-drug antiretroviral therapy regimen recommended internationally as a suppressed-switch option in adults with HIV-1 and no history of virologic failure or drug resistance to reduce the number of drugs in a regimen.1–3 The phase 3 TANGO4 trial randomized virologically suppressed adults to switch to once-daily DTG/3TC or maintain stable tenofovir alafenamide–based regimens and, as the primary endpoint, assessed proportion of the intention-to-treat-exposed (ITT-E) population with HIV-1 RNA ≥50 copies/mL (Snapshot algorithm) at week 48. Switching to DTG/3TC demonstrated durable and noninferior efficacy vs continuing tenofovir alafenamide–based regimens for maintaining virologic suppression through 144 weeks, with a high barrier to resistance and well-tolerated safety profile.5

In year 3, TANGO entered a nonrandomized phase with all participants receiving DTG/3TC. Here, we present 196-week efficacy and safety data for those who switched to DTG/3TC on day 1 and 48-week data for those who switched to DTG/3TC at week 148.

METHODS Study Design

TANGO (ClinicalTrials.gov, NCT03446573) is a randomized, open-label, parallel-group, active-controlled, multicenter, phase 3 study conducted in 10 countries. Study protocols and amendments were reviewed and approved by ethics committees or institutional review boards. TANGO was conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent before study initiation.

Details for the initial phase of TANGO have been published.4,5 Briefly, virologically suppressed (HIV-1 RNA <50 copies/mL) adults on an uninterrupted tenofovir alafenamide–based regimen for >6 months before screening, with no previous virologic failure or documented nucleoside reverse transcriptase inhibitor or integrase strand transfer inhibitor resistance, were eligible.

Procedures

Participants were stratified by baseline third agent class and randomized 1:1 to either switch to once-daily, fixed-dose combination DTG/3TC or continue a 3- or 4-drug tenofovir alafenamide–based regimen from day 1 to week 148. Participants randomized to receive DTG/3TC on day 1 are referred to as the early-switch (ES) group. Participants randomized to continue tenofovir alafenamide–based regimens from day 1 to week 144 switched to DTG/3TC at week 148 and are referred to as the late-switch (LS) group (only those with confirmed virologic suppression at week 144 were eligible to continue as the LS group).

Plasma HIV-1 RNA viral load testing was performed by Q2 Solutions Laboratories (Durham, NC) using Abbott HIV-1 Realtime assay (Abbott Molecular, Des Plaines, IL; quantitative detection range, 40–10,000,000 copies/mL). Whole-blood proviral DNA genotyping and plasma HIV-1 RNA genotyping and phenotyping were performed by Monogram Biosciences (South San Francisco, CA) using Genosure Archive, PhenoSense IN, PhenoSense GT, and GeneSeq IN assays.

Outcomes

Protocol-defined week 196 exploratory endpoints included proportion of participants with HIV-1 RNA <50 copies/mL (Snapshot; ITT-E) and DTG/3TC safety and tolerability. Incidence of confirmed virologic withdrawal (CVW; HIV-1 RNA ≥50 copies/mL followed by a second consecutive HIV-1 RNA ≥200 copies/mL) and viral resistance was evaluated. Change from baseline in lymphocyte counts; weight; and renal, bone, and inflammatory biomarkers was assessed. For the ES group, baseline refers to day 1; for the LS group, LS baseline generally refers to week 148, but if week 148 data were unavailable, the most recent preswitch data were used.

Analyses

The ITT-E population included all randomized participants who received ≥1 dose of study treatment. The safety population included ITT-E participants who received the correct assigned treatment. For this nonrandomized phase of the study, efficacy was analyzed by Snapshot and observed analyses. Descriptive summary statistics are presented for safety and metabolic health parameters. Data tabulations and calculations were performed using SAS software version 9.4 (SAS Institute Inc., Cary, NC).

RESULTS Participants

Overall, 99% (369/371) of randomized participants received DTG/3TC from day 1 through week 196 (ES group). Of participants randomized to continue tenofovir alafenamide–based regimens on day 1, 80% (298/372) remained on study, maintained virologic suppression at week 144, and switched to DTG/3TC at week 148 (LS group). Between weeks 144 and 196, 12 (3%) ES participants and 24 (8%) LS participants discontinued, most commonly for adverse events [AEs; ES, <1% (2/369); LS, 3% (9/298)] and lost to follow-up [ES, 1% (5/369); LS, 2% (6/298); see Supplemental Digital Content (SDC) 1, Supplemental Digital Content, https://links.lww.com/QAI/C246, table showing disposition]. Demographics and baseline characteristics were generally comparable between groups (see SDC 2, Supplemental Digital Content, https://links.lww.com/QAI/C247, table showing participant characteristics). A higher proportion of participants were aged ≥50 years in the LS group (34%) vs the ES group (21%) at time of DTG/3TC start.

Efficacy

At week 196, high proportions of participants had HIV-1 RNA <50 copies/mL (Snapshot; ITT-E): 83% (306/369) in the ES group after 196 weeks of DTG/3TC and 93% (278/298) in the LS group after 48 weeks of DTG/3TC (Fig. 1). Overall ES and LS group virologic response rates were consistent with rates across various demographic and baseline characteristic subgroups (see SDC 3, Supplemental Digital Content, https://links.lww.com/QAI/C248, figure showing virologic response by subgroup). By observed analysis, 99% (306/309) of ES participants on study through week 196 were virologically suppressed. By Snapshot analysis, no LS participants had HIV-1 RNA ≥50 copies/mL at week 196. High proportions of both groups also had HIV-1 RNA <40 copies/mL and target not detected, a more stringent measure of virologic suppression (see SDC 4, Supplemental Digital Content, https://links.lww.com/QAI/C249, table showing HIV-1 RNA <40 copies/mL).

FIGURE 1.:

Virologic outcomes at week 196 by (A) duration of DTG/3TC exposure and (B) Snapshot analysis (ITT-E population).

In the ES group, median (interquartile range) CD4+ cell count increased from baseline by 22.5 (−71.0, 121.5) cells/mm3 48 weeks post-switch to DTG/3TC and by 65.5 (−47.0, 177.0) cells/mm3 196 weeks post-switch. In the LS group, CD4+ cell count increased from LS baseline by 53.5 (−35.3, 163.5) cells/mm3 48 weeks post-switch to DTG/3TC. The ES group median (interquartile range) change from baseline in CD4+/CD8+ ratio was 0.03 (−0.05, 0.11) 48 weeks post-switch to DTG/3TC and 0.10 (−0.03, 0.26) 196 weeks post-switch to DTG/3TC. The LS group change from LS baseline in CD4+/CD8+ ratio was 0.03 (−0.08, 0.16) 48 weeks post-switch to DTG/3TC.

One participant in the ES group met CVW criteria at week 196; no resistance-associated mutations were observed. Viral load measurements at all post-baseline visits before week 196 were <50 copies/mL for this participant (except for an unconfirmed 52 copies/mL at week 172). Although lack of adherence for the week 196 rebound cannot be excluded, no formal explanation (eg, treatment interruption, intercurrent illness, vaccination, or drug–drug interaction) was documented by the investigator. The participant switched to locally available DTG/3TC post-CVW, but no post-study HIV-1 RNA data are available.

Safety

Few new AEs were reported between weeks 144 and 196 in the ES group (Table 1). Safety profiles 48 weeks post-switch to DTG/3TC were comparable between the ES (day 1–week 48)4 and LS groups (weeks 148–196; Table 1). Only 2 serious AEs were considered treatment related, hypertransaminasemia (n = 1, ES group) and type 1 hypersensitivity (n = 1, LS group). Few AEs led to withdrawal across 4 years. Of the AEs leading to withdrawal between weeks 144 and 196, none in the ES group and 9 (n = 6 participants) in the LS group were drug related. None of the 4 fatal AEs were considered treatmentrelated.

TABLE 1. - Summary of AEs in the ES and LS DTG/3TC Groups Through Week 196 (Safety Populations) AEs, n (%) ES DTG/3TC (N = 369) LS DTG/3TC (N = 298) Day 1 to Week 48 Day 1 to Week 144 Day 1 to Week 196 Weeks 148–196 Any AE 295 (80) 336 (91) 347 (94) 239 (80) AEs in ≥10% of participants*  COVID-19 — 33 (9) 77 (21) 55 (18)  Nasopharyngitis 43 (12) 63 (17) 71 (19) 16 (5)  Diarrhea 30 (8) 50 (14) 54 (15) 12 (4)  Upper respiratory tract infection 31 (8) 50 (14) 52 (14) 7 (2)  Syphilis 24 (7) 39 (11) 49 (13) 14 (5)  Back pain 21 (6) 43 (12) 47 (13) 11 (4)  Arthralgia 12 (3) 31 (8) 46 (12) 15 (5)  Anxiety 17 (5) 35 (9) 44 (12) 7 (2)  Headache 24 (7) 35 (9) 41 (11) 17 (6) AEs leading to withdrawal 13 (4) 23 (6) 25 (7) 9 (3) Grade 2–5 AEs 193 (52) 279 (76) 295 (80) 165 (55)  Drug-related grade 2–5 AEs 17 (5) 21 (6) 23 (6) 11 (4) Serious AEs 21 (6) 57 (15) 65 (18) 15 (5) Fatal AEs† 1 (<1) 3 (<1) 4 (1) 0

*Based on AEs reported in ≥10% of ES participants from day 1 to week 196.

†Fatal AEs were gunshot wound (homicide; day 1 to week 48), substance abuse (weeks 48–144), ischemic hepatitis (weeks 48–144), and acute myocardial infarction (weeks 144–196); none were considered related to study treatment.

Mean (SD) weight change was 2.70 (6.14) kg after 4 years of DTG/3TC in the ES group (0.29-kg increase between weeks 144 and 196) and 0.43 (4.32) kg after 48 weeks of DTG/3TC in the LS group. Proportions of participants with weight increase from baseline above ≥5% or ≥10% thresholds were maintained in the ES group between weeks 144 and 196 and comparable between the ES and LS groups 48 weeks post-switch to DTG/3TC (see SDC 5, Supplemental Digital Content, https://links.lww.com/QAI/C250, figure showing weight change by clinically relevant thresholds).

Lipid profiles remained neutral at week 196, with overall decreases from baseline (ES group) and LS baseline (LS group) in most parameters (see SDC 6, Supplemental Digital Content, https://links.lww.com/QAI/C251, figure showing lipid changes). Similar proportions of participants in each group used lipid-modifying agents, both at baseline/LS baseline [ES, 49/369 (13%); LS, 60/298 (20%)] and 48 weeks post-switch to DTG/3TC [ES, 24/369 (7%); LS, 13/298 (4%)].

Creatinine-adjusted estimated glomerular filtration rate decreased in both groups, with larger decreases in the ES group at all time points (see SDC 7A, Supplemental Digital Content, https://links.lww.com/QAI/C252, figure showing renal biomarker changes); at week 196, cystatin-C–adjusted estimated glomerular filtration rate decreased vs baseline in the ES group and increased vs LS baseline in the LS group. Minimal changes from baseline/LS baseline were observed in urine renal biomarkers (see SDC 7B, Supplemental Digital Content, https://links.lww.com/QAI/C252) and bone biomarkers (see SDC 8, Supplemental Digital Content, https://links.lww.com/QAI/C253, figure showing bone biomarker changes). Inflammatory biomarker levels increased or decreased vs baseline levels depending on biomarker, with no consistent trends (see SDC 9, Supplemental Digital Content, https://links.lww.com/QAI/C254, figure showing inflammatory biomarker changes).

DISCUSSION

In TANGO, switching from 3- or 4-drug tenofovir alafenamide–based regimens to the 2-drug regimen DTG/3TC continued to demonstrate durable high efficacy, a high barrier to resistance, and good tolerability through 4 years in virologically suppressed adults. Consistent with 144-week analyses,5 high proportions of participants maintained HIV-1 RNA <50 copies/mL (Snapshot; ITT-E) in the ES group at year 4 (83%), including when the more stringent HIV-1 RNA <40 copies/mL and target not detected endpoint was used (75%). Notably, by observed analysis, 99% (306/309) of ES participants on study at week 196 remained virologically suppressed.

At 48 weeks post-switch to DTG/3TC, median increases in CD4+/CD8+ ratio vs baseline were consistent between the TANGO DTG/3TC ES group (0.03 vs tenofovir alafenamide–based regimen, 0.05)4 and LS group (0.03). At week 144, median change from baseline in CD4+/CD8+ ratio was similar between the DTG/3TC (0.06) and tenofovir alafenamide–based regimen groups (0.10).5 The sustained increases observed in the ES and LS groups at week 196 indicate that DTG/3TC maintains positive immunologic effects through year 4.

One CVW was reported in the ES DTG/3TC group through week 196, consistent with the high barrier to resistance observed in other clinical trials.6–8 The high effectiveness of DTG/3TC is also reproduced in real-world settings.9 A 2021 meta-analysis of 1823 individuals receiving DTG plus 3TC in real-world studies estimated low virologic failure rates through 48 (1.0%; 95% confidence interval: 0.3–2.0) and 96 weeks (1.0%; 95% confidence interval: 0.2–2.2), which included individuals with drug-resistant mutations or previous virologic failure who would have been ineligible for TANGO participation.10

Safety data through 4 years of DTG/3TC were consistent with 48-week4 and 144-week5 analyses and the safety profiles of the individual components.11,12 Over 48 weeks post-switch to DTG/3TC, a smaller proportion of ES vs LS participants reported drug-related AEs and a greater proportion of ES vs LS participants reported serious AEs, but differences were small. Very few additional safety events were reported in the ES group between years 3 and 4. Weight changes were similar between the DTG/3TC and tenofovir alafenamide–based regimen groups throughout the randomized phase, including similar proportions with ≥10% weight increase at week 144.4,5 Proportions of participants with weight gain at or above 5% and 10% thresholds increased from weeks 48 to 144 and remained stable between weeks 144 and 196, indicating that clinically meaningful weight change may plateau with long-term DTG/3TC use. Lipid profiles remained stable over 4 years in the ES group and were reproduced after 1 year in the LS group, in agreement with the neutral or positive lipid profile changes observed with DTG plus 3TC use in real-world studies.13 The clinical impact of such neutral-to-small changes in markers of cardiometabolic health remains to be established. As observed through week 144,5 DTG/3TC had minimal impact on renal and bone biomarkers, consistent with the known safety profile. The small and inconsistent changes in inflammatory biomarkers continue to demonstrate the neutral impact of DTG/3TC on inflammation, consistent with the observed durable virologic suppression.

One limitation is that most TANGO participants were White (80%) and male (93%); however, demographic subgroup outcomes were generally consistent. Whereas the ES group 48-week results were randomized, controlled, and powered to observe statistical differences between the DTG/3TC and tenofovir alafenamide groups,4 the LS group 48-week results were noncomparative. When TANGO began, baseline characteristics were balanced between participants switching to DTG/3TC and continuing tenofovir alafenamide–based regimens4 on day 1; however, because LS baseline (week 148) was 3 years after ES baseline (day 1) per study design, a greater proportion of LS vs ES participants were aged ≥50 years when initiating DTG/3TC (34% vs 21%). The LS group also had slightly higher weight, body mass index, and CD4+ cell count compared with the ES group at DTG/3TC initiation. Despite these differences, consistency between results from the ES group at week 48 and the LS group at week 196 demonstrate that efficacy and safety outcomes of switching from a tenofovir alafenamide–based regimen to DTG/3TC can be reproducible.

These results support DTG/3TC as a robust, durable, and noninferior treatment compared with 3- or 4-drug tenofovir alafenamide–based regimens at week 144 and demonstrate long-term virologic suppression, a consistent tolerability profile, and high barrier to resistance through year 4.

ACKNOWLEDGMENTS

The authors thank the study participants and their families and caregivers; the investigators and site staff who participated in the study; and the ViiV Healthcare, GSK, Pharmaceutical Product Development, and Phastar study team members. Editorial assistance was provided under the direction of the authors by Lindsay Walton, PhD, and Jennifer Rossi, MA, ELS, MedThink SciCom, and funded by ViiV Healthcare.

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