Durable Efficacy of Switching From a 3- or 4-Drug Tenofovir Alafenamide-Based Regimen to the 2-Drug Regimen Dolutegravir/Lamivudine in the TANGO Study Through Week 196.

BACKGROUND: Switching to the 2-drug regimen dolutegravir/lamivudine demonstrated durable non-inferior efficacy vs continuing 3- or 4-drug tenofovir alafenamide-based regimens for maintaining virologic suppression in people with HIV-1 through Week 144 in TANGO. SETTING: 134 centers, 10 countries. METHODS: Adults with HIV-1 RNA <50 copies/mL for >6 months and no history of virologic failure were randomized to switch from stable tenofovir alafenamide-based regimens to dolutegravir/lamivudine on Day 1 (early-switch group) for 196 weeks. Those randomized to continue tenofovir alafenamide-based regimens on Day 1 who maintained virologic suppression at Week 144 switched to dolutegravir/lamivudine at Week 148 (late-switch group). Efficacy, safety, and tolerability (including weight and biomarker changes) of dolutegravir/lamivudine in early-switch and late-switch groups were assessed through Week 196. RESULTS: Overall, 369 participants switched to dolutegravir/lamivudine on Day 1 (early-switch) and 298 switched at Week 148 (late-switch). In the early-switch group, 83% (306/369) maintained virologic suppression through Year 4, and 3% (11/369) reported new adverse events between Weeks 144 and 196. The late-switch group at Week 196 and early-switch group at Week 48 had comparable proportions with virologic suppression (93% each) and similar safety profiles. No late-switch participants and 1 early-switch participant met confirmed virologic withdrawal criteria through Week 196, with no resistance-associated mutations observed. Treatment continued to be well tolerated long-term. CONCLUSION: Switching from tenofovir alafenamide-based regimens to dolutegravir/lamivudine showed durable efficacy, high barrier to resistance, and good tolerability through 4 years. These results support dolutegravir/lamivudine as a robust treatment for maintaining virologic suppression.

Very-Low-Level Viremia, Inflammatory Biomarkers, and Associated Baseline Variables: Three-Year Results of the Randomized TANGO Study.

Background: We compared proportions of participants with target detected, target not detected (TND), and elevated viral load (VL) and assessed baseline variables associated with week 144 inflammatory biomarker levels between dolutegravir-lamivudine (DTG/3TC) and tenofovir alafenamide-based regimens (TBRs) in the TANGO study (post hoc). Methods: TANGO is an open-label, multicenter, phase 3 study that randomized adults with VL <50 copies/mL to switch to once-daily fixed-dose DTG/3TC or continue TBR. At baseline and each study visit, the VL was measured. Elevated VL event frequencies were assessed, including "blips." Interleukin 6, D-dimer, high-sensitivity C-reactive protein, soluble CD14, and soluble CD163 were measured at baseline and at week 144. Loge-transformed week 144 biomarker levels were compared between treatment groups using an analysis of covariance model adjusting for baseline variables. Results: High, comparable proportions of participants had VL <40 copies/mL and TND at week 144 (DTG/3TC, 279 of 369 [76%]; TBR, 267 of 372 [72%], intention-to-treat exposed Snapshot analysis; adjusted difference, 3.9% [95% confidence interval, -2.5% to 10.2%]), with similar TND proportions at all postbaseline visits (123 of 369 [33%] vs 101 of 372 [27%], respectively). Similar proportions of DTG/3TC participants had ≥1 postbaseline VL ≥50 copies/mL (28 of 369 [8%] vs 42 of 372 [11%] for TBR), primarily blips (18 of 369 [5%] and 26 of 372 [7%], respectively). Week 144 inflammatory biomarker levels were low and comparable between groups and associated with multiple demographic and baseline characteristics, including baseline biomarker levels, indicating a multifactorial inflammatory response. Conclusions: Week 144 biomarker levels were low and generally comparable between treatment groups, reflecting similar, robust, and durable viral suppression observed using the stringent TND end point. Trial registration:  ClinicalTrials.gov, NCT03446573.

Assessing the Virologic Impact of Archived Resistance in the Dolutegravir/Lamivudine 2-Drug Regimen HIV-1 Switch Study TANGO through Week 144.

The TANGO study (ClinicalTrials.gov, NCT03446573) demonstrated that switching to dolutegravir/lamivudine (DTG/3TC) was non-inferior to continuing tenofovir alafenamide-based regimens (TBR) through week 144. Retrospective baseline proviral DNA genotypes were performed for 734 participants (post-hoc analysis) to assess the impact of archived, pre-existing drug resistance on 144-week virologic outcomes by last on-treatment viral load (VL) and Snapshot. A total of 320 (86%) participants on DTG/3TC and 318 (85%) on TBR had both proviral genotype data and ≥1 on-treatment post-baseline VL results and were defined as the proviral DNA resistance analysis population. Archived International AIDS Society-USA major nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, protease inhibitor, and integrase strand transfer inhibitor resistance-associated mutations (RAMs) were observed in 42 (7%), 90 (14%), 42 (7%), and 11 (2%) participants, respectively, across both groups; 469 (74%) had no major RAMs at baseline. M184V/I (1%), K65N/R (<1%), and thymidine analogue mutations (2%) were infrequent. Through week 144, >99% of participants on DTG/3TC and 99% on TBR were virologically suppressed (last on-treatment VL <50 copies/mL) regardless of the presence of major RAMs. Results from the sensitivity analysis by Snapshot were consistent with the last available on-treatment VL. In TANGO, archived, pre-existing major RAMs did not impact virologic outcomes through week 144.

Brief Report: Impact of COVID-19 on Cabotegravir Plus Rilpivirine Long-Acting Dosing Across 6 Ongoing Global Phase IIb and III Clinical Trials.

BACKGROUND: Cabotegravir + rilpivirine long-acting (LA) is a novel antiretroviral therapy (ART) administered intramuscularly monthly or every 2 months by a health care provider. The COVID-19 pandemic presents a potential challenge to patients' ability to attend scheduled clinic visits for dosing administration. SETTING: This analysis evaluated implementation fidelity across 6 phase IIb/III/IIIb cabotegravir + rilpivirine LA clinical trials in 16 countries during the COVID-19 pandemic. METHODS: COVID-19-impacted visits were defined as modified dosing visits for which oral therapy was provided to participants unable to attend the clinic or injection visits that were rescheduled. Data from December 1, 2019, to March 1, 2021, were aggregated and analyzed using descriptive statistics. RESULTS: Of 2127 participants in cabotegravir + rilpivirine LA trials, 1997 (94%) had LA dosing visits proceed as planned during the COVID-19 pandemic. Of 130 (6%) participants with injection visits affected by COVID-19, most were from North America (57%) and Europe (26%). Most participants with COVID-19-impacted visits used oral therapy with cabotegravir + rilpivirine (75%) or alternative oral standard-of-care ART (21%) to maintain continuous ART. The most common reasons for missed visits were clinic closure/staffing constraints (48%) and COVID-19-related travel restrictions (23%). Most (98%) participants who used oral ART maintained virologic suppression; 2 participants had viral load between 50 and 100 copies/mL. CONCLUSION: During the COVID-19 pandemic, most trial participants maintained their LA dosing schedules. Flexibility of the LA dosing regimen, with the ability to switch to oral therapy, facilitated continuous ART provision and implementation fidelity.

A repeat-dose thorough QT study of inhaled fluticasone furoate/vilanterol combination in healthy subjects.

AIMS: This study was designed as a thorough QT (TQT) study to evaluate the effects of fluticasone furoate (FF)/vilanterol (VI) in healthy subjects. Supportive data from a TQT study conducted with FF are also presented. METHODS: This was a randomized, placebo- and positive-controlled, double-dummy, double-blind, four-way crossover study, in which healthy subjects (n = 85) were randomized to 7 days of once-daily treatment of FF/VI (200/25 or 800/100 µg) or placebo or single-dose oral moxifloxacin (single-blind, 400 mg). In the supportive TQT study, subjects (n = 40) were randomized to single-dose inhaled FF (4000 µg), oral moxifloxacin (400 mg) or placebo. RESULTS: There was a lack of effect of FF/VI (200/25 µg) on QTcF (Fridericia's correction); all time-matched mean differences from baseline relative to placebo (0-24 h) were <5 ms, with upper 90% confidence intervals (CI) of <10 ms. At 800/100 µg, FF/VI had no significant clinical effect on QTcF except at 30 min postdose when the 90% CI was >10 ms [mean (90% CI), 9.6 ms (7.2, 12.0)]. No effect on QTci (individually corrected) was observed at either strength of FF/VI, with mean time-matched treatment differences <5 ms at all time points [upper 90% CIs <10 ms (0-24 h)]. Assay sensitivity was confirmed; moxifloxacin prolonged QTcF and QTci, with time-matched mean differences from baseline relative to placebo of >10 ms (1-8 h postdose). CONCLUSIONS: Repeat once-daily dosing of FF/VI (200/25 µg), which is the highest therapeutic strength used in phase III studies, is not associated with QTc prolongation in healthy subjects. Supratherapeutic strength FF/VI (800/100 µg) demonstrated a small transient effect on QTcF but not on QTci.