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Randomized Controlled Trial
. 2023 Feb 18;76(4):720-729.
doi: 10.1093/cid/ciac130.

Efficacy and Safety of Switching to the 2-Drug Regimen Dolutegravir/Lamivudine Versus Continuing a 3- or 4-Drug Regimen for Maintaining Virologic Suppression in Adults Living With Human Immunodeficiency Virus 1 (HIV-1): Week 48 Results From the Phase 3, Noninferiority SALSA Randomized Trial

Josep M Llibre  1 , Carlos Brites  2 , Chien-Yu Cheng  3   4 , Olayemi Osiyemi  5 , Carlos Galera  6 , Laurent Hocqueloux  7 , Franco Maggiolo  8 , Olaf Degen  9 , Stephen Taylor  10   11 , Elizabeth Blair  12 , Choy Man  12 , Brian Wynne  12 , James Oyee  13 , Mark Underwood  12 , Lloyd Curtis  13 , Gilda Bontempo  12 , Jean van Wyk  14
Affiliations
Randomized Controlled Trial

Efficacy and Safety of Switching to the 2-Drug Regimen Dolutegravir/Lamivudine Versus Continuing a 3- or 4-Drug Regimen for Maintaining Virologic Suppression in Adults Living With Human Immunodeficiency Virus 1 (HIV-1): Week 48 Results From the Phase 3, Noninferiority SALSA Randomized Trial

Josep M Llibre et al. Clin Infect Dis. .

Abstract

Background: In TANGO, switching to dolutegravir/lamivudine (DTG/3TC) demonstrated long-term noninferior efficacy vs continuing tenofovir alafenamide-based regimens in treatment-experienced adults with HIV-1. The phase 3 SALSA study evaluated efficacy and safety of switching to DTG/3TC compared with continuing various 3-/4-drug current antiretroviral regimens (CARs).

Methods: Adults with HIV-1 RNA <50 copies/mL and no previous virologic failure were randomized (1:1, stratified by baseline third agent class) to switch to once-daily fixed-dose combination DTG/3TC or continue CAR (primary endpoint: proportion of participants with HIV-1 RNA ≥50 copies/mL at week 48; Snapshot, intention-to-treat-exposed population, 5% noninferiority margin).

Results: Overall, 493 adults (39% women; 39% aged ≥50 years; 19% African American/African heritage; 14% Asian) were randomized to switch to DTG/3TC (n = 246) or continue CAR (n = 247). At week 48, 1 (0.4%) participant in the DTG/3TC group and 3 (1.2%) in the CAR group had HIV-1 RNA ≥50 copies/mL (Snapshot), demonstrating noninferiority (adjusted difference, -0.8%; 95% CI, -2.4%, .8%). Zero participants met confirmed virologic withdrawal criteria; therefore, no resistance testing was performed. Drug-related adverse events were more frequent with DTG/3TC (20%) than CAR (6%) through week 48 but comparable post-week 24 (5% vs 2%, respectively). Proximal tubular renal function and bone turnover biomarkers improved with DTG/3TC. Both groups had generally minimal changes in lipids and inflammatory biomarkers.

Conclusions: Switching to DTG/3TC was noninferior to continuing CAR for maintaining virologic suppression at week 48 with no observed resistance, supporting the efficacy, good safety, and high barrier to resistance of DTG/3TC.

Clinical trials registration: www.clinicaltrials.gov, NCT04021290.

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

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Conflict of interest statement

Potential conflicts of interest. J. M. L. has received honoraria or consultation fees from and participated in company-sponsored speakers bureaus for ViiV Healthcare, Gilead, and Janssen-Cilag. C. B. has received grants for an investigator-initiated study from GSK and honoraria for presentations from GSK, Gilead, and Merck Sharpe and Dohme; and has participated in advisory boards for GSK and Gilead. L. H. has received fees for participation in advisory boards or presentations from ViiV Healthcare, Merck Sharpe and Dohme, and Gilead and has received travel support for congress attendance from ViiV Healthcare, Merck Sharpe and Dohme, and Gilead. O. O. has received honoraria from ViiV Healthcare and Gilead. C. G. has received consulting fees and honoraria from ViiV Healthcare, Gilead, Merck Sharp and Dohme, and Janssen and has received support for meeting attendance from Gilead and Janssen. F. M. has received grants from ViiV Healthcare, Gilead, and Janssen, which were paid to his institution; has received honoraria from ViiV Healthcare, Gilead, Janssen, and Merck Sharp and Dohme; and has participated in data safety monitoring/advisory boards for ViiV Healthcare, Gilead, Janssen, and Merck Sharp and Dohme. S. T. has received grants for investigator-initiated studies from Gilead; has participated in and received honoraria for advisory boards or company-sponsored speakers bureaus from ViiV Healthcare, Gilead, and Merck Sharp and Dohme; has received support for registration at scientific conferences from ViiV Healthcare; and is the unpaid Medical Director of Saving Lives. E. B., C. M., B. W., M. U., G. B., and J. v. W. are employees of ViiV Healthcare and may own stock in GSK. J. O. and L. C. are employees of and may own stock in GSK. C.-Y. C. and O. D. report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
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. cProtocol deviations leading to exclusion from the per-protocol population; participants could have had ≥1 reason. Abbreviations: AE, adverse event(s); ART, antiretroviral therapy; CAR, current antiretroviral regimen; DTG/3TC, dolutegravir/lamivudine.
Figure 2.
Figure 2.
Adjusted treatment difference in virologic outcomes at week 48 in the ITT-E population. aPrimary endpoint (Snapshot virologic failure, ITT-E). bBased on Cochran-Mantel-Haenszel stratified analysis (DTG/3TC − CAR) adjusting for baseline third agent class. Abbreviations: CAR, current antiretroviral regimen; DTG/3TC, dolutegravir/lamivudine; HIV-1, human immunodeficiency virus 1; ITT-E, intention-to-treat–exposed.
Figure 3.
Figure 3.
Proportion of participants with HIV-1 RNA <50 copies/mL by subgroup in the ITT-E population by FDA Snapshot algorithm at week 48. aIncludes American Indian or Alaska Native or individuals of multiple races. bThe study population was stratified by baseline third agent class (PI, INSTI, or NNRTI). cAdjusted difference for overall population (DTG/3TC − CAR) and 95% CIs are based on a stratified analysis (adjusting for baseline third agent class) using Cochran-Mantel-Haenszel weights (meeting noninferiority based on −12% margin); unadjusted difference for subgroups calculated by proportion on DTG/3TC − proportion on CAR. Abbreviations: CAR, current antiretroviral regimen; CI, confidence interval; DTG/3TC, dolutegravir/lamivudine; FDA, Food and Drug Administration; HIV-1, human immunodeficiency virus 1; INSTI, integrase strand transfer inhibitor; ITT-E, intention-to-treat–exposed; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor.
Figure 4.
Figure 4.
A, Adjusted mean change from baseline in weight by visit. B, Baseline and adjusted mean change from baseline in weight at week 48. C, Adjusted mean change from baseline in weight at week 48 by baseline TDF use. D, Baseline and adjusted mean change from baseline in BMI at week 48. aAdjusted mean is the estimated mean change from baseline at each visit in each group calculated using mixed-model repeated measures adjusting for treatment, visit, baseline third agent class, CD4+ cell count (continuous), age (continuous), sex, race, baseline weight or BMI (continuous), treatment-by-visit interaction, and baseline value-by-visit interaction, with visit as the repeated factor. Abbreviations: BL, baseline; BMI, body mass index; CAR, current antiretroviral regimen; CI, confidence interval; DTG/3TC, dolutegravir/lamivudine; SE, standard error; TDF, tenofovir disoproxil fumarate.
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