TY - JOUR
T1 - Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2)
T2 - week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials
AU - GEMINI Study Team
AU - Cahn, Pedro
AU - Madero, Juan Sierra
AU - Arribas, José Ramón
AU - Antinori, Andrea
AU - Ortiz, Roberto
AU - Clarke, Amanda E.
AU - Hung, Chien Ching
AU - Rockstroh, Jürgen K.
AU - Girard, Pierre Marie
AU - Sievers, Jörg
AU - Man, Choy
AU - Currie, Alexander
AU - Underwood, Mark
AU - Tenorio, Allan R.
AU - Pappa, Keith
AU - Wynne, Brian
AU - Fettiplace, Anna
AU - Gartland, Martin
AU - Aboud, Michael
AU - Smith, Kimberly
AU - Cassetti, Lidia
AU - David, Daniel
AU - Figueras, Laura
AU - Losso, Marcelo
AU - Lopardo, Gustavo
AU - Lupo, Sergio
AU - Porteiro, Norma
AU - Sánchez, Marisa
AU - Bloch, Mark
AU - Cooper, David
AU - Finlayson, Robert
AU - Kelleher, Anthony
AU - Koh, Kenneth
AU - Lewis, David
AU - McMahon, James
AU - Moore, Richard
AU - Roth, Norman
AU - Shields, Matthew
AU - De Wit, Stephane
AU - Florence, Eric
AU - Goffard, Jean Christophe
AU - Demeester, Remy
AU - Lacor, Patrick
AU - Vandercam, Bernard
AU - Vandekerckhove, Linos
AU - Angel, Jonathan
AU - Baril, Jean Guy
AU - Conway, Brian
AU - De Pokomandy, Alexandra
AU - Kim, Woo Joo
N1 - Funding Information:
PC, JS, ART, KP, BW, MG, MA, and KS participated in the conceptualisation of the studies. JS, CM, AC, MU, and ART curated data. JS, CM, AC, MU, ART, KP, BW, AF, MG, MA, and KS were involved with formal data analysis, methodology, project administration, and supervision. MG and KS were responsible for funding acquisition. PC, JSM, JRA, AA, RO, AEC, C-CH, JKR, and P-MG were study investigators and participated in the conduct of the study, including the recruitment and follow-up of participants. KP, MG, and KS were responsible for study resources. AC and MU handled software and program development and validation. All authors participated in the drafting and review of the manuscript.
Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/1/12
Y1 - 2019/1/12
N2 - Background: Effective two-drug regimens could decrease long-term drug exposure and toxicity with HIV-1 antiretroviral therapy (ART). We therefore aimed to evaluate the efficacy and safety of a two-drug regimen compared with a three-drug regimen for the treatment of HIV-1 infection in ART-naive adults. Methods: We conducted two identically designed, multicentre, double-blind, randomised, non-inferiority, phase 3 trials: GEMINI-1 and GEMINI-2. Both studies were done at 192 centres in 21 countries. We included participants (≥18 years) with HIV-1 infection and a screening HIV-1 RNA of 500 000 copies per mL or less, and who were naive to ART. We randomly assigned participants (1:1) to receive a once-daily two-drug regimen of dolutegravir (50 mg) plus lamivudine (300 mg) or a once-daily three-drug regimen of dolutegravir (50 mg) plus tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg). Both drug regimens were administered orally. We masked participants and investigators to treatment assignment: dolutegravir was administered as single-entity tablets (similar to its commercial formulation, except with a different film colour), and lamivudine tablets and tenofovir disoproxil fumarate and emtricitabine tablets were over-encapsulated to visually match each other. Primary endpoint was the proportion of participants with HIV-1 RNA of less than 50 copies per mL at week 48 in the intention-to-treat-exposed population, using the Snapshot algorithm and a non-inferiority margin of −10%. Safety analyses were done on the safety population. GEMINI-1 and GEMINI-2 are registered with ClinicalTrials.gov, numbers NCT02831673 and NCT02831764, respectively. Findings: Between July 18, 2016, and March 31, 2017, 1441 participants across both studies were randomly assigned to receive either the two-drug regimen (n=719) or three-drug regimen (n=722). At week 48 in the GEMINI-1 intention-to-treat-exposed population, 320 (90%) of 356 participants receiving the two-drug regimen and 332 (93%) of 358 receiving the three-drug regimen achieved plasma HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference −2·6%, 95% CI −6·7 to 1·5); in GEMINI-2, 335 (93%) of 360 in the two-drug regimen and 337 (94%) of 359 in the three-drug regimen achieved HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference −0·7%, 95% CI −4·3 to 2·9), showing non-inferiority at a −10% margin in both studies (pooled analysis: 655 [91%] of 716 in the two-drug regimen vs 669 [93%] of 717 in the three-drug regimen; adjusted treatment difference −1·7%, 95% CI −4·4 to 1·1). Numerically, more drug-related adverse events occurred with the three-drug regimen than with the two-drug regimen (169 [24%] of 717 vs 126 [18%] of 716); few participants discontinued because of adverse events (16 [2%] in the three-drug regimen and 15 [2%] in the two-drug regimen). Two deaths were reported in the two-drug regimen group of GEMINI-2, but neither was considered to be related to the study medication. Interpretation: The non-inferior efficacy and similar tolerability profile of dolutegravir plus lamivudine to a guideline-recommended three-drug regimen at 48 weeks in ART-naive adults supports its use as initial therapy for patients with HIV-1 infection. Funding: ViiV Healthcare.
AB - Background: Effective two-drug regimens could decrease long-term drug exposure and toxicity with HIV-1 antiretroviral therapy (ART). We therefore aimed to evaluate the efficacy and safety of a two-drug regimen compared with a three-drug regimen for the treatment of HIV-1 infection in ART-naive adults. Methods: We conducted two identically designed, multicentre, double-blind, randomised, non-inferiority, phase 3 trials: GEMINI-1 and GEMINI-2. Both studies were done at 192 centres in 21 countries. We included participants (≥18 years) with HIV-1 infection and a screening HIV-1 RNA of 500 000 copies per mL or less, and who were naive to ART. We randomly assigned participants (1:1) to receive a once-daily two-drug regimen of dolutegravir (50 mg) plus lamivudine (300 mg) or a once-daily three-drug regimen of dolutegravir (50 mg) plus tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg). Both drug regimens were administered orally. We masked participants and investigators to treatment assignment: dolutegravir was administered as single-entity tablets (similar to its commercial formulation, except with a different film colour), and lamivudine tablets and tenofovir disoproxil fumarate and emtricitabine tablets were over-encapsulated to visually match each other. Primary endpoint was the proportion of participants with HIV-1 RNA of less than 50 copies per mL at week 48 in the intention-to-treat-exposed population, using the Snapshot algorithm and a non-inferiority margin of −10%. Safety analyses were done on the safety population. GEMINI-1 and GEMINI-2 are registered with ClinicalTrials.gov, numbers NCT02831673 and NCT02831764, respectively. Findings: Between July 18, 2016, and March 31, 2017, 1441 participants across both studies were randomly assigned to receive either the two-drug regimen (n=719) or three-drug regimen (n=722). At week 48 in the GEMINI-1 intention-to-treat-exposed population, 320 (90%) of 356 participants receiving the two-drug regimen and 332 (93%) of 358 receiving the three-drug regimen achieved plasma HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference −2·6%, 95% CI −6·7 to 1·5); in GEMINI-2, 335 (93%) of 360 in the two-drug regimen and 337 (94%) of 359 in the three-drug regimen achieved HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference −0·7%, 95% CI −4·3 to 2·9), showing non-inferiority at a −10% margin in both studies (pooled analysis: 655 [91%] of 716 in the two-drug regimen vs 669 [93%] of 717 in the three-drug regimen; adjusted treatment difference −1·7%, 95% CI −4·4 to 1·1). Numerically, more drug-related adverse events occurred with the three-drug regimen than with the two-drug regimen (169 [24%] of 717 vs 126 [18%] of 716); few participants discontinued because of adverse events (16 [2%] in the three-drug regimen and 15 [2%] in the two-drug regimen). Two deaths were reported in the two-drug regimen group of GEMINI-2, but neither was considered to be related to the study medication. Interpretation: The non-inferior efficacy and similar tolerability profile of dolutegravir plus lamivudine to a guideline-recommended three-drug regimen at 48 weeks in ART-naive adults supports its use as initial therapy for patients with HIV-1 infection. Funding: ViiV Healthcare.
UR - http://www.scopus.com/inward/record.url?scp=85059913132&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(18)32462-0
DO - 10.1016/S0140-6736(18)32462-0
M3 - Article
C2 - 30420123
AN - SCOPUS:85059913132
VL - 393
SP - 143
EP - 155
JO - The Lancet
JF - The Lancet
SN - 0140-6736
IS - 10167
ER -