Comparison of the design and methodology of Phase 3 clinical trials of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) and dolutegravir-based dual therapy (DTG) in HIV: a systematic review of the literature

Figures & data

Table 1. Preferred starting ART combinations recommended by GeSIDA [7].

Regimen	Abbreviation	Groups
Bictegravir/Emtricitabine/Tenofovir	BIC/FTC/TAF	INI/NRTI/NRTI
Dolutegravir/Abacavir/Lamivudine	DTG/ABC/3TC	INI/NRTI/NRTI
Dolutegravir/Emtricitabine/Tenofovir	DTG+FTC/TAF	INI/NRTI/NRTI
Dolutegravir/Lamivudine	DTG/3TC	INI/NRTI

INI: integrase inhibitors; NRTI: Nucleoside reverse transcriptase inhibitors.

This list does not include Dolutegravir/Rilpivirine (DTG/RPV), a combination of an INI with rilpivirine, an NNRTI (non-nucleoside reverse transcriptase inhibitor).

Table 2. Randomized clinical trials of BIC/FTC/TAF and DTG/3TC in naïve patients.

Treatment regimen	Study	Design	Treatments	N	Non-inferiority Mean (95%CI)	Virological suppression* 48 weeks	Virological suppression* 144 weeks	References
BIC/FTC/TAF	1489	RCT, DB, Phase 3 DB 144 weeks Virological suppression (<50 copies/ml HIV-1 RNA): Non-inferiority (−12%) 144 weeks Week 48 (PEE) Week 96 (SEE) IT analysis with drug exposure	BIC/FTC/TAF DTG/ABC/3TC	314 315	−2.6% (−8.5%;3.4%) (144 weeks)	92.4% 93.3%	82% 84%	Gallant, 2017 [24] Wohl, 2019 [25] Orkin, 2020 [19]
	1490	RCT, DB, Phase 3 DB 144 weeks Virological suppression (<50 copies/ml HIV-1 RNA): Non-inferiority (−12%) 144 weeks Week 48 (PEE) Week 96 (SEE) IT analysis with drug exposure	BIC/FTC/TAF DTG+FTC/TAF	320 325	−1.9% (−7.8%;3.9%) (144 weeks)	89% 93%	81% 84%	Sax, 2017 [26] Stellbrink, 2019 [27] Orkin, 2020 [19]
DTG/3TC	GEMINI 1 and 2	RCT, DB, Phase 3 DB 96 weeks Virological suppression (<50 copies/ml HIV-1 RNA): Non-inferiority (−10%) 96 weeks Week 48 (PEE) Week 96 (SEE) Week 144 (PS) IT analysis with drug exposure	DTG/3TC DTG+FTC/TDF	716 717	GEMINI 1 and 2: -3.4 (−6.7; 0.0007) (96 weeks) -1.8% (−5.8, 2.1) (144 weeks)	91% 93%	86% 89.5%	Cahn, 2019 [37] Cahn, 2020a [38] Cahn, 2020b [39] Eron, 2020 [29] Cahn, 2022 [40]

*Percentage of patients with <50 copies of HIV RNA per ml of plasma. BIC/FTC/TAF: Bictegravir/Emtricitabine/Tenofovir; DB: double-blind; DTG/3TC: Dolutegravir/Lamivudine; DTG/ABC/3TC: Dolutegravir/Abacavir/Lamivudine; DTG+FTC/TAF: Dolutegravir/Emtricitabine/ Tenofovir disoproxil fumarate; DTG+FTC/TDF: Dolutegravir/Emtricitabine/Tenofovir disoproxil fumarate; RCT, randomized clinical trial; IT, intention-to-treat; PEE, primary efficacy endpoint; SEE, secondary efficacy endpoint.

Table 3. Randomized clinical trials of BIC/FTC/TAF in virologically suppressed (switch) patients.

Treatment regimen	Study	Design	Treatments	N	Non-inferiority Mean (95%CI)	No virological suppression* 48 weeks	References
BIC/FTC/TAF	1844	Switch from: DTG/ABC/3TC RCT, DB, Phase 3 No virological suppression (≥50 copies/ml HIV-1 RNA): Non-inferiority (−4%) Week 48 (PEE)	BIC/FTC/TAF DTG/ABC/3TC	282 281	0.7% (−1.0%;2.8%)	1.1% 0.4%	Molina, 2018 [42]
	1878	Switch from: regimes with PI (DRV-ABC-3TC or ATC-ABC-3TC or DRV-FTC-TDF or ATC-FTC-TDF) RCT, unblinded, Phase 3 No virological suppression (≥50 copies/ml HIV-1 RNA): Non-inferiority (−4%) Week 48 (PEE)	BIC/FTC/TAF Regimes with PI	290 287	0.0% (−2.5%;2.5%)	2% 2%	Daar, 2018 [43]
	1961	Switch from: EVG/c/FTC/TAF, EVG/c/FTC/TDF, or ATV/r + FTC/TDF RCT, unblinded, Phase 3 No virological suppression (≥50 copies/ml HIV-1 RNA): Non-inferiority (−4%) Week 48 (PEE)	BIC/FTC/TAF Regimes with TAF or TDF	234 236 (Women only)	0.0% (−2.9%;2.9%)	1.7% 1.7%	Kityo, 2019 [19]

*Percentage of patients with ≥50 copies of HIV RNA in plasma. ATC-FTC-TDF: Atazanavir/ Emtricitabine/Tenofovir disoproxil fumarate; ATV/r+ FTC/TDF: Atazanavir/Ritonavir+Emtricitabine/Tenofovir disoproxil fumarate; ATC-ABC-3TC: Atazanavir/Abacavir/Lamivudine; BIC/FTC/TAF: Bictegravir/Emtricitabine/Tenofovir; DB: double-blind; DRV-ABC-3TC: Darunavir/Abacavir/Lamivudine; DRV-FTC-TDF: Darunavir/Emtricitabine/Tenofovir disoproxil fumarate; DTG/ABC/3TC: Dolutegravir/Abacavir/Lamivudine; RCT: randomized clinical trial; EVG/c/FTC/TAF: Elvitegravir/Cobicistat/Emtricitabine/Tenofovir; EVG/c/FTC/TDF: Elvitegravir/Cobicistat/Emtricitabine/Tenofovir disoproxil fumarate; PI: protease inhibitors; PEE: primary efficacy endpoint.

Table 4. Randomized clinical trials of DTG/3TC and DTG/RPV in virologically suppressed (switch) patients.

Treatment regimen	Study	Design	Treatments	N	Non-inferiority Mean (95%CI)	No virological suppression 48 weeks	References
DTG/3TC	TANGO	Switch from: TAF-based regime RCT, Unblinded, Phase 3 No virological suppression (≥50 copies/ml HIV-1 RNA): Non-inferiority (−4%) Week 48 (PEE)	DTG/3TC Regime with TAF	369 372	−0.3% (−1.2%; 0.7%)	0.3% 0.5%	Van Wyk, 2020a [51]
DTG/RPV	SWORD 1 and 2	Switch from: NNRTI (54%), PI (27%) and INI (20%) RCT, Unblinded, Phase 3 No virological suppression (≥50 copies/ml HIV-1 RNA): Non-inferiority (−8%) Week 48 (PEE) Week 100 Week 148	DTG/RPV Current ART	513 511	−0.2% (−3.0%; 2.5%) (48 weeks)	DTG/RPV: 3% (early switch) 2% (late switch) (148 weeks)	Llibre, 2018 [71] Aboud, 2019 [72] Van Wyk, 2020 [73]

DTG/3TC: Dolutegravir/Lamivudine; DTG/RPV: Dolutegravir/Rilpivirine; INI: integrase inhibitors: NNRTI, non-nucleoside reverse transcriptase inhibitor; PEEP, primary efficacy endpoint; TAF: Tenofovir; ART: antiretroviral treatment.

Figure 1. Quality of clinical trials conducted with BIC/FTC/TAF, DTG/3TC and DTG/RPV, according to the Jadad scale, with a score between 0 (lowest quality) and 5 (highest quality). Low quality: 0–2 points; Medium quality: 3 points; High quality: 4–5 points [16,17].

BIC/FTC/TAF: Bictegravir/Emtricitabine/Tenofovir; DTG/3TC: Dolutegravir/Lamivudine; DTG/RPV: Dolutegravir/Rilpivirine. CT: clinical trial.

Table 5. Main methodological differences hindering comparability of clinical trials with BIC/FTC/TAF TT and DT with DTG/3TC and DTG/RPV.

Item	BIC/FTC/TAF	DTG/3TC	DTG/RPV	Impact of the methodological problem
Treatment-naïve
Double-blind	YES	YES	Not applicable	If the answer is ‘No,’ the risk of biases (systematic errors) increases
Duration of blinding (weeks)	144	96^a	Not applicable	If the duration is shorter, the risk of biases (systematic errors) increases
Pre-randomization losses	3.1%	7.3%	Not applicable	Pre-randomization losses reduce the external validity of the study
Treatment-experienced
Double-blind	YES^b	NO	NO	If the answer is ‘No,’ the risk of biases (systematic errors) increases
Inclusion of patients with liver diseases	YES	NO	NO	If patients with liver disease are excluded, there is a risk of recruiting patients with a better prognosis
Criteria for virological failure: Confirmed Virological Withdrawal (CVW)	NO	YES^c	NO	Non-comparability of efficacy results

BIC/FTC/TAF: Bictegravir/Emtricitabine/Tenofovir; DT: dual therapy; DTG/3TC: Dolutegravir/Lamivudine; DTG/RPV: Dolutegravir/Rilpivirine; TT: triple therapy.

(a) Applicable to the third-year analysis (secondary analysis). (b) In the 1844 study, not in the 1878 and 1961 studies. (c) A snapshot assessment of virological failure is also performed in the TANGO study.

Panel de Expertos de GeSIDA y División de control de VIH, ITS, Hepatitis virales y Tuberculosis. Plan Nacional sobre el SIDA. Documento de consenso de GeSIDA/Plan Nacional sobre el SIDA respecto al tratamiento antirretroviral en adultos infectados por el virus de la inmunodeficiencia humana (update 2022). GeSIDA/Ministerio de Sanidad. Available from: https://gesida-seimc.org/wp-content/uploads/2022/05/GuiaGeSIDAPlanNacionalSobreElSidaRespectoAlTratamientoAntirretroviralEnAdultosInfectadosPorElVirusDeLaInmunodeficienciaHumanaActualizacionEnero2022.pdf (cited 2022 May 30). •• GeSIDA Consensus Document/National Plan on AIDS.

 Google Scholar

Gallant J, Lazzarin A, Mills A, et al. Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, Abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US-380-1489): a double-blind, multicentre, phase 3, randomised controlled non-inferiority trial. Lancet. 2017;390(10107):2063–2072.

 PubMed Web of Science ®Google Scholar

Wohl DA, Yazdanpanah Y, Baumgarten A, et al. Bictegravir combined with emtricitabine and tenofovir alafenamide versus dolutegravir, Abacavir, and lamivudine for initial treatment of HIV-1 infection: week 96 results from a randomised, double-blind, multicentre, phase 3, non-inferiority trial. Lancet HIV. 2019;6(6):e355–63.

 PubMed Web of Science ®Google Scholar

Orkin C, DeJesus E, Sax PE, et al. GS-US-380-1490 study investigators. Fixed-dose combination bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir-containing regimens for initial treatment of HIV-1 infection: week 144 results from two randomised, double-blind, multicentre, phase 3, non-inferiority trials. Lancet HIV. 2020;7(6):e389–400.

 PubMed Web of Science ®Google Scholar

Sax PE, Pozniak A, Montes ML, et al. Coformulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection (GS-US-380-1490): a randomised, double-blind, multicentre, phase 3, non-inferiority trial. Lancet. 2017;390:2073–2082. /Protocol 1490: Study to Evaluate the Safety and Efficacy of Bictegravir/Emtricitabine/Tenofovir Alafenamide Versus Dolutegravir + Emtricitabine/Tenofovir Alafenamide in Human Immunodeficiency Virus (HIV-1) Infected, Antiretroviral Treatment-Naive Adults. Available from: https://clinicaltrials.gov/ct2/show/NCT02607956?term=GS-US-380%E2%80%931490&draw=2&rank=1

 PubMed Web of Science ®Google Scholar

Stellbrink HJ, Arribas JR, Stephens JL, et al. Co-formulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide for initial treatment of HIV-1 infection: week 96 results from a randomised, double-blind, multicentre, phase 3, non-inferiority trial. Lancet HIV. 2019;6(6):e364–72.

 PubMed Web of Science ®Google Scholar

Cahn P, Madero JS, Arribas JR, et al.; GEMINI Study Team. Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naïve adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials. Lancet. 2019;393(10167):143–155. https://clinicaltrials.gov/ct2/show/NCT02831673?term=gemini+1+dolutegravir&draw=2&rank=1Protocol GEMINI 1: An Efficacy, Safety, and Tolerability Study Comparing Dolutegravir Plus Lamivudine With Dolutegravir Plus Tenofovir/Emtricitabine in Treatment naïve HIV Infected Subjects (Gemini 1). Available from: https://clinicaltrials.gov/ct2/show/NCT02831673?term=gemini+1+dolutegravir&draw=2&rank=1 (cited: 02/06/2021)./Protocol GEMINI 2: An Efficacy, Safety, and Tolerability Study Comparing Dolutegravir (DTG) Plus Lamivudine (3TC) With Dolutegravir Plus Tenofovir/Emtricitabine in Treatment naïve HIV Infected Subjects (Gemini 2). Available at URL: https://clinicaltrials.gov/ct2/show/NCT02831764?term=gemini+1+dolutegravir&draw=2&rank=4 (cited: 02/06/2021).

 PubMed Web of Science ®Google Scholar

Cahn P, Madero JS, Arribas JR, et al. Durable efficacy of dolutegravir plus lamivudine in antiretroviral treatment-naïve adults with HIV-1 infection: 96-week results from the GEMINI-1 and GEMINI-2 randomised clinical trials. J Acquir Immune Defic Syndr. 2020;83(3):310–318.

 PubMed Web of Science ®Google Scholar

Cahn P, Sierra J, Arribas JR, et al. Durable efficacy of dolutegravir (DTG) plus lamivudine (3TC) in antiretroviral treatment -naïve adults with HIV-1 infection- 3 -year results from the GEMINI studies Poster P018. HIV Drug Therapy: Glasgow;2020, 2020 October 6-8

 Google Scholar

Eron J, Hung CC, Baril JG, et al. Brief report: virologic response by baseline viral load with dolutegravir plus lamivudine vs dolutegravir plus tenofovir disoproxil fumarate/emtricitabine: pooled analysis. J Acquir Immune Defic Syndr. 2020;84(1):60–65.

 PubMed Web of Science ®Google Scholar

Cahn P, Sierra Madero J, Arribas JR, et al. Three-year durable efficacy of dolutegravir plus lamivudine in antiretroviral therapy- naïve adults with HIV-1 infection. AIDS. 2022;36(1):39–48.

 PubMed Web of Science ®Google Scholar

Molina JM, Ward D, Brar I, et al. Switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from dolutegravir plus Abacavir and lamivudine in virologically suppressed adults with HIV-1: 48 weeks results of a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial. Lancet HIV. 2018;5(7):e357–65.

 PubMed Web of Science ®Google Scholar

Daar ES, DeJesus E, Ruane P, et al. Efficacy and safety of switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from boosted protease inhibitor-based regimens in virologically suppressed adults with HIV-1: 48 week results of a randomised, open-label, multicentre, phase 3, non-inferiority trial. Lancet HIV. 2018;5(7):e347–56.

 PubMed Web of Science ®Google Scholar

van Wyk J, Ajana F, Bisshop F, et al. Efficacy and safety of switching to dolutegravir/lamivudine fixed-dose 2-drug regimen vs continuing a tenofovir alafenamide-based 3- or 4-drug regimen for maintenance of virologic suppression in adults living with human immunodeficiency virus type 1: phase 3, randomized, noninferiority TANGO study. Clin Infect Dis. 2020;71(8):1920–1929. /Protocol TANGO: Switch Study to Evaluate Dolutegravir Plus Lamivudine in Virologically Suppressed Human Immunodeficiency Virus Type 1 Positive Adults (TANGO). Available at URL: https://clinicaltrials.gov/ct2/show/NCT03446573?term=TANGO+dolutegravir&draw=2&rank=1 (cited: 02/06/2021).

 PubMed Web of Science ®Google Scholar

Aboud M, Orkin C, Podzamczer D, et al. Efficacy and safety of dolutegravir-rilpivirine for maintenance of virological suppression in adults with HIV-1: 100-week data from the randomised, open-label, phase 3 SWORD-1 and SWORD-2 studies. Lancet HIV. 2019;6(9):e576–87.

 PubMed Web of Science ®Google Scholar

van Wyk J, Orkin C, Rubio R, et al. Brief report: durable suppression and low rate of virologic failure 3 years after switch to Dolutegravir + Rilpivirine 2-drug regimen: 148-week results from the SWORD-1 and SWORD-2 randomized clinical trials. J Acquir Immune Defic Syndr. 2020;85(3):325–330.

 PubMed Web of Science ®Google Scholar

Achhra AC, Mwasakifwa G, Amin J, et al. Efficacy and safety of contemporary dual-drug antiretroviral regimens as first-line treatment or as a simplification strategy: a systematic review and meta-analysis. Lancet HIV. 2016;3(8):e351–60.

 PubMed Web of Science ®Google Scholar

Jadad A, Moore A, Carroll D, et al. Assessing the quality of reports of randomised clinical trials: is blinding necessary? Controll Clin Trials. 1996;17(1):1–12.

 PubMedGoogle Scholar

Berger VW, Alperson SY. A general framework for the evaluation of clinical trial quality. Rev Recent Clin Trials. 2009;4(2):79–88.

 PubMedGoogle Scholar