DTG/3TC dual therapy is non-inferior to triple-ART in GEMINI study
Simon Collins, HIV i-Base
Summary results from using a two-drug combination of dolutegravir (DTG) plus lamivudine (3TC) were presented by Pedro Cahn from Fundación Huésped, Buenos Aires, in a press conference at the AIDS 2018 conference in Amsterdam. 
Full results were presented later that morning in an oral presentation. Unlike many other studies that had embargos lifted at the press conference, advance slides of this study was not available beforehand, limiting the details in any early reports. 
As background, several years ago, the high genetic barrier to drug resistance reported for dolutegravir, prompted a small single-arm pilot study to report use of this two-drug maintenance therapy in 20 treatment-naive participants. 
The results were sufficiently encouraging for the manufacturer (ViiV Healthcare) to launch several large randomised studies dropping one of its own drugs (abacavir) from an already approved fixed dose combination (FDC) and using dolutegravir plus TDF/FTC as the standard-of-care control arm. [4, 5]
The top-line results of these strategy trials were released several weeks before AIDS 2018: reporting that 2-drug ART was non-inferior to 3-drug standard of care. 
GEMIMI 1 and 2 are identically designed studies. Both are large, international phase 3 studies, and each randomised just over 700 treatment-naive participants to either DTG+3TC or DTG+TDF/FTC. The primary endpoint was the proportion of participants with plasma viral load <50 copies/mL at week-48 (using ITT snapshot analysis).
GEMINI 1 and 2 randomised 714 and 719 treatment-naive participants respectively with screening viral load <500,000 copies/mL. Baseline characteristics included median CD4 and viral load of 432 cells/mm3 (range: 19 to 1497), with 10% <200 cells/mm3, and 4.4 log copies/mL (range: 1.6 to 6.4) respectively, with 20% >100,000 copies/mL.
Approximately 2% of participants in each arm were later reported as having viral load above entry criteria threshold of 500,000 copies/mL (explained by fluctuations between screening and baseline).
Other baseline characteristics included median age 32 years (range 18 to 72); 85% were men and 15% women; 70% were white, 12% African-American, 10% Asian and 10% other ethnicity.
At week-48, viral load was <50 copies/mL in the 2- vs 3-drug arms in 90% (320/356) vs 93% (332/358) in GEMINI 1 and 93% (335/360) vs 94% (337/359) in GEMINI 2. This resulted in adjusted between-arm differences that were slightly lower in the two-drug arm, though with a 95%CI that was well within the predefined margin of –10%: –2.6 (95%CI: –6.7 to +1.5) and –0.7 (–4.3 to +2.9), in GEMINI 1 and 2 respectively. Although the adjusted treatment differences favoured the triple therapy arm, non-inferiority was also easily met in the combined analysis: –1.7 (–4.4 to +1.1).
Virologic non-response in dual vs triple arm were 4% vs 2% in GEMINI 1 and 2% vs 2% in GEMINI 2. The percentage of participants with missing data was 6% vs 6% and 5% vs 4% in GEMINI 1 and 2 respectively.
Virologic responses by prespecified criteria of viral load above vs below 100,000 copies/mL were broadly similar, at 90-94% with no suggestion that dual therapy was less effective.
However, there was a significant difference when results were stratified by baseline CD4 count above vs below 200 cells/mm3. While each arm reported 93% (51/55) viral suppression to <50 copies/mL at week-48 when CD4 count was >200 cells/mm3, this dropped to only 79% (50/63) of the participants who started with CD4 counts <200 cells/mm3.
Only 1/13 had confirmed viral failure, with 2/3 participants with viral load >50 copies/mL resupressing without changing treatment. Two participants discontinued due to adverse events (TB, Chagas disease), two were protocol violations, two were lost to follow-up, one withdrew consent, one withdrew to start HCV treatment and one changed in ART (due to incarceration).
Across both studies, six participants on DTG+3TC vs four on DTG+TDF/FTC met protocol-defined virologic failure. Of these, none developed new primary mutations associated with INSTI or NRTI drug resistance.
Overall rates of side effects were similar between arms, with 2% of participants in each group discontinuing for this reason. More drug related side-effects were reported with DTG+TDF/FTC.
Although the presentation emphasised that each side effect was only reported by one or two people, this was largely linked to separating similar or related side effects. For example, single reports of anxiety, depression, suicide attempt, suicide ideation, insomnia and sleep disorder, would more commonly be combined as under neuropsychological events.
The fewer side effects reported overall for the dual therapy arm, were not statistically different to the triple-ART arm.
Differences in renal and bone biomarkers significantly favoured the dual-therapy group at week-24, similar to other TDF vs non-TDF comparing studies.
Lipid differences were not presented but a back-up slide of a pooled analysis showed that changes in lipid parameters, all significantly favoured the triple-ART arm, including the difference in TC:HDL ratio (p<0.05), but these changes were generally small with limited clinical significance.
Note: This report and linked comments have been edited since the initial post to included more details on baseline characteristics and study results.
The GEMINI studies show that dual therapy with DTG/3TC was non-inferior to the triple ART, with these particular drugs.
On the basis of these results, the fixed dose formulation of dolutegravir/3TC is expected to soon be submitted to the FDA and EMA for regulatory approval.
Viral load changes between screening and baseline led to some participants having baseline viral load >1,000,000 copies/mL when entry criteria included an upper threshold of 500,000 copies/mL. Just under 10% of participants in each arm had baseline CD4 counts <200 copies/mL with some CD4 counts in both arms as low as 19 cells/mm3. These details were not included in ViiV’s press release. 
In response to a question by Andrew Hill after the presentation, Dr Cahn confirmed that the results could only be interpreted for settings in a high-income country and were not applicable in other settings. An editorial review in AIDS, co-authored by Dr Hill and colleagues suggested that the disadvantages of dual therapy (for example, when HBV is a concern) are currently likely to outweigh advantages in low- and middle-income settings. 
In high-income settings, with easier access to monitoring, the use for DTG/3TC is likely to be very different. The results are also encouraging for people who have complication related to use of current NRTIs.
- Press conference. GEMINI study results. Tuesday 24 July 2018. 10.00 am.
- Cahn P et al. Non-inferior efficacy of dolutegravir (DTG) plus lamivudine (3TC) versus DTG plus tenofovir/emtricitabine (TDF/FTC) fixed-dose combination in antiretroviral treatment-naïve adults with HIV-1 infection – 48-week results from the GEMINI studies. AIDS 2018, 23-27 July 2018, Amsterdam. Late breaker oral abstract TUAB0106LB.
- Cahn P et al. Dolutegravir-lamivudine as initial therapy in HIV-infected, ARV naive patients: 48 week results of the PADDLE trial. AIDS 2016, 18-22 July 2016, Durban. Oral late breaker abstract FRAB0104LB.
http://www.natap.org/2016/IAC/IAC_92.htm (Slides thanks to natap.org)
- ClinicalTrials.gov. An efficacy, safety, and tolerability study comparing dolutegravir (DTG) plus lamivudine (3TC) with dolutegravir plus tenofovir/emtricitabine in treatment naive HIV positive subjects (Gemini 1). NCT02831673.
- ClinicalTrials.gov. An efficacy, safety, and tolerability study comparing dolutegravir (DTG) plus lamivudine (3TC) with dolutegravir plus tenofovir/emtricitabine in treatment naive HIV positive subjects (Gemini 2). NCT02831764.
- ViiV Press release. ViiV Healthcare reports positive results for landmark phase III studies for dolutegravir and lamivudine. (14 June 2018)
- ViiV press statement. ViiV Healthcare presents phase III data at AIDS 2018 from landmark GEMINI studies showing two-drug regimen of dolutegravir and lamivudine has similar efficacy to a three-drug regimen in treatment naïve HIV patients
with no emergence of resistance. (24 July 2018).
- Vitoria M et al. The transition to dolutegravir and other antiretrovirals in low-income and middle-income countires: what are the issues? AIDS 32(12):1551-1561. (31 July 2018).