Dolutegravir/lamivudine dual therapy non-inferior to triple ART at week-96
Simon Collins, HIV i-Base
Results out to 96-weeks using the dual combination of dolutegravir/lamivudine as first-line therapy were presented as a late-breaking oral abstract at IAS 2019. The dual combination continued to show non-inferiority compared to the three-drug combination of dolutegravir plus TDF/FTC.
Dolutegravir/lamivudine was approved as a dual fixed dose combination (FDC) by the FDA and EMA in April and July 2019, respectively, with tradename Dovato.
Combined results from the GEMINI 1 and 2 phase 3 studies were presented as a late-breaker oral abstract by Pedro Cahn from Fundación Huesped, Buenos Aires.  Week 48 results presented at the IAS 2018 conference last year. 
Overall, 1433 participants were randomised to either dual or triple ART. Baseline characteristics have been previously described and included median age 32 years (range 18 to 70); 15% women/85% men; and race included 69% white, 12% African American and 10% Asian.
Baseline median (range) viral load and CD4 count were 4.4 log copies/mL (1.6 to 6.3) and 430 cells/mm3 (19 to 1497). Approximately 20% participants started with viral load >100,000 copies/mL and 8% with a CD4 count <200 cells/mm3.
At week-48, 91% vs 93% in the dual vs triple groups had viral load <50 copies/mL. These levels were largely sustained at week 96 by ITT analysis: 86% vs 89%. respectively. Non-inferiority was also maintained between the two arms (difference:−3.4 (95%CI: −6.7 to 0.0). See Table 1.
Table 1: Viral responses at week 96 in phase 3 GEMINI studies
|GEMINI 1||GEMINI 2||Pooled|
|DTG+3TC||300/356 (84%)||316/360 (88%)||616/716 (86%)|
|DTG+TDF/FTC||320/358 (89%)||322/359 (90%)||642/717 (90%)|
|Adj. diff. (95% CI)||4.9 (–9.8 to 0)||–1.8 (–6.4 to + 2.7)||–3.4 (–6.7 to 0)|
As the proportion of participants with viral load >50 copies/mL was the same at week-96 as week-48 (3% vs 2%), the differences between the two timepoints were explained by lack of virologic data:11% vs 9% at week-96 compared to 6% vs 5 % at week 48, in the dual vs triple arms. Over the second year, approximately another 10 people in each arm discontinued due to side effects but more people in the dual therapy arm discontinued for other reasons (n=27 vs 16).
There were no new cases of treatment emergent drug resistance in participants who had protocol defined viral failure during the second year (n=5 vs 3).
Overall, similar adverse events (AE) were reported for the two groups: any drug-related side effect (20% vs 25%), AE leading to withdrawal (3% vs 3%) and serious AE (9% vs 9%).
Increased weight was reported as an AE in 13 (1.8%) vs 10 (1.4%) participants in the dual vs triple arms. Overall, the mean change in weight from baseline was +3.1 kg vs +2.1 kg in the dual vs triple arms.
Changes in renal and bone biomarkers were significantly improved in the dual compared to the triple arms, as expected for non-TDF vs TDF containing ART, although the clinical implications from these changes was not presented.
Conversely, lipid differences significantly favoured the triple therapy arm linked to use of TDF, but again with limited likely clinical significance.
Further results supporting this dual combination were included in a poster and reported no differences in the likelihood of low level viral blips over the first 48-weeks. 
By all definition for a blip, there were no differences between arms – whether single blips to between 50 – 200, with or without rebound to >200 once – or to >200 twice (ie confirmed viral withdrawal, CVW). See Table 2. Risk of blips was not related to baseline viral load being above or below 100,000 copies/mL
Table 2: Low level viral blips in GEMINI studies by week-48
|DTG+3TC (N=716)||DTG+TDF/FTC (N=717)|
|1. VL 50-200 (after <50 c/mL)||98 (14%)||101 (14%)|
|a. VL 50-200 c/mL with adjacent values <50 c/mL (‘blips’)||83 (12%)||93 (13%)|
|b. ≥2 consecutive VL 50-200 c/mL||15 (2%)||8 (1%)|
|2. VL ≥200 c/mL after <50 c/mL||19 (3%)||22 (3%)|
|a. Single VL ≥200 with adjacent VL<200 c/mL||14 (2%)||19 (3%)|
|b. ≥2 consecutive VLs ≥200 c/mL (CVW)||5* (0.7%)||3** (0.4%)|
|3. VL never <50 c/mL (most had only baseline visits.||8 (1%)||7 (1%)|
|Total (all categories)||125||130|
* One CVW in DTG+3TC was also counted in category 3.
** One CVW in DTG+TDF/FTC arm was only confirmed at week 60, so is counted in category 2a.
Earlier this year, a presentation at CROI 2019 also reported no differences between the two arms when looking at participants with viral load <40 copies/mL having either a target detected (TD) or target not detected (TND) result.
At the primary 48 week endpoint and at all earlier time points there were no significant differences between the dual triple arms for TND: 77% vs 73% (adjusted difference: 3.8%, 95% CI –0.6%, 8.2%). 
- Cahn P et al. Durable efficacy of dolutegravir (DTG) plus lamivudine (3TC) in antiretroviral treatment-naïve adults with HIV-1 infection – 96-week results from the GEMINI studies. 10th IAS Conference on HIV Science (IAS 2019), 21-24 July 2019, Mexico City.Late-breaker oral abstract WEAB0404LB.
- 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.
- Underwood M et al. Dolutegravir (DTG) plus lamivudine (3TC) versus DTG plus tenofovir/emtricitabine (TDF/FTC) fixed-dose combination in the GEMINI studies – viral load rebound including ‘blips’ through 48 weeks. 10th IAS Conference on HIV Science (IAS 2019), 21-24 July 2019, Mexico City.Poster abstract MOPEB231.
- Underwood M et al. HIV replication at <40 c/mL for DTG+3TC vs DTG+TDF/FTC in the GEMINI 1 & 2 studies. CROI, 4-7 March 2019, Seattle. Poster abstract 490.