1. DTG + 3TC vs DTG + TDF/FTC
GEMINI

2. No major HIV resistance mutations
GEMINI 1 & 2 Studies: DTG + 3TC vs DTG + TDF/FTC in first-line
Design
Randomisation *
1 : 1
Double-blind
W96
HIV+ ≥ 18 years
ARV-naïve
HIV RNA c/mL
No HBV co-infection
No major HIV resistance mutations
N = 716
DTG + 3TC
DTG + TDF/FTC
N = 717
* Randomisation stratified by HIV RNA (≤ or > c/mL) and CD4 (≤ or > 200/mm3)
Primary endpoint
2 parallel studies (GEMINI-1 and GEMINI-2), each with a combined number of patients and similar endpoint
Proportion of patients with HIV RNA < 50 c/mL at W48, ITT-E analysis, snapshot algorithm ; non-inferiority if lower margin of a one-sided 97.5% CI for the difference = - 10%, 90% power
GEMINI
Cahn P. Lancet. 2019; 393(10167):

3. Baseline characteristics
GEMINI 1 & 2 Studies: DTG + 3TC vs DTG + TDF/FTC in first-line
Baseline characteristics
DTG + 3TC
N = 716
DTG + TDF/FTC
N = 717
Median age, years 32 33
Female, % 16 14
HIV RNA, log10 c/mL, mean
≤ c/mL, %
> c/mL, %
4.42
80 20
4.45
79 21
CD4/mm3, mean
< 200, %
≥ 200, %
462
9 91
461
8 92
HCV co-infection, % 5 7
GEMINI
Cahn P. Lancet. 2019; 393(10167):

4. HIV RNA < 50 c/mL by visit, ITT-E snapshot
GEMINI 1 & 2 Studies: DTG + 3TC vs DTG + TDF/FTC in first-line 74
HIV RNA < 50 c/mL by visit, ITT-E snapshot 20 40 60 80
100 4 8 12 16 36 48 24
Week 70 85 89 90 72 87 88 93 91 %
DTG + TDF/FTC (N = 717)
DTG + 3TC (N = 716)
Mean adjusted increase in CD4 between baseline and W48
DTG + 3TC: + 224/mm3
DTG + TDF/FTC: + 218/mm3
GEMINI
Cahn P. Lancet. 2019; 393(10167):

5. Adjusted difference (95% CI)
GEMINI 1 & 2 Studies: DTG + 3TC vs DTG + TDF/FTC in first-line 75
HIV RNA < 50 c/mL at W48,
GEMINI 1 & 2 pooled
Adjusted difference (95% CI)
-1.3
-3.9
1.2
Per
Protocol ***
DTG + TDF/FTC
DTG + 3TC
GEMINI-1 & 2 ITT-E *
- 4.4
1.1
- 1.7 2 4 6 8 10 -2 -4 -6 -8
-10
GEMINI-2 ITT-E **
- 4.3
2.9
- 0.7
GEMINI-1 ITT-E **
- 6.7
1.5
- 2.6
Virologic
success
Non-response
No virologic
data 20 40 60 80
100 91 93 3 5 6 2 %
DTG + TDF/FTC
DTG + 3TC N= 1 4 94
716
717
694
693
ITT-exposed, snapshot
Per protocol
* Adjusted on HIV RNA, CD4, study (GEMINI 1 or 2)
** Adjusted on HIV RNA and CD4 ** ITT-E population except patients with protocol violation
Conclusion: non inferiority of DTG + 3TC
GEMINI
Cahn P. Lancet. 2019; 393(10167):

6. W48 ITT-E snapshot analysis, %
GEMINI 1 & 2 Studies: DTG + 3TC vs DTG + TDF/FTC in first-line
W48 ITT-E snapshot analysis, %
DTG + 3TC
N = 716
DTG + TDF/FTC
N = 717
HIV RNA < 50 c/mL
91.5
93.3
Virologic non-reponse
HIV RNA ≥ 50 c/mL in window
Discontinued for lack of efficacy
Discontinued for other reason and HIV RNA ≥ 50 c/mL
Change in ART
2.8
1.1
0.7
0.3
1.8
0.1
No virologic data
Discontinued for AE or death
Discontinued for other reasons
On study but missing data
5.7
1.4
4.0
4.9
3.1 0
GEMINI
Cahn P. Lancet. 2019; 393(10167):

7. GEMINI 1 & 2 Studies: DTG + 3TC vs DTG + TDF/FTC in first-line76
HIV RNA < 50 c/mL according to baseline CD4 and HIV RNA, ITT-E snapshot
DTG + TDF/FTC
DTG + 3TC
> ≤
> 200
≤ 200 *
HIV RNA, c/mL
CD4/mm3 20 40 60 80
100 91 94 92 90 93 79 % N=
576
564
140
153
653
662 63 55
* Reasons for snapshot non-response in participants with baseline CD4 < 200/mm3
DTG + 3TC (N = 13): 3 with HIV RNA > 50 c/mL, 1 confirmed virologic withdrawal, 2 discontinuations for non-treatment-related adverse event, 2 protocol violations, 2 lost to follow-up, 1 withdrew consent, 1 withdrew to start HCV treatment, 1 change in ART due to incarceration
DTG + TDF/FTC (N = 4): 1 with HIV RNA > 50 c/mL, 1 lost to follow-up, 1 withdrew consent, 1 investigator discretion
GEMINI
Cahn P. Lancet. 2019; 393(10167):

8. HIV RNA < 50 c/mL at W48 (%) in subgroups of the pooled analysis
GEMINI 1 & 2 Studies: DTG + 3TC vs DTG + TDF/FTC in first-line
HIV RNA < 50 c/mL at W48 (%) in subgroups of the pooled analysis
Difference, % (95%CI)
DTG + TDF/FTC
DTG + 3TC
-2.8
1.9
-1.5
-13.4
-0.7
-3.0
-0.8
-2.3
-1.6
-0.4
-0.1
-3.8 10 20 30
-10
-20
-30
-1.7
DTG + TDF/FTC
DTG + 3TC
717 n
>
140 92
Baseline HIV-1 RNA, copies/ml
153 90 ≤
576 91
564 94 93
> 200
653
Baseline CD4+ count, cells/mm3 49
662 93 63 79
≤ 200 55
668 93
≥ 50 65 89 80 90
Age
35 to < 50
231 91
229 94
< 35
420 92
408 93
Female
113 88 98 91
Sex
Male
603 92
619 94
African heritage 99 84 76 84
Asian 71 94 72 94
Race 93
White
480
497 95 66 88
Other 72 92 20 40 60 80
100
GEMINI
Orkin C (Abs. P021). JIAS 2018; 21 , suppl. 8: 31

9. Participants with baseline HIV-1 RNA > 100 000 c/mL
GEMINI 1 & 2 Studies: DTG + 3TC vs DTG + TDF/FTC in first-line
Time to viral suppression, HIV RNA < 50 c/ml (cumulative incidence): pooled ITT-E population
All participants
Participants with baseline HIV-1 RNA > c/mL 4 8 12 16 24 36 48 60
0,2
0,4
0,6
0,8
1,0
Weeks
DTG + 3TC (N = 716)
DTG + TDF/FTC (N = 717) 4 8 12 16 24 36 48 60
0,2
0,4
0,6
0,8
1,0
Weeks
DTG + 3TC (N = 140)
DTG + TDF/FTC (N = 153)
Median time to viral suppression : DTG + 3TC vs DTG + TDF/FTC = 29.0 vs 29.0 days
Median time to viral suppression : DTG + 3TC vs DTG + TDF/FTC = 57.0 vs 57.0 days
GEMINI
Eron J. HIV DART and Emerging Viruses 2018; Miami, FL. Oral Presentation #7.

10. GEMINI 1 & 2 Studies: DTG + 3TC vs DTG + TDF/FTC in first-line96
Virologic outcome at W48 (ITT snapshot)
in patients with baseline HIV RNA > c/mL
DTG + 3TC (N = 13 *)
DTG + TDF/FTC (N = 15 *)
Baseline HIV RNA, c/mL N
ITT snapshot, W48 8
HIV RNA < 50 c/mL, N = 7
No data **, N = 1 9
HIV RNA ≥ 50 c/mL, N = 1 3
HIV RNA < 50 c/mL, N = 3 5
HIV RNA < 50 c/mL, N = 4 2
HIV RNA < 50 c/mL, N = 1
No data ***, N = 1 1
* CD4 < 200/mm3 in 3/13 and 5/15
** Discontinuation for other reason
*** Discontinuation for selection criteria violation (screening HIV RNA > c/mL
GEMINI
Eron J. HIV DART and Emerging Viruses 2018; Miami, FL. Oral Presentation #7.

11. Time to HIV RNA < 40 c/mL with target not detected (Kaplan-Meier )
GEMINI 1 & 2 Studies: DTG + 3TC vs DTG + TDF/FTC in first-line
Time to HIV RNA < 40 c/mL with target not detected (Kaplan-Meier )
Baseline HIV RNA < c/mL 4 8 12 16 24 36 48 60 72
0.2
0.4
0.6
0.8
1.0
80 %
79 %
Weeks
(N = 576)
(N = 564)
All participants
DTG + 3TC (N = 716)
DTG + TDF/FTC (N = 717) 4 8 12 16 24 36 48 60 72
0.2
0.4
0.6
0.8
1.0
77 %
73 %
Weeks
Baseline HIV RNA > c/mL 4 8 12 16 24 36 48 60 72
0.2
0.4
0.6
0.8
1.0
64 %
52 %
Weeks
(N = 140)
(N = 153)
GEMINI
Underwood M, CROI 2019, Abs. 490

12. GEMINI 1 & 2 Studies: DTG + 3TC vs DTG + TDF/FTC in first-line
Confirmed virologic withdrawal (CVW)
Decrease from baseline in HIV RNA < 1 log10 c/mL, unless HIV RNA < 200 c/mL, by W12
Confirmed HIV RNA ≥ 200 c/mL at or after W24
Confirmed rebound (HIV RNA ≥ 200 c/mL) after confirmed HIV RNA < 200 c/mL
Genotypic and phenotypic resistance tests on initial suspected plasma sample
Number of CVW
DTG + 3TC, N = 6 vs DTG + TDF/FTC, N = 4
All were virologic rebounds
No emergence of treatment-emergent INSTI or NRTI resistance mutations
GEMINI
Cahn P. Lancet 2018, Nov 9, Epub ahead of print

13. GEMINI 1 & 2 Studies: DTG + 3TC vs DTG + TDF/FTC in first-line
Adverse events
DTG + 3TC
N = 716
DTG + TDF/FTC
N = 717
Serious adverse events
Fatal 7
0.3 (Burkitt lymphoma, MI) 8
Drug-related adverse events
Grade 2-5 18 6 24
Discontinuation for adverse event 2
Adverse event in ≥ 5% of participants
Headache
Diarrhea
Nasopharyngitis
Upper respiratory tract infection
Pharyngitis
Back pain
Nausea
Insomnia
GEMINI
Cahn P. Lancet. 2019; 393(10167):

14. GEMINI 1 & 2 Studies: DTG + 3TC vs DTG + TDF/FTC in first-line78
Renal markers: adjusted mean change at W48
Serum
Urine
Protein/ creatinine (g/moL)
Retinol-binding protein/ creatinine (µg/mmoL)
Beta-2 microglobulin/ creatinine (mg/mmoL) 10
-10
-20 20 %
-13.1
-7.4
-7.7
31.2
11.4
2.9 30 40
p < for all comparisons DTG + 3TC vs DTG + TDF/FTC
GFR from creatinine, CKD-EPI (mL/min/1,73 m2)
Creatinine
(µmol/L) -5
-10
-15
-20 5 10 15
GFR from cystatin C, CKD-EPI (mL/min/1,73 m2)
6.3
4.1
10.4
13.5
-12.1
-15.5
DTG + TDF/FTC (N = 717)
DTG + 3TC (N = 716)
Bone turnover biomarkers: adjusted mean change at W48
Significant higher increase of the biomarkers in DTG + TDF/FTC arm (specific alkaline phosphatase, osteocalcin, procollagen 1-N terminal propeptide and type 1 collagen C-telopeptide)
GEMINI
Cahn P. Lancet. 2019; 393(10167):

15. Adjusted mean change in fasting lipids from baseline, mmol/L (ITT-E)
GEMINI 1 & 2 Studies: DTG + 3TC vs DTG + TDF/FTC in first-line
Adjusted mean change in fasting lipids from baseline, mmol/L (ITT-E) 5 4 3 2 1
Total cholesterol **
↑0.32
↓0.15 *
DTG + TDF/FTC (N = 717)
DTG + 3TC (N = 716)
↑0.15
↑0.02
↓0.14
↓0.08
↑0.17
↑0.03
↓0.24
↑0.12
HDL cholesterol
LDL cholesterol
Triglycerides
Total cholesterol/ HDL cholesterol ratio
** p < 0.001
* p < 0.05
Baseline values are represented by the main legend colors, changes at W48 by lighter colors
GEMINI
Cahn P. Lancet. 2019; 393(10167):

16. GEMINI 1 & 2 Studies: DTG + 3TC vs DTG + TDF/FTC in first-line
Conclusion
The 2DR of dolutegravir plus lamivudine provides high antiviral potency with a high barrier to resistance and favorable safety and tolerability profiles
The non-inferior efficacy and similar tolerability of dolutegravir plus lamivudine to a guideline-recommended 3DR at 48 weeks in ART-naive adults supports its use as an initial therapy for HIV-1 infection
GEMINI
Cahn P. Lancet. 2019; 393(10167):