DTG + 3TC vs DTG + TDF/FTC GEMINI

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 1 000-500 000 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 > 100 000 c/mL) and CD4 (≤ or > 200/mm3) Primary endpoint 2 parallel studies (GEMINI-1 and GEMINI-2), each with a combined number of 710-720 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):143-155

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 ≤ 100 000 c/mL, % > 100 000 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):143-155

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):143-155

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):143-155

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):143-155

GEMINI 1 & 2 Studies: DTG + 3TC vs DTG + TDF/FTC in first-line 76 HIV RNA < 50 c/mL according to baseline CD4 and HIV RNA, ITT-E snapshot DTG + TDF/FTC DTG + 3TC > 100 000 ≤ 100 000 > 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):143-155

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 > 100 000 140 92 Baseline HIV-1 RNA, copies/ml 153 90 ≤ 100 000 576 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

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 > 100 000 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.

GEMINI 1 & 2 Studies: DTG + 3TC vs DTG + TDF/FTC in first-line 96 Virologic outcome at W48 (ITT snapshot) in patients with baseline HIV RNA > 500 000 c/mL DTG + 3TC (N = 13 *) DTG + TDF/FTC (N = 15 *) Baseline HIV RNA, c/mL N ITT snapshot, W48 500 000 - 750 000 8 HIV RNA < 50 c/mL, N = 7 No data **, N = 1 9 HIV RNA ≥ 50 c/mL, N = 1 750 000 - 1 000 000 3 HIV RNA < 50 c/mL, N = 3 5 HIV RNA < 50 c/mL, N = 4 1 000 000 - 2 500 000 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 > 500 000 c/mL GEMINI Eron J. HIV DART and Emerging Viruses 2018; Miami, FL. Oral Presentation #7.

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 < 100 000 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 > 100 000 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

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

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 10 9 8 8 5 5 4 4 10 11 11 6 4 4 7 6 GEMINI Cahn P. Lancet. 2019; 393(10167):143-155

GEMINI 1 & 2 Studies: DTG + 3TC vs DTG + TDF/FTC in first-line 78 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 < 0.001 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):143-155

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):143-155

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):143-155