GEMINI 1 & 2 Studies: DTG + 3TC vs DTG + TDF/FTC in first-line

Cahn P. Lancet. 2019; 393(10167):143-155 & IAS 2019, Abs. WEAB0404LB; Van Wyk J. IDWeek 2019, Abs. 2842; Orkin C. JIAS 2018;21, suppl.8:31; Eron J. HIV DART and Emerging Viruses 2018, OP#7; Underwood M, CROI 2019, Abs. 490

Type of ARV Trial
Head-to-head comparative trials for first line ART since 2006
» 2 drugs vs 3 drugs
» DTG + 3TC vs DTG + FTC/TDF
Drugs
FTC/TDF, 3TC, DTG

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  • The 2DR of dolutegravir plus lamivudine provides high antiviral potency with a high barrier to resistance and favorable safety and tolerability profiles
    • Non-inferior efficacy and similar tolerability was demonstrated at 48 weeks
    • Non-inferior efficacy was maintained over 96 weeks
    • Low rates of confirmed virologic withdrawal through week 96, and no resistance development in either arm
    • Overall safety and tolerability were comparable between groups
    • Lower risk of drug-related AEs with DTG + 3TC
    • Change in renal and bone biomarkers significantly favors DTG + 3TC
    • Improvements in TC:HDL ratio in both arms

Design


* 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

Baseline characteristics

HIV RNA < 50 c/mL by visit, ITT-E snapshot

  • Mean adjusted increase in CD4 between baseline and W48
    • DTG + 3TC: + 224/mm3
    • DTG + TDF/FTC: + 218/mm3

HIV RNA < 50 c/mL at W48, GEMINI 1 & 2 pooled

Adjusted difference (95% CI)


* 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

ITT-E snapshot analysis, %

HIV RNA < 50 c/mL according to baseline CD4 and HIV RNA, ITT-E snapshot


* Reasons for snapshot non-response at W96 in participants with baseline CD4 < 200/mm3

  • DTG + 3TC (N = 20): 2 with HIV RNA > 50 c/mL, 3 confirmed virologic withdrawal, 1 discontinuation for treatment-related AE, 2 discontinuations for non-treatment-related AE, 3 protocol violations, 3 lost to follow-up, 4 withdrew consent, 1 withdrew to start HCV treatment, 1 change in ART due to incarceration
  • DTG + TDF/FTC (N = 7): 1 confirmed virologic withdrawal, 3 lost to follow-up, 2 withdrew consent, 1 investigator discretion (incarcerated)

HIV RNA < 50 c/mL at W48 (%) in subgroups of the pooled analysis

Time to viral suppression, HIV RNA < 50 c/ml (cumulative incidence): pooled ITT-E population

Virologic outcome at W48 and W96 (ITT snapshot) in patients with baseline HIV RNA > 500 000 c/mL


* 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)

Time to HIV RNA < 40 c/mL with target not detected (Kaplan-Meier )

  • 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

CVW up to W96

  • All were virologic rebounds

Adverse events

Renal markers: adjusted mean change at W48

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)

Adjusted mean change in fasting lipids at week 48, mmol/L (ITT-E)

  • Baseline values are represented by the main legend colors, changes at W48 by lighter colors