Explore the clinical data

Week 48 Results for DTG + 3TC Demonstrated:[1]

Download the GEMINI Slide Set Access the GEMINI Clinical Paper

WHY 2DRs?

WHY INVESTIGATE DTG + 3TC AS A 2-DRUG REGIMEN?

STUDY DESIGN

PATIENT DEMOGRAPHICS

PRIMARY ENDPOINT RESULT

BARRIER TO RESISTANCE

ADVERSE EVENTS

BONE MARKERS

LIPIDS

RENAL

CONCLUSIONS

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Tivicay + lamivudine is only suitable for the treatment of HIV-1 infection where there is no known or suspected resistance to the integrase inhibitor class, or to lamivudine.

Reference:

  1. Cahn P et al. Presented at: International AIDS Conference; July 23-27, 2018; Amsterdam, Netherlands.

No one should take more medicine than they need

A 20-year old starting a 3-drug regimen (3DR) may be on therapy for nearly 6 decades, which translates to more than 60,000 doses of individual medications.[2] Managing comorbidities, DDIs and potential long-term effects of treatment are important considerations
The Positive Perspectives Survey highlighted that 72% (n=783/1085) of PLHIV worry about the long-term impact of their medicines on their bodies.[3] Access the full report here.
The potential benefits associated with 2-drug regimens (2DRs) include reduced ARV exposure and may reduce long term toxicities, drug preservation for future treatment options and increased treatment access
Traditional 3DRs achieve viral suppression by targeting two different intracellular viral replication processes[4]; modern 2DRs can be expected to achieve the same as they also target two distinct viral replication processes[5], [6]

ARV, antiretroviral; DDIs, drug-drug interactions; PLHIV, people living with HIV

Tivicay + lamivudine is only suitable for the treatment of HIV-1 infection where there is no known or suspected resistance to the integrase inhibitor class, or to lamivudine.

References:

  1. Cahn P et al. Presented at: International AIDS Conference; July 23-27, 2018; Amsterdam, Netherlands
  2. The Antiretroviral Therapy Cohort Collaboration. Survival of HIV-positive patients starting antiretroviral therapy between 1996 and 2013: a collaborative analysis of cohort studies. Lancet HIV. 2017;4(8):e349-e356
  3. Marcotullio S, et al. EACS 2017, poster PE25/9
  4. European AIDS Clinical Society. Guidelines. Version 9.0. October 2017. http://eacsociety.org/files/guidelines_9.0-English.pdf. Accessed May 2019
  5. JULUCA▼ (dolutegravir/rilpivirine) Summary of Product Characteristics. Available from: www.medicines.ie. Accessed: May 2019.
  6. TIVICAY Summary of Product Characteristics. Available from: www.medicines.ie. Accessed: May 2019.

Why investigate DTG + 3TC as a 2-drug regimen?

  • The requirement for lifelong ART for HIV infection has highlighted interest in 2DRs to minimize cumulative drug exposure[2]
  • Lower ARV exposure may translate to less long-term drug toxicity
  • The potency, safety profile and high resistance barrier of DTG make it an optimal core agent for 2DRs
  • The safety profile, tolerability and efficacy of 3TC make it a reliable partner for initial HIV-1 treatment
  • Previous pilot studies have evaluated DTG + 3TC as a complete 2DR in treatment-naive participants
    • PADDLE: 90% (18/20) had VL <50 c/mL at Week 482[3]
    • ACTG A5353: 90% (108/120) had VL <50 c/mL at Week 243[4]
  • In the GEMINI-1 and -2 studies DTG + 3TC was evaluated vs a traditional 3-drug regimen (3DR) DTG + TDF/FTC for treatment-naive patients with HIV-1 infection through 48 weeks[1]

ART, antiretroviral therapy

Tivicay + lamivudine is only suitable for the treatment of HIV-1 infection where there is no known or suspected resistance to the integrase inhibitor class, or to lamivudine.

References:

  1. Cahn P et al. Presented at: International AIDS Conference; July 23-27, 2018; Amsterdam, Netherlands.
  2. Kelly et al. Drugs. 2016;76(5):523-531.
  3. Cahn et al. J Int AIDS Soc. 2017;20(1):21678.
  4. Taiwo et al. Clin Infect Dis. 2018;66(11):1689-1697.

GEMINI-1 and GEMINI-2:
2 Fully Powered Studies with More Than 700 Patients Each

2 identical, double-blind, treatment-naïve Phase III studies:[1]
  • Objective: demonstrate non-inferior efficacy of DTG 50 mg + 3TC 300 mg vs DTG 50 mg + TDF/FTC 300 mg/200 mg
  • Eligibility criteria: (i) treatment naive, (ii) viral load <500,000 copies/mL, (iii) HBV negative, (iv) no major RAMs, (v) ≥18 years old.
  • Primary Endpoint: percentage of patients with plasma HIV-1 RNA <50 copies/mL at Week 48 (by snapshot algorithm)

RAMs=resistance-associated mutations.

Tivicay + lamivudine is only suitable for the treatment of HIV-1 infection where there is no known or suspected resistance to the integrase inhibitor class, or to lamivudine.

Reference:

  1. Cahn P et al. Presented at: International AIDS Conference; July 23-27, 2018; Amsterdam, Netherlands.

GEMINI-1 and GEMINI-2:
Baseline Characteristics

Adapted from Cahn et al. 2018[1]

Tivicay + lamivudine is only suitable for the treatment of HIV-1 infection where there is no known or suspected resistance to the integrase inhibitor class, or to lamivudine.

Reference:

  1. Cahn P et al. Presented at: International AIDS Conference; July 23-27, 2018; Amsterdam, Netherlands.

VIROLOGICAL SUPPRESSION IN TREATMENT-NAÏVE ADULTS:
Results Non-Inferior to Comparator at Week 48[1]

Primary Analysis

Adapted from Cahn et al., 2018 [1]

Pooled Analysis

Adapted from Cahn et al., 2018 [1]

Baseline Viral Load Strata

Adapted from Cahn et al., 2018 [1]

  • 2% of participants in each arm had baseline HIV-1 RNA >500,000 copies/mL

Baseline CD4+ T-cell Count Strata

Adapted from Cahn et al., 2018 [1]

Efficacy by Study Visit

Adapted from Cahn et al., 2018 [1]

*Treatment-related discontinuation=failure population accounts for confirmed virological withdrawal, withdrawal due to lack of efficacy, withdrawal due to treatment-related adverse event, and participants who met protocol-defined stopping criteria. [1]

DTG + 3TC CD4+ T-cell count <200 Snapshot non-response (n=13): 1 confirmed virological withdrawal, 3 with viral load >50 copies/mL in window (2 of 3 re-suppressed), 2 discontinued due to adverse event (tuberculosis, Chagas disease), 2 protocol violations, 2 lost to follow-up, 1 withdrew consent, 1 withdrew to start hepatitis C treatment, 1 change in ART (incarcerated). [1]

DTG + TDF/FTC CD4+ T-cell count <200 Snapshot non-response (n=4):1 investigator discretion, 1 withdrew consent, 1 lost to follow-up, 1 viral load >50 copies/mL (re-suppressed). [1]

ITT–E = intent – to – treat exposed.

Tivicay + lamivudine is only suitable for the treatment of HIV-1 infection where there is no known or suspected resistance to the integrase inhibitor class, or to lamivudine.

Reference:

  1. Cahn P et al. Presented at: International AIDS Conference; July 23-27, 2018; Amsterdam, Netherlands.

TIVICAY + Lamivudine:
Built on the Proven High Barrier to Resistance of Dolutegravir



CVW criteria

Tivicay + lamivudine is only suitable for the treatment of HIV-1 infection where there is no known or suspected resistance to the integrase inhibitor class, or to lamivudine.

TIVICAY + lamivudine
High Virological Barrier
High Pharmacological Barrier
Target Binding
High potency [2-4]
DTG: high genetic barrier [5]
DTG: high inhibitory quotient [6]
Well-matched PK [7-11]
Low potential for DDIs [10,12]
Adherence and tolerability
DTG: long target binding [13-15]
Blocks the viral life cycle at
2 different targets [10,12]
High potency
Proof of concept 10-day monotherapy studies demonstrate the inherent potency of DTG and 3TC [2,3]
2.46 log10 viral load decrease after 10 days DTG 50 mg QD monotherapy and 1.50 log10 viral load decrease after 10 days 3TC 150 mg BID monotherapy[2,3]
Rapid and sustained viral load decline with DTG + 3TC in GEMINI-1 and GEMINI-2, including in patients with high viral loads (baseline HIV-1 RNA >100,000 copies/mL)[4]
DTG: high genetic barrier
Slower in vitro passage for resistance selection compared with elvitegravir[5]
DTG: high inhibitory quotient
DTG 50 mg QD exposure 19-fold above IC90 at 24 hours after achieving steady state[6]
Well-matched PK
Serum DTG and intracellular 3TC-triphosphate have a well-matched half-life of approximately 15 hours[7-11]
Low potential for DDIs
DTG and 3TC have a low potential for significant drug-drug interactions[10,12]
Adherence and tolerability
DTG: Long target binding
DTG has a streamlined structure compared with first-generation INIs[13]
DTG has a dissociation half-life of 71 to 79 hours[14,15]
DTG + 3TC blocks the viral life cycle at 2 different targets[10,12]

Reference:

  1. Cahn P et al. Presented at: International AIDS Conference; July 23-27, 2018; Amsterdam, Netherlands.
  2. Min S, Sloan L, DeJesus E, et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults. AIDS. 2011;25(14):1737-1745.
  3. Rousseau FS, Wakeford C, Mommeja-Marin H, et al; for the FTC-102 Clinical Trial Group. Prospective randomized trial of emtricitabine versus lamivudine short-term monotherapy in human immunodeficiency virus-infected patients. J Infect Dis. 2003;188(11):1652-1658.
  4. Eron J, Hung C-C, Baril J-G, et al. Initial viral load decline and response rates by baseline viral load strata with dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate/emtricitabine: pooled results from the GEMINI studies. Presented at: HIV DART and Emerging Viruses; November 27-29, 2018; Miami, FL.
  5. Tsiang M, Jones GS, Goldsmith J, et al. Antiviral activity of bictegravir (GS-9883), a novel potent HIV-1 integrase strand transfer inhibitor with an improved resistance profile. Antimicrob Agents Chemother. 2016;60(12):7086-7097.
  6. van Lunzen J, Maggiolo F, Arribas JR, et al. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis. 2012;12(2):111- 118.
  7. Min S, Song I, Borland J, et al. Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers. Antimicrob Agents Chemother. 2010;54(1):254-258.
  8. Moore KH, Barrett JE, Shaw S, et al. The pharmacokinetics of lamivudine phosphorylation in peripheral blood mononuclear cells from patients infected with HIV-1. AIDS. 1999;13(16):2239-2250.
  9. Yuen GJ, Lou Y, Bumgarner NF, et al. Equivalent steady-state pharmacokinetics of lamivudine in plasma and lamivudine triphosphate within cells following administration of lamivudine at 300 milligrams once daily and 150 milligrams twice daily. Antimicrob Agents Chemother. 2004;48(1):176-182.
  10. TIVICAY Summary of Product Characteristics. April 2019.
  11. Else LJ, Jackson A, Puls R, et al. Pharmacokinetics of lamivudine and lamivudine-triphosphate after administration of 300 milligrams and 150 milligrams once daily to healthy volunteers: results of the ENCORE 2 study. Antimicrob Agents Chemother. 2012;56(3):1427-1433.
  12. EPIVIR Summary of Product Characteristics. January 2019.
  13. DeAnda F, Hightower KE, Nolte RT, et al. Dolutegravir interactions with HIV-1 integrase-DNA: structural rationale for drug resistance and dissociation kinetics. PLoS ONE. 2013;8(10):e77448.
  14. Hightower KE, Wang R, DeAnda F, et al. Dolutegravir (S/GSK1349572) exhibits significantly slower dissociation than raltegravir and elvitegravir from wild-type and integrase inhibitor-resistant HIV-1 integrase-DNA complexes. Antimicrob Agents Chemother. 2011;55(10):4552-4559.
  15. White K, Niedziela-Majka A, Novikov A, et al. Bictegravir dissociation half-life from HIV-1 G140S/Q148H integrase-DNA complexes. Presented at: Conference on Retroviruses and Opportunistic Infections; February 13-16, 2017; Seattle, WA. Poster 497.

Overall Adverse Events (AEs) were comparable across both arms at 48 weeks.[1]

  • Fewer drug-related adverse events with TIVICAY + lamivudine

To learn more in relation to the safety and tolerability of DTG + 3TC click here.

*2 deaths (acute myocardial infarction, n=1; Burkitt's lymphoma, n=1) in GEMINI-2 study; both were in the DTG + 3TC group and were considered unrelated to the study drug regimen.[1]

Tivicay + lamivudine is only suitable for the treatment of HIV-1 infection where there is no known or suspected resistance to the integrase inhibitor class, or to lamivudine.

Reference:

  1. Cahn P et al. Presented at: International AIDS Conference; July 23-27, 2018; Amsterdam, Netherlands.

Bone Markers

Adapted from Cahn et al., 2018[1]

Statistically significant smaller change in bone turnover markers in the DTG + 3TC arm[1]

The clinical significance of these values may vary in individual patients.

Tivicay + lamivudine is only suitable for the treatment of HIV-1 infection where there is no known or suspected resistance to the integrase inhibitor class, or to lamivudine.

Reference:

  1. Cahn P et al. Presented at: International AIDS Conference; July 23-27, 2018; Amsterdam, Netherlands.

Lipids

TC/HDL ratio improved in both arms with a statistically significant greater reduction in the DTG + TDF/FTC arm[1]

The clinical significance of these values may vary in individual patients.

Tivicay + lamivudine is only suitable for the treatment of HIV-1 infection where there is no known or suspected resistance to the integrase inhibitor class, or to lamivudine.

Reference:

  1. Cahn P et al. Presented at: International AIDS Conference; July 23-27, 2018; Amsterdam, Netherlands.

Renal

  • Statistically significant change in eGFR (cystatin C) favouring DTG+3TC vs DTG+TDF/FTC[1]
  • Statistically significant change in urine protein/creatinine, retinol-binding protein/creatinine and beta-2 microglobulin/creatinine ratios favouring DTG+3TC vs DTG+TDF/FTC[1]

The clinical significance of these values may vary in individual patients.

Tivicay + lamivudine is only suitable for the treatment of HIV-1 infection where there is no known or suspected resistance to the integrase inhibitor class, or to lamivudine.

Reference:

  1. Cahn P et al. Presented at: International AIDS Conference; July 23-27, 2018; Amsterdam, Netherlands.

Conclusions[1]

  • GEMINI-1 and GEMINI-2 results demonstrate non-inferior virologic efficacy for the 2DR DTG + 3TC vs a traditional 3DR DTG + TDF/FTC at Week 48
  • Both DTG + 3TC and DTG + TDF/FTC were associated with low rates of confirmed virologic withdrawals through Week 48
    • No treatment-emergent INI or NRTI mutations were observed among participants who met CVW criteria
  • Overall safety and tolerability profile at Week 48 was comparable between the 2 regimens
    • Fewer drug-related AEs with DTG + 3TC vs DTG+TDF/FTC
    • Statistically significant change in renal and bone biomarkers from baseline favours DTG + 3TC vs DTG + TDF/FTC
  • GEMINI-1 and GEMINI-2 data support DTG + 3TC as a 2DR for the treatment of HIV-1 infection in treatment-naïve HBV-negative patients with viral loads up to 500,000 copies/mL

Tivicay + lamivudine is only suitable for the treatment of HIV-1 infection where there is no known or suspected resistance to the integrase inhibitor class, or to lamivudine.

Reference:

  1. Cahn P et al. Presented at: International AIDS Conference; July 23-27, 2018; Amsterdam, Netherlands.

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Tivicay + lamivudine is only suitable for the treatment of HIV-1 infection where there is no known or suspected resistance to the integrase inhibitor class, or to lamivudine.

Reference:

  1. Cahn P et al. Presented at: International AIDS Conference; July 23-27, 2018; Amsterdam, Netherlands.

Adverse events should be reported directly to the HPRA; Freepost, Pharmacovigilance Section, Health Products Regulatory Authority, Earlsfort Terrace, Dublin 2, Tel: +353 1 676 4971 medsafety@hpra.ie. Adverse events should also be reported to GlaxoSmithKline on 1800 244 255.

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PC. May 2019. PM-IE-DLM-WCNT-190002