Study to Evaluate the Efficacy of MONotherapy of TiviCAY® Versus a Triple Therapy in HIV-1-infected Patients

NCT02596334 | Terminated Phase 3 DMC

• 1 other identifier: CHRO 2015-03
• Study Type: interventional
• Target: 158
• Locations: 1 country
• Sites: 9

Brief Summary

Triple antiretroviral regimens have greatly improved the prognosis of patients living with HIV (PLHIV). Patients virologically controlled and having a good immune restoration can have a life expectancy close or equal to that of people not infected with HIV.\[1\] However, this is under the condition of a "lifetime" maintenance of an undetectable plasma viral load (pVL) (\<50 cp/ml). On the other hand it is well established that aging increases comorbidities among PLHIV and the burden of co-medications.\[2\] This also has the consequence of frequent drug-drug interactions. In this context it is important to decrease pills burden, side-effects and drug-drug interactions, while maintaining undetectability. Currently, there is a strong interest for medical research to validate lightened regimens (i.e. bithérapies \[3-7\] and monothérapies \[8,9\], particularly in a maintenance strategy, with the primary objective of reducing burden of pills and side effects. Several monotherapy trials using a boosted protease inhibitor (PI/r) showed high level of viral suppression, even if this proportion was not always non-inferior to maintaining a triple therapy. \[8,9\] Fortunately, when virological failure occurred under monotherapy virologic suppression was easily restored by the addition of two NRTI. Patients who are most likely to maintain viral suppression under a reduced scheme are those that have a high nadir (\> 100 CD4 / mm3), no previous AIDS event and a sustained virologic suppression (\>12 months). Monotherapy is the option that best reduces the burden of pills and the risk of side effects or drug-drug interactions. It must be considered using very powerful molecule that harbor a strong binding to its ligand in order to minimize the risk of selecting resistant mutants in the case of virologic failure. To be as simple as possible in its use, it must be a single agent administered as a single dose once a day and not boosted if possible. The molecule must have very good tolerance. Finally, to be effective in viral sanctuaries this molecule should have a good (or sufficient) diffusion to ensure effective Cmin on wild viral strains. Dolutegravir meets all these exigences.\[10\] In addition, our team recently presented results of a pilot study showing that the switch of a successful combined antiretroviral regimen to dolutegravir monotherapy maintained undetectable viral load (\<20 cp/ml) after a median of 7 months (range 6.5-10 months).

Conditions

HIV

Keywords

HIV-1 infected patient; monotherapy; dolutegravir

Outcome Measures

Primary Outcomes (1)

• Viral Load

  Percentage of patients having a viral load \<50 copies/ml in each arm at week 24

  Week 24

Secondary Outcomes (16)

• Viral load

  between Week 4 and Week 48

• Delta CD 4

  until Week 48

• Residual activation measures (sub study)

  Week 24

• Residual activation marker measures (sub study)

  Week 24

• Pro-inflammatory cytokins measures (sub study)

  Week 24

Study Arms (2)

triple therapy

ACTIVE COMPARATOR

dolutegravir + abacavir + lamivudine (TRIUMEQ) : oral administration, one tablet daily during 48 weeks.

Drug: dolutegravir 50mg +abacavir 600mg +lamivudine 300mg

monotherapy

EXPERIMENTAL

dolutegravir (TIVICAY) : 50 mg, oral administration, one tablet daily during 48 weeks.

Drug: dolutegravir

Interventions

dolutegravir 50mg +abacavir 600mg +lamivudine 300mg DRUG

Also known as: Triumeq, EU/1/14/940/001

triple therapy

dolutegravir DRUG

Also known as: Tivicay , EU/1/13/892/001

monotherapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• HIV-1-infected patients with no previous AIDS event (excluding a healed tuberculosis);
• Current antiretroviral treatment associating dolutegravir + abacavir + lamivudine for at least 1 month;
• Nadir CD4 ≥ 100/mm3;
• Plasma RNA viral load \< 50 copies/ml for at least 12 months;
• Plasma RNA viral load \<20 or 40 copies/ml (according to the threshold of the method used by local laboratory) at the screening visit;
• No documented virologic failure or known resistance to any integrase inhibitor,
• Patient having provided a written consent;
• Patients follow-up possible in ambulatory;
• Patient age \> 18 years;
• Covered by health insurance

You may not qualify if:

• Non-compliant patient
• Subject is pregnant, or lactating, or of childbearing potential and without contraception;
• Active opportunistic infections (defining AIDS);
• Known hypersensibility to abacavir or lamivudine or dolutegravir;
• Patients harboring HLA B\*5701;
• Major overweight (BMI ≥ 40);
• Weight \<40 kg;
• Creatinine clearance \< 50ml/min;
• Cirrhosis or severe liver failure (factor V \< 50%);
• Life Prognosis threatened within 6 months;
• Circumstances that may impair judgment or understanding of the information given to the patient;
• Co-medication with carbamazepin, oxcarbamazepin, fosphenytoïn, phenobarbital, phenytoïn, primidon, St John's wort or dofetilid;
• Malabsorption syndromes;
• The following laboratory criteria:
• Serum AST,ALT \> 5 x upper limit of normal (ULN)

Sponsors & Collaborators

• Centre Hospitalier Régional d'Orléans: lead

Study Sites (9)

CHD de VENDEE

La Roche-sur-Yon, 85925, France

Location

CH de LA ROCHELLE

La Rochelle, 17019, France

Location

CHRU de NANTES

Nantes, 44093, France

Location

CH de NIORT

Niort, 79021, France

Location

CHR d'ORLEANS

Orléans, 45032, France

Location

CHRU de POITIERS

Poitiers, 86021, France

Location

CHU de STRASBOURG

Strasbourg, 67000, France

Location

CHRU de TOURS

Tours, 37044, France

Location

CHU de NANCY

Vandœuvre-lès-Nancy, 54511, France

Location

Related Publications (12)

• May MT, Gompels M, Delpech V, Porter K, Orkin C, Kegg S, Hay P, Johnson M, Palfreeman A, Gilson R, Chadwick D, Martin F, Hill T, Walsh J, Post F, Fisher M, Ainsworth J, Jose S, Leen C, Nelson M, Anderson J, Sabin C; UK Collaborative HIV Cohort (UK CHIC) Study. Impact on life expectancy of HIV-1 positive individuals of CD4+ cell count and viral load response to antiretroviral therapy. AIDS. 2014 May 15;28(8):1193-202. doi: 10.1097/QAD.0000000000000243.

  PMID: 24556869 BACKGROUND

• Nachega JB, Parienti JJ, Uthman OA, Gross R, Dowdy DW, Sax PE, Gallant JE, Mugavero MJ, Mills EJ, Giordano TP. Lower pill burden and once-daily antiretroviral treatment regimens for HIV infection: A meta-analysis of randomized controlled trials. Clin Infect Dis. 2014 May;58(9):1297-307. doi: 10.1093/cid/ciu046. Epub 2014 Jan 22.

  PMID: 24457345 BACKGROUND

• Cahn P, Andrade-Villanueva J, Arribas JR, Gatell JM, Lama JR, Norton M, Patterson P, Sierra Madero J, Sued O, Figueroa MI, Rolon MJ; GARDEL Study Group. Dual therapy with lopinavir and ritonavir plus lamivudine versus triple therapy with lopinavir and ritonavir plus two nucleoside reverse transcriptase inhibitors in antiretroviral-therapy-naive adults with HIV-1 infection: 48 week results of the randomised, open label, non-inferiority GARDEL trial. Lancet Infect Dis. 2014 Jul;14(7):572-80. doi: 10.1016/S1473-3099(14)70736-4. Epub 2014 Apr 27.

  PMID: 24783988 BACKGROUND

• Prazuck T, Zucman D, Avettand-Fenoel V, Ducasse E, Bornarel D, Mille C, Rouzioux C, Hocqueloux L. Long-term HIV-1 virologic control in patients on a dual NRTI regimen. HIV Clin Trials. 2013 May-Jun;14(3):120-6. doi: 10.1310/hct1403-120.

  PMID: 23835514 BACKGROUND

• Reynes J, Lawal A, Pulido F, Soto-Malave R, Gathe J, Tian M, Fredrick LM, Podsadecki TJ, Nilius AM. Examination of noninferiority, safety, and tolerability of lopinavir/ritonavir and raltegravir compared with lopinavir/ritonavir and tenofovir/ emtricitabine in antiretroviral-naive subjects: the progress study, 48-week results. HIV Clin Trials. 2011 Sep-Oct;12(5):255-67. doi: 10.1310/hct1205-255.

  PMID: 22180523 BACKGROUND

• Calin R, Paris L, Simon A, Peytavin G, Wirden M, Schneider L, Valantin MA, Tubiana R, Agher R, Katlama C. Dual raltegravir/etravirine combination in virologically suppressed HIV-1-infected patients on antiretroviral therapy. Antivir Ther. 2012;17(8):1601-4. doi: 10.3851/IMP2344. Epub 2012 Sep 3.

  PMID: 22941896 BACKGROUND

• Monteiro P, Perez I, Laguno M, Martinez-Rebollar M, Gonzalez-Cordon A, Lonca M, Mallolas J, Blanco JL, Gatell JM, Martinez E. Dual therapy with etravirine plus raltegravir for virologically suppressed HIV-infected patients: a pilot study. J Antimicrob Chemother. 2014 Mar;69(3):742-8. doi: 10.1093/jac/dkt406. Epub 2013 Oct 14.

  PMID: 24128667 BACKGROUND

• Katlama C, Valantin MA, Algarte-Genin M, Duvivier C, Lambert-Niclot S, Girard PM, Molina JM, Hoen B, Pakianather S, Peytavin G, Marcelin AG, Flandre P. Efficacy of darunavir/ritonavir maintenance monotherapy in patients with HIV-1 viral suppression: a randomized open-label, noninferiority trial, MONOI-ANRS 136. AIDS. 2010 Sep 24;24(15):2365-74. doi: 10.1097/QAD.0b013e32833dec20.

  PMID: 20802297 BACKGROUND

• Arribas JR, Horban A, Gerstoft J, Fatkenheuer G, Nelson M, Clumeck N, Pulido F, Hill A, van Delft Y, Stark T, Moecklinghoff C. The MONET trial: darunavir/ritonavir with or without nucleoside analogues, for patients with HIV RNA below 50 copies/ml. AIDS. 2010 Jan 16;24(2):223-30. doi: 10.1097/QAD.0b013e3283348944.

  PMID: 20010070 BACKGROUND

• Greig SL, Deeks ED. Abacavir/dolutegravir/lamivudine single-tablet regimen: a review of its use in HIV-1 infection. Drugs. 2015 Apr;75(5):503-14. doi: 10.1007/s40265-015-0361-6.

  PMID: 25698454 BACKGROUND

• Hocqueloux L, Gubavu C, Prazuck T, De Dieuleveult B, Guinard J, Seve A, Mille C, Gardiennet E, Lopez P, Rouzioux C, Lefeuvre S, Avettand-Fenoel V. Genital Human Immunodeficiency Virus-1 RNA and DNA Shedding in Virologically Suppressed Individuals Switching From Triple- to Dual- or Monotherapy: Pooled Results From 2 Randomized, Controlled Trials. Clin Infect Dis. 2020 Apr 15;70(9):1973-1979. doi: 10.1093/cid/ciz511.

  PMID: 31350995 DERIVED

• Hocqueloux L, Raffi F, Prazuck T, Bernard L, Sunder S, Esnault JL, Rey D, Le Moal G, Roncato-Saberan M, Andre M, Billaud E, Valery A, Avettand-Fenoel V, Parienti JJ, Allavena C; MONCAY study group. Dolutegravir Monotherapy Versus Dolutegravir/Abacavir/Lamivudine for Virologically Suppressed People Living With Chronic Human Immunodeficiency Virus Infection: The Randomized Noninferiority MONotherapy of TiviCAY Trial. Clin Infect Dis. 2019 Oct 15;69(9):1498-1505. doi: 10.1093/cid/ciy1132.

  PMID: 30601976 DERIVED

MeSH Terms

Interventions

dolutegravir; abacavir; Lamivudine; abacavir, dolutegravir, and lamivudine drug combination

Intervention Hierarchy (Ancestors)

Zalcitabine; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Dideoxynucleosides

Study Officials

• HOCQUELOUX Laurent

  CHR d'ORLEANS

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 16, 2015
• First Posted: November 4, 2015
• Study Start: December 23, 2015
• Primary Completion: June 23, 2017
• Study Completion: June 23, 2018
• Last Updated: November 13, 2018

Record last verified: 2018-11

Locations

FR (9)