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

HIV Clinical Trial

— MONCAY  

Official title:

Randomized Clinical Trial to Evaluate the Efficacy of a Dolutegravir Monotherapy (Tivicay®) Versus the Maintenance of a Successful Triple Therapy Using Abacavir + Lamivudine + Dolutegravir (Triumeq®) in HIV-1- Infected Patients

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02596334
• Other study ID #: CHRO 2015-03
• Status: Terminated
• Phase: Phase 3
• Start date: December 23, 2015
• Est. completion date: June 23, 2018

Study information

• Verified date: November 2018
• Source: Centre Hospitalier Régional d'Orléans
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 158
• Est. completion date: June 23, 2018
• Est. primary completion date: June 23, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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)

• Thrombocytopenia with platelet count < 50.000/ml

• Anemia with hemoglobin < 8g/dl

• Polynuclear neutrophil count < 500/mm3

Related Conditions & MeSH terms

• HIV

Intervention

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

• dolutegravir

Locations

Country	Name	City	State
France	CHD de VENDEE	La Roche sur Yon
France	CH de LA ROCHELLE	La Rochelle
France	CHRU de NANTES	Nantes
France	CH de NIORT	Niort
France	CHR d'ORLEANS	Orleans
France	CHRU de POITIERS	Poitiers
France	CHU de STRASBOURG	Strasbourg
France	CHRU de TOURS	Tours
France	CHU de NANCY	Vandoeuvre Les Nancy

Sponsors (1)

Lead Sponsor	Collaborator
Centre Hospitalier Régional d'Orléans

Country where clinical trial is conducted

France, 

References & Publications (10)

Arribas JR, Horban A, Gerstoft J, Fätkenheuer 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. — View Citation

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. — View Citation

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. — View Citation

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. Review. Erratum in: Drugs. 2015 Apr;75(5):561. — View Citation

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. — View Citation

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. — View Citation

Monteiro P, Perez I, Laguno M, Martínez-Rebollar M, González-Cordon A, Lonca M, Mallolas J, Blanco JL, Gatell JM, Martínez 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. — View Citation

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. — View Citation

Prazuck T, Zucman D, Avettand-Fènoël 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. — View Citation

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-naïve subjects: the progress study, 48-week results. HIV Clin Trials. 2011 Sep-Oct;12(5):255-67. doi: 10.1310/hct1205-255. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Viral Load	Percentage of patients having a viral load <50 copies/ml in each arm at week 24	Week 24
Secondary	Viral load	Percentage of patients having a confirmed viral load > 50 copies/ml between week 4 and week 48	between Week 4 and Week 48
Secondary	Delta CD 4	delta CD4 in each arms from Baseline to W48, comparison between arms	until Week 48
Secondary	Residual activation measures (sub study)	CD4+CD38+DR+, CD8+CD38+DR+	Week 24
Secondary	Residual activation marker measures (sub study)	sCD14, sCD163,	Week 24
Secondary	Pro-inflammatory cytokins measures (sub study)	TNFa, IFN?, IL6, IP-10	Week 24
Secondary	Inflammatory marker measures (sub study)	CRPus	Week 24
Secondary	virus genotype	Evolution of viruses genotype profiles of patients who present a virologic failure	Until Week 48
Secondary	RNA and DNA viral load (sub study)	RNA and DNA viral load in the genital tract (cervico-vaginal secretions or sperm): comparison between arms	Week 24 to week 48
Secondary	HIV DNA evolution	HIV DNA evolution in each arm from baseline to W48; comparison between arms	between day 0 and week 48
Secondary	Virological failure predictive factors	Determination of virological failure predictive factors	48 weeks
Secondary	Impact of the strategy on the acceptability and quality of life	determination of quality of life with questionnary, comparison between arms	48 weeks
Secondary	Proportion of patients with an adverse event		48 weeks
Secondary	Proportion of patients with a severe adverse event		48 weeks
Secondary	Creatinine clearance change	Biological parameters evolution in each arm	48 weeks
Secondary	Lipidic profiles	Biological parameters evolution in each arm	48 weeks
Secondary	Clinical events	Clinical events with progression to AIDS or death. Proportion of individuals developing a new CDC-event (as defined by cdc 1993 classification) from baseline to week 48.	48 weeks