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

Study Overview
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Brief Summary
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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).

Official Title
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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

Conditions
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HIV

Intervention / Treatment
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* Drug: dolutegravir 50mg +abacavir 600mg +lamivudine 300mg
* Drug: dolutegravir


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: triple therapy<br>dolutegravir + abacavir + lamivudine (TRIUMEQ) : oral administration, one tablet daily during 48 weeks. | Drug: dolutegravir 50mg +abacavir 600mg +lamivudine 300mg<br> <br> * Other names: Triumeq, EU/1/14/940/001;|
| Experimental: monotherapy<br>dolutegravir (TIVICAY) : 50 mg, oral administration, one tablet daily during 48 weeks. | Drug: dolutegravir<br> <br> * Other names: Tivicay , EU/1/13/892/001;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Viral Load | Percentage of patients having a viral load <50 copies/ml in each arm at week 24 | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Delta CD 4 | delta CD4 in each arms from Baseline to W48, comparison between arms | until Week 48 | 
| Residual activation measures (sub study) | CD4+CD38+DR+, CD8+CD38+DR+ | Week 24 | 
| Residual activation marker measures (sub study) | sCD14, sCD163, | Week 24 | 
| Pro-inflammatory cytokins measures (sub study) | TNFα, IFNγ, IL6, IP-10 | Week 24 | 
| Inflammatory marker measures (sub study) | CRPus | Week 24 | 
| virus genotype | Evolution of viruses genotype profiles of patients who present a virologic failure | Until Week 48 | 
| 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 | 
| HIV DNA evolution | HIV DNA evolution in each arm from baseline to W48; comparison between arms | between day 0 and week 48 | 
| Virological failure predictive factors | Determination of virological failure predictive factors | 48 weeks | 
| Impact of the strategy on the acceptability and quality of life | determination of quality of life with questionnary, comparison between arms | 48 weeks | 
| Proportion of patients with an adverse event |  | 48 weeks | 
| Proportion of patients with a severe adverse event |  | 48 weeks | 
| Creatinine clearance change | Biological parameters evolution in each arm | 48 weeks | 
| Lipidic profiles | Biological parameters evolution in each arm | 48 weeks | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV-1 infected patient, monotherapy, dolutegravir