Clinical trial NCT02596334: Study to Evaluate the Efficacy of MONotherapy of TiviCAY® Versus a Triple Therapy in HIV-1-infected Patients
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: HIV
Keywords: HIV-1 infected patient
monotherapy
dolutegravir
Lead sponsor: Centre Hospitalier Régional d'Orléans
Sponsor class: OTHER
First posted: 2015-11-04
Enrollment: 158
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


Eligibility criteria: 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

Primary outcomes:
measure: Viral Load
timeFrame: Week 24
Secondary outcomes:
measure: Viral load
timeFrame: between Week 4 and Week 48
measure: Delta CD 4
timeFrame: until Week 48
measure: Residual activation measures (sub study)
timeFrame: Week 24
measure: Residual activation marker measures (sub study)
timeFrame: Week 24
measure: Pro-inflammatory cytokins measures (sub study)
timeFrame: Week 24
measure: Inflammatory marker measures (sub study)
timeFrame: Week 24
measure: virus genotype
timeFrame: Until Week 48
measure: RNA and DNA viral load (sub study)
timeFrame: Week 24 to week 48
measure: HIV DNA evolution
timeFrame: between day 0 and week 48
measure: Virological failure predictive factors
timeFrame: 48 weeks
measure: Impact of the strategy on the acceptability and quality of life
timeFrame: 48 weeks
measure: Proportion of patients with an adverse event
timeFrame: 48 weeks
measure: Proportion of patients with a severe adverse event
timeFrame: 48 weeks
measure: Creatinine clearance change
timeFrame: 48 weeks
measure: Lipidic profiles
timeFrame: 48 weeks
measure: Clinical events
timeFrame: 48 weeks
Other outcomes:
Locations:
city: La Roche sur Yon
country: France
facility: CHD de VENDEE
city: La Rochelle
country: France
facility: CH de LA ROCHELLE
city: Nantes
country: France
facility: CHRU de NANTES
city: Niort
country: France
facility: CH de NIORT
city: Orleans
country: France
facility: CHR d'ORLEANS
city: Poitiers
country: France
facility: CHRU de POITIERS
city: Strasbourg
country: France
facility: CHU de STRASBOURG
city: Tours
country: France
facility: CHRU de TOURS
city: Vandoeuvre Les Nancy
country: France
facility: CHU de NANCY
Study officials:
affiliation: CHR d'ORLEANS
name: HOCQUELOUX Laurent
role: STUDY_DIRECTOR
References:
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citation: 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.
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