HIV-1-infection
Conditions
Keywords
Africa, Antiretroviral Treatment, HIV-1, Adults, Dual maintenance therapy, Dolutegravir, Atazanavir
Brief summary
MODERATO is a phase III, open-label, randomized, multicenter, non-inferiority trial conducted in West and Central Africa (Cameroon, Côte d'Ivoire, Burkina Faso). HIV-1 infected adults receiving first line ART with TDF+XTC+EFV or DTG+XTC+TDF virologically suppressed will be recruited and followed during 100 weeks. The objective is to assess the non-inferiority of a strategy consisting of switching to a dual maintenance therapy (DTG+3TC or ATV/r+3TC), comparing to WHO standard first line regimen (TDF+3TC+EFV or DTG+3TC+TDF), in terms of virological success at 96 weeks
Detailed description
In HIV-1 infected adults receiving first line ART with TDF+XTC+EFV or DTG+XTC+TDF virologically suppressed (viral load \< detection limit of the technique used) for at least two years: to assess the non-inferiority of a strategy consisting of switching to a dual maintenance therapy (DTG+ 3TC or ATV/r+3TC), comparing to WHO standard first line regimen (TDF+3TC+EFV or DTG+3TC+TDF), in terms of virological success at 96 weeks, in Cameroon, Côte d'Ivoire and Burkina Faso. This is a trial including two strategies (dual maintenance therapy and triple reference therapy) and three ART regimens (DTG+3TC and ATV/r+3TC used in the maintenance strategy and TDF+3TC+EFV/ DTG+3TC+TDF used in the reference strategy). The primary analysis will compare the two strategies. Secondary analyses will compare the three ART regimens two by two. In order to make these secondary analyses possible, participants will be randomly assigned, at inclusion, to each of the three ART regimens (arm 1: DTG+3TC; arm 2: ATV/r+3TC; arm 3: TDF+3TC+EFV / DTG+3TC+TDF). The maintenance strategy will include arm 1 and 2. The reference strategy will include arm 3 Number of participants : 480 (160 in each ART regimen, ie 320 in the dual maintenance therapy strategy and 160 in the triple therapy reference strategy) The primary endpoint is treatment success, as defined by using the FDA snapshot algorithm : patients who are still continuing the assigned strategy and whose last available plasma HIV-1 RNA in the the window analysis (90 to 102 weeks) is \<50 copies/ml at the end of the window analysis (90 to 102 weeks)
Interventions
DRUGdolutegravir
One daily tablet (50mg) during 96 weeks
DRUGatazanavir boosted with ritonavir
One daily tablet with atazanavir (300 mg) boosted with ritonavir (100 mg) during 96 weeks
DRUGtenofovir + lamivudine +efavirenz or dolutegravir + lamivudine + tenofovir
One daily tablet with tenofovir 245 mg + lamivudine (300 mg) + efavirenz (400 mg) during 96 weeks OR One daily tablet with dolutegravir 50 mg + lamivudine (300 mg) + tenofovir (300 mg) during 96 weeks
DRUGLamivudine
One daily tablet (300mg) during 96 weeks
Sponsors
Mylan Laboratories
ANRS, Emerging Infectious Diseases
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* HIV-1 infection * Age of legal majority * CD4 \> 200 cells/mm3 at pre-inclusion * Start first-line ART with non-nucleotide reverse transcriptase inhibitors including TDF+XTC+EFV for at least two years without a past history of virological failure, OR * Be on TDF+XTC+EFV for at least two years then DTG+XTC+TDF without a past history of virological failure, OR * Be on DTG+XTC+TDF (1st line regimen) for at least two years without a past history of virological failure * Absence of past history of virological failure (viral load above the threshold corresponding to the test used); two blips between 50 and 200 copies/ml are allowed. * At least 2 consecutive HIV-1 RNA \< 50 copies/ml within past 2 years, including HIV-1 RNA at pre-inclusion * Women with pregnancy potential are required to use an effective contraceptive method throughout the study follow up. * Signed informed consent
Exclusion criteria
* HIV-2 infection or HIV-1+2 infection * CD4 nadir \<100 cells/mm3 * Chronic Hepatitis B (HBs Ag positive in the pre-inclusion balance) * Ongoing active Tuberculosis * Ongoing severe opportunistic infection * Ongoing chemotherapy or immunotherapy * Grade \> 2 hemoglobin, neutrophil or platelet disorder * ALT≥ 3 times the upper limit of normal value * Creatinine clearance \< 50 ml/min (CKD-EPI) * Allergy to a trial drugs or drug component * Ongoing pregnancy or Refusal of contraception * Patient at risk of non-compliance * Ongoing treatment with a drug that should not be associated with one of the drugs used in the study (cf appendix E page 77) * Any symptoms or biological findings suggestive of a systemic disorder (renal, hepatic, cardiovascular, pulmonary) or other medical conditions that may interfere with the interpretation of test results or jeopardize the health of patients
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The treatment success, as defined by using the FDA snapshot algorithm | 90 to 102 weeks | Success : The proportion of patients who are still continuing the assigned strategy and whose last available plasma HIV-1 RNA in the the window analysis is \<50 copies/ml at the end of the window analysis. Failure : patients who have discontinued the assigned strategy or whose last available plasma HIV-1 RNA in the window analysis (90 to 102 weeks) is ≥ 50 copies/ml or with no available HIV-1 RNA in the window analysis |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ANRS grade 3-4 overall morbidity | Between Day 0 and Week 96 | Incidence of ANRS grade 3-4 overall morbidity (toxicity) |
| ANRS grade 3-4 renal morbidity | Between Day 0 and Week 96 | Incidence of ANRS grade 3-4 renal morbidity |
| ANRS grade 3-4 neurologic morbidity | Between Day 0 and Week 96 | Incidence of ANRS grade 3-4 neurologic morbidity |
| ANRS grade 3-4 hepatic morbidity | Between Day 0 and Week 96 | Incidence of ANRS grade 3-4 hepatic morbidity |
| Creatinine clearance | Between Day 0 and Week 96 | Evolution of creatinine clearance |
| Grade 1,2,3 or 4 renal disorders | Between Day 0 and Week 96 | Evolution of the percentage of patients with grade 1,2,3 or 4 renal disorders |
| Grade 1,2,3 or 4 hepatic liver disorders or abnormalities | Between Day 0 and Week 96 | Evolution of the percentage of patients with grade 1,2,3 or 4 hepatic liver disorders or abnormalities |
| Grade 1,2,3 or 4 CNS disorders | Between Day 0 and Week 96 | Evolution of the percentage of patients with grade 1,2,3 or 4 CNS disorders |
| Failure combined endpoint | Between Day 0 and Week 96 | Percentage of participants who reach the following combined endpoint : new drug-resistant resistance mutations observed, decline of at least 20% in creatinine clearance and occurrence of at least one grade 3-4 neuropsychiatric disorder |
| Plasma HIV-1 RNA | Between Day 0 and Week 96 | Evolution of plasma HIV-1 RNA |
| WHO stage 3-4 morbidity | Between Day 0 and Week 96 | Incidence of WHO stage 3-4 morbidity ( AIDS events and non AIDS severe morbidity) |
| CD4 lymphocyte | Between Day 0 and Week 96 | Evolution of CD4 lymphocyte absolute count and percentage |
| Virological failure and new resistance mutations | Week 48 and Week 96 | Percentage of participants with virological failure and new resistance mutations |
| New HIV-1 drug resistance mutations | Week 48 and Week 96 | Profile of new HIV-1 drug resistance mutations observed in participants with virological failure |
| Bone mineral density | Between Day 0 and Week 96 | Evolution of bone mineral density measured using CT bone density scan |
| Adherence to treatment using a self-questionnaire | Between Day 0 and Week 96 | Evolution of adherence to treatments measured using a self-questionnaire |
| Life quality | Between Day 0 and Week 96 | Evolution of quality of life measured using the ProQOL questionnaire |
| Symptoms | Between Day 0 and Week 96 | Evolution of symptoms using the symptoms experienced questionnaire |
| ARV drug plasma concentrations in participants with treatment failure | Between Day 0 and Week 96 | ARV drug plasma concentrations in participants with treatment failure |
| Switched back to triple therapy | Between Day 0 and Week 96 | Percentage of patients on dual therapy who switched back to triple therapy |
| Cost-effectiveness of the 3 ARV strategies | Week 96 | Cost-effectiveness of the 3 ARV strategies |
| Virological success | Between Day 0 and Week 96 | Evolution of the percentage of participants with virological success (VL\< 50 copies/Ml) |
Countries
Burkina Faso, Cameroon, Côte d’Ivoire
Outcome results
None listed