HIV Infections
Conditions
Keywords
Controlled, virological and therapeutic success, treatment discontinution, 4 days per week
Brief summary
The trial is an open-label, multicenter, prospective, randomized trial in 2 parallel groups, evaluating at W48, the non-inferiority of antiretroviral treatment taken 4 consecutive days a week versus continuous therapy, in HIV infected patients with controlled viral load for at least 12 months and stable antiretroviral treatment since 4 months.
Detailed description
Open-label, multicenter, prospective, randomized trial in 2 parallel groups, evaluating at W48, the non-inferiority of antiretroviral treatment taken 4 consecutive days a week versus continuous therapy, in HIV infected patients with controlled viral load for at least 12 months and stable antiretroviral treatment since 4 months. The non-inferiority margin (delta) is 5%. The randomization will be stratified according to the family of the third antiretroviral agent (II, PI, and NNRTI). A minimum of 200 patients will be included in the integrase inhibitor strata to provide a sufficient power to assess the efficacy of strategy in this population. At W48, all patients with virological success in the continuous therapy group will switch to the 4/7 days therapy.
Interventions
• Receiving tritherapy. Allowed treatment drugs are : 1. nucleoside analogs : tenofovir (TDF ou TAF), emtricitabine, abacavir, lamivudine 2. protease inhibitors : lopinavir/r, darunavir/r ou atazanavir/r 3. non nucleoside reverse transcriptase inhibitors : efavirenz, rilpivirine ou etravirine 4. integrase inhibitors : dolutegravir, elvitegravir/cobicistat ou raltegravir
Sponsors
ANRS, Emerging Infectious Diseases
Institut de Médecine et d'Epidémiologie Appliquée - Fondation Internationale Léon M'Ba
Institut National de la Santé Et de la Recherche Médicale, France
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-label, randomized trial in 2 parallel groups
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* HIV-1 infection, coinfection HIV-1/HIV-2 possible * Age≥18 years old * Current therapy unchanged for the last 4 months * Receiving tritherapy with 2 nucleoside reverse transcriptase inhibitor+protease inhibitors or 2 nucleoside reverse transcriptase inhibitor+non-nucleoside reverse transcriptase inhibitors or 2 nucleoside reverse transcriptase inhibitor+integrase inhibitors. Allowed treatment drugs are : 1\. nucleoside analogs : tenofovir (TDF ou TAF), emtricitabine, abacavir, lamivudine 2. protease inhibitors : lopinavir/r, darunavir/r ou atazanavir/r 3. Non nucleoside reverse transcriptase inhibitors : efavirenz, rilpivirine ou etravirine 4. integrase inhibitors : dolutegravir, elvitegravir/cobicistat ou raltegravir * Viruses susceptible to all antiretroviral drugs present in the ongoing tritherapy (AC11-ANRS algorithm). 1. If a genotype is available in the patient medical history; viruses must be susceptible to all ongoing antiretroviral drugs 2. If no RNA genotype available, a genotype will be performed on DNA at screening and will not have to show any resistance to the ongoing antiretroviral drugs * Viral load (VL) \< 50 cp/mL in the past year, with at least 3 VL measurements including screening; only one episode of viral blip \< 200 copies/mL is authorized in the last year * CD4 T cells \> 250/mm3 at the screening visit * Estimated glomerular filtration rate \> 60 mL/min (Chronic Kidney Disease - Epidemiology Collaboration method) * Transaminases : aspartate aminotransférase et alanine aminotransférase \< 3N * Haemoglobin \> 10 g/dL * Platelets \> 100 000/mm3 * For women of childbearing age, negative pregnancy test at screening; agree to use mechanical contraception during the study * Social security system coverage * Informed consent form signed by patient and investigator
Exclusion criteria
* Infection by HIV-2 * Chronic and active Viral B Hepatitis with positive antigen HBs * Chronic and active Viral C Hepatitis with treatment expected in the next 98 weeks * Concomitant treatment using interferon, interleukins, any other immune-therapy or chemotherapy, antivitaminK for patients on ARVT using a booster * Concomitant prophylactic or curative treatment for an opportunistic infection * All conditions (use of alcohol, drugs, etc.) judged by the investigator to possibly interfere with study protocol compliance, observance and/or study treatment tolerance * Pregnant or breast feeding women * Subjects under "sauvegarde de justice" (judicial protection due to temporarily and slightly diminished mental or physical faculties), or under legal guardianship
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of patients with therapeutic success at Week 48. | Week 48 | To evaluate after 48 weeks the therapeutic success of a weekly strategy of 4 consecutive days on treatment followed by 3 days off treatment, defined by : * absence of virological failure : a measure of the viral load will be done, this measure have to be \< 50 cp/mL. If it's \> 50 cp/mL, a second measure will be done at 2 to 4 weeks apart. If it's still \> 50 cp/mL, it's a virological failure * no discontinuation or modification of the study strategy for more than 30 consecutive days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of patients with therapeutic success at Week 96 | Week 96 | To evaluate after 96 weeks the therapeutic success of a weekly strategy of 4 consecutive days on treatment followed by 3 days off treatment, defined by : * absence of virological failure : a measure of the viral load will be done, this measure have to be \< 50 cp/mL. If it's \> 50 cp/mL, a second measure will be done at 2 to 4 weeks apart. If it's still \> 50 cp/mL, it's a virological failure * no discontinuation or modification of the study strategy for more than 30 consecutive days. |
| Virological success | Week 48 and Week 96 | The HIV-1 viral load at week 48 must be inferior to 50 copies/mL |
| Number of virological " blips " | between Week 0 and Week 48, and between Week 0 and Week 96 | viral load \> 50 copies/mL followed by a control value ≤ 50 cp/mL |
| Percentage of patients with a viral load signal detected | between Week 0 and Week 48 and Week 0 and Week 96 | (subgroup of patients tested with Roche-Taqman, threshold\<20 copies/mL) |
| Proportion of patients with acquisition of drugs resistance mutations in case of virological failure detected by Sanger and by next generation sequencing | Week 4, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 96 (if it's necessary) | — |
| Frequency of minority resistant variants archived in DNA at Week 0 and their impact on virological failure (2 consecutive VL> 50 copies / mL) and on the acquisition of drugs resistance mutations | Week 0 | — |
| Evolution of ultra sensitive viral load and total DNA in the peripheral blood mononuclear cells at Week 0, Week 24, Week 48 and Week 96; evolution of viral genotypic sequence between Week 0, Week 48 and Week 96 (subgroup of 120 patients) | between Week 0, Week 48 and Week 96 | Immuno-viro-pharmacological sub-study of 120 patients |
| Description of the factors associated with virological rebound (viral load >50 cp/mL). | Week 4, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 96 (if it's necessary) | (viral load \>50 cp/mL). |
| Evolution of T cluster of differentiation 4 and cluster of differentiation 8 cells count, and T cluster of differentiation 4 /cluster of differentiation 8 ratio | from Week-4 to Week 48 and Week 96 | Measurement of T cluster of differentiation 4 cell count, T cluster of differentiation 8 cell count, and T cluster of differentiation 4 /T cluster of differentiation 8 ratio |
| Evolution of fasting metabolic parameters | until Week 48 and Week 96 | Measurement of total cholesterol total, LDL-C, HDL-C, Triglycerides and glycemia |
| Evolution of inflammation and immune activation parameters | from Week 0 to Week 24 and Week 48 | Measurement of sCD14, sCD163, IP-10, C-reactive protein, interleukin-6 et D-dimerus, soluble TNF receptor 1, soluble TNF receptor 2 Immuno-viro-Pharmacological Sub-study in 120 patients |
| HIV RNA viral load in semen | Week 0, Week 24 and Week 48 | Sperm sub-study (120 patients) |
| Residual plasmatic concentrations of the third antiretroviral agent | Week 0, Week 4, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84 and Week 96 | Measurement of the third antiretroviral agent plasmatic concentration (protease inhibitors or non-nucleoside reverse transcriptase inhibitors or integrase inhibitors) |
| Residual plasmatic concentrations of tenofovir (TDF or TAF) | Week 0, Week 4, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84 and Week 96 | Measurement of tenofovir plasmatic concentration |
| Residual intracellular concentrations of the third antiretroviral agents | Week 0, Week 24 and Week 48 | Immuno-viro-Pharmacological sub-study (120 patients) Measurement of the third antiretroviral agent intracellular concentration (protease inhibitors or non-nucleoside reverse transcriptase inhibitors or integrase inhibitors) |
| Treatment adherence | Week 0, Week 12, Week 24, Week 36, Week 48, Week 72,and Week 96 | Evaluation by a self-reported questionnaire |
| Patient Quality of life | Week-4, Week 0, Week 48 and Week 96 | Evaluation by a self-reported questionnaire |
| Patient satisfaction | Week 0, Week 12, Week 48 and Week 96 | Evaluation by a self-reported questionnaire |
| Pharmaco-economic aspects of the strategy | Between Week 0 and Week 98 | Assessment and comparison of cost essay between each arm. |
| Median time to virologic failure | Between week 0 and 98 | Measure the delay between week 0 and the date of different virologic failure |
| Frequency of grade 3 or more adverse events, adverse effects, drug-modifying adverse events, drug-related adverse events and serious adverse events (SAE) | Between Week 0 and Week 98 | according to the sponsor's grading scale |
Countries
France
Contacts
PRINCIPAL_INVESTIGATORPierre De Truchis, MD
Hôpital Raymond Poincaré
Outcome results
None listed