Evaluation of Three Strategies of Second-line Antiretroviral Treatment in Africa (Dakar - Bobo-Dioulasso - Yaoundé)

Study Overview
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Brief Summary
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Since the first line antiretroviral (ARV) treatment is now largely accessible in the Sub-Saharian Africa countries, documentation of virological failure, drug resistance patterns and second line treatment evaluation are still to be consolidated in settings where viral load monitoring is not available and non-B HIV subtype is predominant. This trial aims at evaluating the efficacy and tolerance of 3 different second line treatment strategies: two recommended by WHO combine two non-nucleoside reverse transcriptase inhibitor associated with a ritonavir boosted protease inhibitor (emtricitabine-tenofovir-lopinavir/ritonavir and abacavir-didanosine-lopinavir/ritonavir); the third strategy combines emtricitabine-tenofovir-darunavir/ritonavir and is not yet evaluated in Sub-Saharian Africa. Darunavir has a potentially superior antiviral efficacy, a better tolerance and its single daily administration may facilitate treatment adherence.

Official Title
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Multicentric, Non-inferiority, Randomized, Non-blinded Phase 3 Trial Comparing Virological Response at 48 Weeks of 3 Antiretroviral Treatment Regimens in HIV-1-infected Patients With Treatment Failure After 1st Line Antiretroviral Therapy (Cameroon, Burkina Faso, Senegal)

Conditions
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HIV, HIV Infections

Intervention / Treatment
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* Drug: emtricitabine/tenofovir + lopinavir/ritonavir (WHO recommended second line)
* Drug: abacavir + didanosine + lopinavir/ritonavir (WHO recommended second line)
* Drug: emtricitabine/tenofovir + darunavir + ritonavir (Second line strategy under evaluation)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient over the age of 18 years at pre-inclusion and monitored under outpatient conditions Documented HIV-1 infection regardless of clinical stage and CD4 lymphocyte count Patient with treatment failure after first-line antiretroviral treatment with a combination including a non-nucleoside reverse transcriptase inhibitor and two nucleoside reverse transcriptase inhibitors, failure being defined as 2 measurements (at 1 month interval) of plasma HIV RNA levels > 1000 copies/ml after at least 6 months of uninterrupted treatment Adherence (> 80%) to first- line antiretroviral treatment (questionnaire) at pre inclusion Patient agrees not to take any concomitant medication during the trial without informing the investigator Informed consent signed no later than D-15 For women in childbearing age: negative pregnancy test at inclusion, with no plan of pregnancy in the coming 12 months and agreeing to use mechanical contraception (with or without hormonal contraception) during the study Exclusion Criteria: Infection with HIV-2 or HIV-1 groups O or N or HIV1+2 Deficiency of the patient, making it difficult, if not impossible, for him/her to take part in the trial or understand the information provided to him/her Participation in any other clinical trial Presence of an uncontrolled, ongoing opportunistic infection or of any severe or progressive disease First-line treatment with a protease inhibitor, abacavir, tenofovir or ddI Ongoing treatment with rifampicin Severe hepatic insufficiency (TP < 50%) ALAT > 3 x ULN Creatinine clearance calculated by Cockcroft formula < 50 ml/min Hb ≤ 8 g/dl Platelets < 50,000 cells/mm3 Neutrophiles < 500 cells/ mm3 Use of drugs prohibited in the context of this trial (drugs contraindicated by the SCP of the trial drugs) - in the event of tuberculosis or malaria during the trial, a list of authorized medicines and, if necessary, a dose adjustment of the antiretroviral medication will be provided Pregnancy or lactation

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: Arm A<br>emtricitabine/tenofovir + lopinavir/ritonavir (WHO recommended second line) | Drug: emtricitabine/tenofovir + lopinavir/ritonavir (WHO recommended second line)<br>* Emtricitabine 200 mg/tenofovir 300 mg 1 tablet/day with food + Lopinavir 200 mg/Ritonavir 50 mg 2 tablets in the morning and 2 tablets in the evening<br>|
| Active Comparator: Arm B<br>abacavir + didanosine + lopinavir/ritonavir (WHO recommended second line) | Drug: abacavir + didanosine + lopinavir/ritonavir (WHO recommended second line)<br>* Didanosine 1 entero-coated capsule/day in fasting conditions (dosage 250 mg if weight < 60 kg, 400 mg if weight > 60 kg) + abacavir 300 mg 1 tablet in the morning and in the evening + Lopinavir 200 mg/Ritonavir 50 mg 2 tablets morning and evening<br>|
| Active Comparator: Arm C<br>emtricitabine/tenofovir + darunavir + ritonavir (Second line strategy under evaluation) | Drug: emtricitabine/tenofovir + darunavir + ritonavir (Second line strategy under evaluation)<br>* Emtricitabine 200 mg/tenofovir 300 mg 1 tablet/day with food + darunavir 400 mg 2 tablets + ritonavir 100 mg 1 capsule, in a single dose with food<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Plasma HIV RNA < 50 Copies/mL |  | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With WHO Stage 3 and 4 HIV Related Events | patients having a diagnosis of HIV related event classified as stage 3 or 4 | between baseline and 48 weeks | 
| Patients With Plasma HIV RNA < 200 Copies/ml | number of patients with plasma HIV RNA below 200 copies/ml | 48 weeks | 
| Gain in CD4 Cells Between Baseline and W48 | median gain in circulating CD4 cells between baseline and W48 | between baseline and 48 weeks | 
| Number of Patients Discontinuing Study Treatment | number of patients discounting treatment because of adverse events | between baseline and W48 | 
| Tolerance: Gastrointestinal Complains | Gastrointestinal complaints (grade 1 to 4) between baseline and W48. | between baseline and 48 weeks | 
| Tolerance: Neuropathies (Grade 1 to 4) | any symptom of peripheral neuropathy | between baseline and W48 | 
| Tolerance: Equal or Superior to a 25% Reduction in eGFR (Glomerular Filtration Rate) | evaluation of estimated glomerular filtration rate and number of participant with a decrease equal or superior to 25% of the baseline value | between baseline and W48 | 
| Adherence | number of patients in different categories of adherence as measured by questionnaire | between baseline and W48 | 
| Number of Patients With Resistance Mutations | number of patients with resistance mutations after second line treatment failure (HIV RNA> 1000 copies/ml) | between W12 and W48 | 
| Development of Metabolic Syndrome | number of patients developing metabolic syndrome over a period of 48 weeks | from baseline to week 48 | 
| Number of Patients With HIV Plasma Viral Load < 50 Copies/ml | Snapshot of patients with HIV viral load less then 50 copies/ml at week 24 | Week 24 | 
| Number of Patients With HIV Plasma Viral Load < 200 Copies/ml | number of patients having a plasma viral load below 200 copies/ml at week 24 | Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Second line treatment, WHO recommendations, Africa, Treatment strategies, treatment experienced