Evaluation of a Maintenance Strategy With Protease Inhibitors With or Without Lamivudine in Virologically Suppressed HIV Patients on Second Line Antiretroviral Treatment in Africa

Study Overview
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Brief Summary
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Multicenter, randomized, superiority trial to evaluate efficacy of a mono or bi-therapy of protease inhibitors with or without lamivudine over a period of 96 weeks. The primary outcome will be the failure rate at 96 weeks. This study will include 260 participants, former participants of the 2LADY trial. It will be carried out in Yaoundé, Bobo Dioulasso and Dakar.

Detailed Description
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Justification: The interest of treating HIV infection with a single molecule has been clear for a long time. Many clinical trials have been testing the efficacy of such a strategy, mainly using a boosted protease inhibitor (PI). Despite the remaining doubts about low level viremia, viral control in reservoirs, durability of the effect, the trials showed attractive results with an absolute increase in the risk of virological failure between 2% and 13% compared to the standard of care and a possible decrease in costs and toxicity. In resource-limited countries the interest of treatment simplification is even more important: decrease in costs, toxicity (often poorly monitored), number of pills taken per day, etc. In addition, for patients in second line for whom some kind of resistance to NRTI is highly probable, the interruption of the second line NRTI could help to avoid the accumulation of mutations in the RT in the presence of residual low level replication, sparing future treatment options. The 184 mutation of the retro-transcriptase which causes resistance to lamivudine/emtricitabine seems to hinder viral replication. The persistence of this mutation could eventually facilitate the action of PI monotherapy while protecting patients from further mutations. The choice of viral load (VL) threshold for the diagnosis of failure in resource-limited countries is not easy, the 2LADY trial used in clinical practice, the threshold of 1000 copies/ml which allows genotyping for evidence of mutations. This value will probably be selected as a reference value by the WHO in its next recommendations. To minimize the risk of viral escape and the development of resistances in the MOBIDIP study the threshold of 200 copies/ml has been chosen for the switch to monotherapy and of 500 copies/ml for the definition of failure. Principal objective: To evaluate the failure rate at 96 weeks of a PI monotherapy with or without lamivudine, in HIV positive patients on second line treatment (ART) for at least 48 weeks, and with a VL of less than 200 copies/ml in Africa (Yaoundé, Bobo Dioulasso, Dakar). Specific objectives: To evaluate: viral efficacy at a threshold of 50 copies/ml at 48 and 96 weeks, failure rate at 500 copies/ml after 24 weeks from the reintroduction of NRTI backbone in case of monotherapy failure, clinical and immunological outcomes, development of mutations, tolerance and impact on metabolic profile and neuro-cognitive disorders, adherence Methods: multicenter, randomized, superiority trial to evaluate efficacy of a mono or bi-therapy of protease inhibitors with or without lamivudine over a period of 96 weeks. The primary outcome will be the failure rate at 96 weeks. Failure is defined as: 1) viral load ≥500 copies/ml, 2) reintroduction of NRTI backbone, 3) interruption of the PI. A sample of 260 participants is planned. Schedule: After approval by national Ethical committees and national authorities, patients followed in 2LADY trial for at least 48 weeks, and presenting the eligibility criteria, will stop their NRTI backbone and be randomized (over 6 months) to add or not lamivudine to their PI monotherapy. All patients will be followed for 96 weeks. In case of viral load above 500 copies/ml during the study, the original NRTI backbone will be re-introduced and the patient will be followed for an extra 24 weeks to verify viral response. The complete trial is due to last 3 years. Expected results: This study will allow the validation of a maintenance strategy for patients in second line ART less expensive and toxic. In addition results could be used to guide clinical practice for physicians in resources poor countries In march 2016 an interim analysis asked by the DSMB showed increased risk of failure in the monotherpay arm and the arm was stopped. Participant are switched on standard second line triple therapy and followed until Week 96. Participant on dual therapy continue their follow up. Comparative analysis are planned for data on week 60 visit (last visit with all participants on the randomized treatment).

Official Title
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Multicenter, International, Prospective, Phase III, Randomized, Superiority Trial Comparing Two Maintenance Strategies With Mono or Bi-therapy of Protease Inhibitors With or Without Lamivudine in Virologically Suppressed HIV Patients on Second Line Antiretroviral Treatment Over a Period of 96 Weeks in Africa (Dakar, Bobo Dioulasso, Yaounde)

Conditions
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HIV Infection

Intervention / Treatment
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* Drug: monoPI - boosted lopinavir or boosted darunavir
* Drug: bi therapy - (boosted lopinavir or boosted darunavir) + lamivudine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV infection on second line treatment in the 2lady trial for at least 48 weeks VL ≤ 200 copies/ml since at least 6 months No change in ART in the last 3 months previous to the study CD4> 100 cells/ml Signed informed consent Adherence >90 Exclusion Criteria: Previous viral failure (at least 2 consecutive HIV RNA >1000 copies/ml) while receiving a PI Ongoing pregnancy and breast feeding women HBsAg positive patients opportunistic infection or any severe or progressive disease ongoing or treated in the 3 months before screening Subject who in the investigator's opinion is unable to complete the study History or symptoms of HIV encephalopathy

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: monoPI - boosted lopinavir or boosted darunavir<br>boosted lopinavir (LPV/rtv 200/50 mg 2 tbs BID) or boosted darunavir (DRV 400 mg 2 tbs plus RTV 100 mg QD) This arm has been stopped on advise of DSMB (approved by Scientific Committee), patients are switched to standard second line triple therapy and followed until the end of the study at week 96. | Drug: monoPI - boosted lopinavir or boosted darunavir<br>* boosted lopinavir (LPV/rtv 200/50 mg 2 tbs BID) or boosted darunavir (DRV 400 mg 2 tbs plus RTV 100 mg QD) This arm was stopped by the Scientific Committee on advise of the DSMB after interim analysis showing increased risk of failure for these participants. Participants are switched to standard second line triple therapy and will be followed until the last visit at week 96.<br>* Other names: boosted lopinavir monotherapy;|
| Active Comparator: bi therapy - (boosted lopinavir or darunavir) + lamivudine<br>boosted lopinavir (LPV/rtv 200/50 mg 2 tbs BID) with lamivudine 300 mg QD or boosted darunavir (DRV 400 mg 2 tbs plus RTV 100 mg QD)with lamivudine 300 mg QD | Drug: bi therapy - (boosted lopinavir or boosted darunavir) + lamivudine<br>* boosted lopinavir (LPV/rtv 200/50 mg 2 tbs BID) with lamivudine 300 mg QD or boosted darunavir (DRV 400 mg 2 tbs plus RTV 100 mg QD)with lamivudine 300 mg QD. This arm is going on, patients will be followed on this intervention until the end of the study at week 96<br>* Other names: LPV/r with lamivudine and DRV/r with lamivudine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients in virological failure | Number of patients with a treatment failure. Definition of treatment failure: 1) viral load ≥ 500 copies/ml confirmed in 2 samples with 1 month interval, or 2) the reintroduction of the two NRTIs or 3) interruption of the boosted PI. | 96 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment failure after reintroduction of the baseline NRTI backbone regimen | Number of patients in virological failure after reintroduction NRTI regimen. Treatment failure defined by viral load > 200 and/or > 500 copies/ml within 24 weeks from the reintroduction of the baseline NRTI backbone regimen | 24 weeks from reintroduction NRTI regimen | 
| Virological response | Number of patient with VL < 50 copies/ml | 48 weeks | 
| The viral resistance | The frequency of resistance mutations in the case of treatment failure | 24 weeks from reintroduction NRTI regimen | 
| The clinical course of the HIV infection | Numbers of : AIDS events, non-AIDS events, death, adverse events | Inclusion to 96 weeks | 
| The Immune response | The variation in the level of circulating CD4+ lymphocytes | Between the inclusion and 96 weeks | 
| Tolerability | Changes to the parameters in baseline lipid profile, renal function and bone mineral density | Between the inclusion and 96 weeks | 
| Assessment of the adherence | Adherence is considered high if consumption is greater than or equal to 95%, average if it is between 80 and 95% and low if it is less than 80%. It is measured at each visit, by means of a questionnaire and by tablet count. | 96 weeks but an average of mesures of each visits | 
| Changes in anthropometric measures | Changes to the following anthropometric measurements: waist circumference, hip circumference and thigh circumference | between the inclusion and 96 weeks | 
| Assessment neurocognitive functions | screening questions (EACS Guidelines) | 96 weeks | 
| virological response | Number of patient with VL < 50 copies/ml | 96 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV infection, second line ART, maintenance strategies, Protease inhibitors, mono or bi-therapy