Evaluation of a Maintenance Strategy With Protease Inhibitors With or Without Lamivudine in Virologically Suppressed HIV Patients on Second Line Antiretroviral Treatment in Africa
- Conditions
- HIV Infection
- Interventions
- Drug: monoPI - boosted lopinavir or boosted darunavirDrug: bi therapy - (boosted lopinavir or boosted darunavir) + lamivudine
- Registration Number
- NCT01905059
- Lead Sponsor
- ANRS, Emerging Infectious Diseases
- Brief Summary
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
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).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 265
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description monoPI - boosted lopinavir or boosted darunavir monoPI - boosted lopinavir or boosted darunavir 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. bi therapy - (boosted lopinavir or darunavir) + lamivudine bi therapy - (boosted lopinavir or boosted darunavir) + lamivudine 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
- Primary Outcome Measures
Name Time Method Proportion of patients in virological failure 96 weeks 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.
- Secondary Outcome Measures
Name Time Method The Immune response Between the inclusion and 96 weeks The variation in the level of circulating CD4+ lymphocytes
Tolerability Between the inclusion and 96 weeks Changes to the parameters in baseline lipid profile, renal function and bone mineral density
The viral resistance 24 weeks from reintroduction NRTI regimen The frequency of resistance mutations in the case of treatment failure
The clinical course of the HIV infection Inclusion to 96 weeks Numbers of : AIDS events, non-AIDS events, death, adverse events
Assessment neurocognitive functions 96 weeks screening questions (EACS Guidelines)
virological response 96 weeks Number of patient with VL \< 50 copies/ml
Virological response 48 weeks Number of patient with VL \< 50 copies/ml
Treatment failure after reintroduction of the baseline NRTI backbone regimen 24 weeks from reintroduction NRTI 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
Assessment of the adherence 96 weeks but an average of mesures of each visits 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.Changes in anthropometric measures between the inclusion and 96 weeks Changes to the following anthropometric measurements: waist circumference, hip circumference and thigh circumference
Trial Locations
- Locations (5)
Day Care Center CHU Sanou Sauro
🇧🇫Bobo Dioulasso, Burkina Faso
Central Hospital
🇨🇲Yaounde, Cameroon
CRCF Hopital de Fann
🇸🇳Dakar, Senegal
Military Hospital
🇨🇲Yaounde, Cameroon
CTA CHU de Fann
🇸🇳Dakar, Senegal