Clinical trial NCT01905059: Evaluation of a Maintenance Strategy With Protease Inhibitors With or Without Lamivudine in Virologically Suppressed HIV Patients on Second Line Antiretroviral Treatment in Africa
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Infection
Keywords: HIV infection
second line ART
maintenance strategies
Protease inhibitors
mono or bi-therapy
Lead sponsor: ANRS, Emerging Infectious Diseases
Sponsor class: OTHER_GOV
Collaborators: name: Janssen Pharmaceuticals
First posted: 2013-07-23
Enrollment: 265
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

Eligibility criteria: 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

Primary outcomes:
measure: Proportion of patients in virological failure
timeFrame: 96 weeks
Secondary outcomes:
measure: Treatment failure after reintroduction of the baseline NRTI backbone regimen
timeFrame: 24 weeks from reintroduction NRTI regimen
measure: Virological response
timeFrame: 48 weeks
measure: The viral resistance
timeFrame: 24 weeks from reintroduction NRTI regimen
measure: The clinical course of the HIV infection
timeFrame: Inclusion to 96 weeks
measure: The Immune response
timeFrame: Between the inclusion and 96 weeks
measure: Tolerability
timeFrame: Between the inclusion and 96 weeks
measure: Assessment of the adherence
timeFrame: 96 weeks but an average of mesures of each visits
measure: Changes in anthropometric measures
timeFrame: between the inclusion and 96 weeks
measure: Assessment neurocognitive functions
timeFrame: 96 weeks
measure: virological response
timeFrame: 96 weeks
Other outcomes:
Locations:
city: Bobo Dioulasso
country: Burkina Faso
facility: Day Care Center CHU Sanou Sauro
city: Yaounde
country: Cameroon
facility: Central Hospital
city: Yaounde
country: Cameroon
facility: Military Hospital
city: Dakar
country: Senegal
facility: CRCF Hopital de Fann
city: Dakar
country: Senegal
facility: CTA CHU de Fann
Study officials:
affiliation: University of Yaounde
name: Koulla Shiro Sinata, Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: Hopital de Jour CHU Bobo Dioulasso
name: Sawadogo Adrien, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Service Maladies Infectieuses CHU Fann Dakar
name: Ndour Cheik Tidiane, Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: UMI 233 IRD Montpellier
name: Ciaffi Laura, Dr
role: PRINCIPAL_INVESTIGATOR
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