Evaluation of a Maintenance Strategy With Protease Inhibitors With or Without Lamivudine in Virologically Suppressed HIV Patients on Second Line Antiretroviral Treatment in Africa
NCT ID: NCT01905059
Last Updated: 2017-07-21
Study Results
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Basic Information
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COMPLETED
PHASE3
265 participants
INTERVENTIONAL
2014-02-28
2017-02-28
Brief Summary
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Detailed Description
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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).
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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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.
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 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.
bi therapy - (boosted lopinavir or 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
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. This arm is going on, patients will be followed on this intervention until the end of the study at week 96
Interventions
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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 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.
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. This arm is going on, patients will be followed on this intervention until the end of the study at week 96
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
* 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
18 Years
ALL
No
Sponsors
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Janssen Pharmaceuticals
INDUSTRY
ANRS, Emerging Infectious Diseases
OTHER_GOV
Responsible Party
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Principal Investigators
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Koulla Shiro Sinata, Prof
Role: PRINCIPAL_INVESTIGATOR
University of Yaounde
Sawadogo Adrien, Dr
Role: PRINCIPAL_INVESTIGATOR
Hopital de Jour CHU Bobo Dioulasso
Ndour Cheik Tidiane, Prof
Role: PRINCIPAL_INVESTIGATOR
Service Maladies Infectieuses CHU Fann Dakar
Ciaffi Laura, Dr
Role: PRINCIPAL_INVESTIGATOR
UMI 233 IRD Montpellier
Locations
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Day Care Center CHU Sanou Sauro
Bobo-Dioulasso, , Burkina Faso
Central Hospital
Yaoundé, , Cameroon
Military Hospital
Yaoundé, , Cameroon
CRCF Hopital de Fann
Dakar, , Senegal
CTA CHU de Fann
Dakar, , Senegal
Countries
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References
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Cameron DW, da Silva BA, Arribas JR, Myers RA, Bellos NC, Gilmore N, King MS, Bernstein BM, Brun SC, Hanna GJ. A 96-week comparison of lopinavir-ritonavir combination therapy followed by lopinavir-ritonavir monotherapy versus efavirenz combination therapy. J Infect Dis. 2008 Jul 15;198(2):234-40. doi: 10.1086/589622.
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Vernazza P, Daneel S, Schiffer V, Decosterd L, Fierz W, Klimkait T, Hoffmann M, Hirschel B. The role of compartment penetration in PI-monotherapy: the Atazanavir-Ritonavir Monomaintenance (ATARITMO) Trial. AIDS. 2007 Jun 19;21(10):1309-15. doi: 10.1097/QAD.0b013e32814e6b1c.
Gutmann C, Cusini A, Gunthard HF, Fux C, Hirschel B, Decosterd LA, Cavassini M, Yerly S, Vernazza PL; Swiss HIV Cohort Study (SHCS). Randomized controlled study demonstrating failure of LPV/r monotherapy in HIV: the role of compartment and CD4-nadir. AIDS. 2010 Sep 24;24(15):2347-54. doi: 10.1097/QAD.0b013e32833db9a1.
Katlama C, Valantin MA, Algarte-Genin M, Duvivier C, Lambert-Niclot S, Girard PM, Molina JM, Hoen B, Pakianather S, Peytavin G, Marcelin AG, Flandre P. Efficacy of darunavir/ritonavir maintenance monotherapy in patients with HIV-1 viral suppression: a randomized open-label, noninferiority trial, MONOI-ANRS 136. AIDS. 2010 Sep 24;24(15):2365-74. doi: 10.1097/QAD.0b013e32833dec20.
Arribas JR, Horban A, Gerstoft J, Fatkenheuer G, Nelson M, Clumeck N, Pulido F, Hill A, van Delft Y, Stark T, Moecklinghoff C. The MONET trial: darunavir/ritonavir with or without nucleoside analogues, for patients with HIV RNA below 50 copies/ml. AIDS. 2010 Jan 16;24(2):223-30. doi: 10.1097/QAD.0b013e3283348944.
Mathis S, Khanlari B, Pulido F, Schechter M, Negredo E, Nelson M, Vernazza P, Cahn P, Meynard JL, Arribas J, Bucher HC. Effectiveness of protease inhibitor monotherapy versus combination antiretroviral maintenance therapy: a meta-analysis. PLoS One. 2011;6(7):e22003. doi: 10.1371/journal.pone.0022003. Epub 2011 Jul 19.
Gilks CF, Walker AS, Dunn DT, Gibb DM, Kikaire B, Reid A, Musana H, Mambule I, Kasirye R, Robertson V, Ssali F, Spyer M, Pillay D, Yirrell D, Kaleebu P; DART Virology Group and Trial Team. Lopinavir/ritonavir monotherapy after 24 weeks of second-line antiretroviral therapy in Africa: a randomized controlled trial (SARA). Antivir Ther. 2012;17(7):1363-73. doi: 10.3851/IMP2253. Epub 2012 Jul 19.
Bartlett JA, Ribaudo HJ, Wallis CL, Aga E, Katzenstein DA, Stevens WS, Norton MR, Klingman KL, Hosseinipour MC, Crump JA, Supparatpinyo K, Badal-Faesen S, Kallungal BA, Kumarasamy N. Lopinavir/ritonavir monotherapy after virologic failure of first-line antiretroviral therapy in resource-limited settings. AIDS. 2012 Jul 17;26(11):1345-54. doi: 10.1097/QAD.0b013e328353b066.
Castagna A, Danise A, Menzo S, Galli L, Gianotti N, Carini E, Boeri E, Galli A, Cernuschi M, Hasson H, Clementi M, Lazzarin A. Lamivudine monotherapy in HIV-1-infected patients harbouring a lamivudine-resistant virus: a randomized pilot study (E-184V study). AIDS. 2006 Apr 4;20(6):795-803. doi: 10.1097/01.aids.0000218542.08845.b2.
Bunupuradah T, Chetchotisakd P, Ananworanich J, Munsakul W, Jirajariyavej S, Kantipong P, Prasithsirikul W, Sungkanuparph S, Bowonwatanuwong C, Klinbuayaem V, Kerr SJ, Sophonphan J, Bhakeecheep S, Hirschel B, Ruxrungtham K; HIV STAR Study Group. A randomized comparison of second-line lopinavir/ritonavir monotherapy versus tenofovir/lamivudine/lopinavir/ritonavir in patients failing NNRTI regimens: the HIV STAR study. Antivir Ther. 2012;17(7):1351-61. doi: 10.3851/IMP2443. Epub 2012 Jul 2.
Ciaffi L, Koulla-Shiro S, Sawadogo AB, Ndour CT, Eymard-Duvernay S, Mbouyap PR, Ayangma L, Zoungrana J, Gueye NFN, Diallo M, Izard S, Bado G, Kane CT, Aghokeng AF, Peeters M, Girard PM, Le Moing V, Reynes J, Delaporte E; MOBIDIP study group. Boosted protease inhibitor monotherapy versus boosted protease inhibitor plus lamivudine dual therapy as second-line maintenance treatment for HIV-1-infected patients in sub-Saharan Africa (ANRS12 286/MOBIDIP): a multicentre, randomised, parallel, open-label, superiority trial. Lancet HIV. 2017 Sep;4(9):e384-e392. doi: 10.1016/S2352-3018(17)30069-3. Epub 2017 May 28.
Related Links
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Sponsor site
Other Identifiers
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ANRS 12286MOBIDIP
Identifier Type: -
Identifier Source: org_study_id
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