Efficacy and Tolerance of the Switch From Enfuvirtine to Raltegravir in Antiretroviral Therapy Regimen in HIV Patients With Undetectable Viral Load - Full Text View

Purpose

Switching from enfuvirtide to raltegravir in the treatment of HIV-infected patients who sustain viral suppression with a combination therapy including enfuvirtide (or : with an enfuvirtide-based combination therapy)

Condition	Intervention	Phase
HIV Infections	Drug: FTC/TDF + EFV or LPV/R +T20 Drug: FTC/TDF + EFV or LPV/R	Phase 3


Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Randomized Non-inferiority Study Comparing a Strategy Maintaining Current Enfuvirtide-based Antiretroviral Therapy to a Strategy Replacing Enfuvirtide by an Integrase Inhibitor (Raltegravir) in HIV-1 Infected Subjects With Plasma Hiv-1 RNA Levels Below 400 Copies Per ml.ANRS 138 EASIER

Resource links provided by NLM:

MedlinePlus related topics: HIV/AIDS

Drug Information available for: Emtricitabine Enfuvirtide Lopinavir Raltegravir

U.S. FDA Resources

Further study details as provided by French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS):

Primary Outcome Measures:

comparison of the proportions of virologic failure, defined as two consecutive pVL above 400 cp per ml, through 24 weeks in enfuvirtide-maintained arm versus raltegravir arm [ Time Frame: W24 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

comparison of time to onset of virologic failure [ Time Frame: W24 and W48 ] [ Designated as safety issue: No ]
proportions of pts with pVL under 50 and 400 cp per ml respectively at week 24 and week 48 ; [ Time Frame: W24 & W48 ] [ Designated as safety issue: No ]
plasma viral mutations in the event of virologic failure, compared to HIV-DNA archived mutations at baseline; [ Time Frame: virologic failure ] [ Designated as safety issue: Yes ]
change in CD4 levels [ Time Frame: between W0 and W48 ] [ Designated as safety issue: No ]
incidence of HIV-related events [ Time Frame: between W0 and W48 ] [ Designated as safety issue: Yes ]
drug plasma and male genital tract pharmacokinetics; [ Time Frame: W24 & W48 ] [ Designated as safety issue: No ]
incidence and type of adverse events, including adverse reactions [ Time Frame: between W0 & W48 ] [ Designated as safety issue: Yes ]
proportions of discontinuing allocated treatment strategy [ Time Frame: between W0 & W48 ] [ Designated as safety issue: Yes ]
quality of life and adherence [ Time Frame: W4, W12, W24 and W48 ] [ Designated as safety issue: No ]
morphological and metabolic disorders outcome [ Time Frame: between W0 & W48 ] [ Designated as safety issue: No ]


Enrollment:	170
Study Start Date:	May 2007
Study Completion Date:	September 2008
Primary Completion Date:	September 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Intensification arm emtricitabine/TDF + efavirenz or lopinavir/ritonavir + enfuvirtide	Drug: FTC/TDF + EFV or LPV/R +T20 emtricitabine 200mg/TDF 300mg (1 pill per day) + efavirenz 600mg (1 pill per day) or lopinavir/ritonavir (3 pills twice a day) + enfuvirtide 90mg twice a day
Active Comparator: Standard arm emtricitabine/TDF + efavirenz or lopinavir/ritonavir	Drug: FTC/TDF + EFV or LPV/R emtricitabine 200mg/TDF 300mg (1 pill per day) + efavirenz 600mg (1 pill per day) or lopinavir/ritonavir (3 pills twice a day)

Detailed Description:

In patients who have failed under the three main classes of antiretroviral agents (NRTI, NNRTI and PI) and in whom the control of viral replication in the plasma has ultimately been achieved with enfuvirtide, the aim is to sustain this virological success for as long as possible to thus enable satisfactory immune reconstitution, avoid further accumulation of viral mutations conferring resistance to the drugs and protect the patient from the risk of opportunistic disease and death.

Indeed, enfuvirtide is the lead compound in the new class of antiretroviral drugs which inhibit the fusion of HIV-1 virus with its target cell. Its in vivo efficacy was demonstrated during the pivotal studies TORO 1 and 2. Despite its efficacy, maintaining long-term treatment with enfuvirtide is nonetheless difficult for patients because of the constraints related to twice-daily subcutaneous parenteral injections. Furthermore, these subcutaneous injections are associated with inflammatory reactions at the injection site in 98 per cent of patients, without any reduction in frequency or severity over time. It is thus critical for patients who are well controlled by enfuvirtide to be able to simplify their treatment by replacing enfuvirtide with another active compound taken by mouth, which would enable maintenance of the virological response and acceptable safety in patients who have usually failed under the three main classes of antiretroviral drugs. A new antiviral compound, viral integrase inhibitor called raltegravir, could be proposed instead of enfuvirtide.

Eligibility


Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Chronic HIV-1 infection
Treatment with a well-tolerated combination of antiretroviral drugs unchanged for at least 3 months, including enfuvirtide
Absence of any uncontrolled opportunistic disease
No restrictions on CD4 lymphocyte levels
Plasma HIV-1 RNA below 400 copies per ml for at least 3 months (at least two consecutive tests below 400 copies per ml prior to inclusion in the study, not including that on W -4)
For women of childbearing age, use of mechanical contraception during any sexual intercourse and negative pregnancy test (plasma ß HCG) at W -4

Exclusion Criteria:

HIV-2 infection
Plasma HIV-1 RNA levels above 400 copies/ml on one occasion during the 3 months prior to screening (or the pre-inclusion visit at W -4)
Poor compliance with antiretroviral therapy current at W -4
Current treatment with an investigational drug (except cohort ATU)
Patient previously treated with an integrase inhibitor in the context of a clinical study
Woman who is pregnant or likely to become so, is breastfeeding or refuses to use contraception
Multiple drug therapy ongoing or necessary in the foreseeable future for Kaposi's disease or lymphoma
Treatment with interferon ongoing or necessary in the foreseeable future for chronic hepatitis B or C
Acute hepatitis whatever the case, or decompensated cirrhosis
Current treatment with interferon, interleukin or anti-HIV vaccine
Any condition (including, but not limited to, the consumption of alcohol or drugs) which might, in the investigator's opinion, compromise the safety of treatment and/or patient compliance with the protocol
Significant biological abnormalities (hemoglobin below 8g per dl, polynuclear neutrophils below 750 per mm3, platelets below 50,000 per mm3, serum creatinine above 3 times the level deemed normal by the laboratory (N), ASAT or ALAT above 5N, serum lipase above 2N) and total bilirubin above 2N (except if the patient is receiving atazanavir or indinavir)
Concomitant treatments including one or more compounds interacting with UGT1A1
- anti-infective agents: rifampicin/rifampin
- psychotropic/anti-epileptic drugs: phenytoin, phenobarbital.

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00454337

Locations


France
Service des maladies infectieuses et tropicales Hopital Saint Louis
Paris, France, 75010

Sponsors and Collaborators

French National Agency for Research on AIDS and Viral Hepatitis

Merck Sharp & Dohme Corp.

Investigators


Principal Investigator:	Nathalie De Castro, MD	AP-HP Hopital Saint Louis Paris
Principal Investigator:	Jean M Molina, MD	AP-HP Hopital saint Louis Paris
Study Chair:	Jean P Aboulker, MD	INSERM SC10 Villejuif France

More Information

Publications:

Goldwirt L, Braun J, de Castro N, Charreau I, Barrail-Tran A, Delaugerre C, Raffi F, Lascoux-Combe C, Aboulker JP, Taburet AM, Molina JM. Switch from enfuvirtide to raltegravir lowers plasma concentrations of darunavir and tipranavir: a pharmacokinetic substudy of the EASIER-ANRS 138 trial. Antimicrob Agents Chemother. 2011 Jul;55(7):3613-5. doi: 10.1128/AAC.01827-10. Epub 2011 May 16.

Barau C, Delaugerre C, Braun J, de Castro N, Furlan V, Charreau I, Gérard L, Lascoux-Combe C, Molina JM, Taburet AM. High concentration of raltegravir in semen of HIV-infected men: results from a substudy of the EASIER-ANRS 138 trial. Antimicrob Agents Chemother. 2010 Feb;54(2):937-9. doi: 10.1128/AAC.01261-09. Epub 2009 Dec 7.

Delaugerre C, Charreau I, Braun J, Néré ML, de Castro N, Yeni P, Ghosn J, Aboulker JP, Molina JM, Simon F; ANRS 138 study group. Time course of total HIV-1 DNA and 2-long-terminal repeat circles in patients with controlled plasma viremia switching to a raltegravir-containing regimen. AIDS. 2010 Sep 24;24(15):2391-5. doi: 10.1097/QAD.0b013e32833d214c.

Boulet T, Pavie J, Charreau I, Braun J, Reynes J, Morlat P, Piroth L, Spire B, Molina JM, Aboulker JP; Easier-Anrs 138 Study Group. Impact on health-related quality of life of a switch from enfuvirtide to raltegravir among multidrug-resistant HIV-1-infected patients: a randomized open-label trial (EASIER-ANRS 138). HIV Clin Trials. 2010 Sep-Oct;11(5):283-93. doi: 10.1310/hct1105-283.

Gallien S, Delaugerre C, Charreau I, Braun J, Boulet T, Barrail-Tran A, de Castro N, Molina JM, Kuritzkes DR. Emerging integrase inhibitor resistance mutations in raltegravir-treated HIV-1-infected patients with low-level viremia. AIDS. 2011 Mar 13;25(5):665-9. doi: 10.1097/QAD.0b013e3283445834.

Gallien S, Braun J, Delaugerre C, Charreau I, Reynes J, Jeanblanc F, Verdon R, de Truchis P, May T, Madelaine-Chambrin I, Aboulker JP, Molina JM; EASIER ANRS 138 Study Group. Efficacy and safety of raltegravir in treatment-experienced HIV-1-infected patients switching from enfuvirtide-based regimens: 48 week results of the randomized EASIER ANRS 138 trial. J Antimicrob Chemother. 2011 Sep;66(9):2099-106. doi: 10.1093/jac/dkr269. Epub 2011 Jun 28.

Delaugerre C, Braun J, Charreau I, Delarue S, Nere ML, de Castro N, May T, Marchou B, Simon F, Molina JM, Aboulker JP; ANRS 138-EASIER study group. Comparison of resistance mutation patterns in historical plasma HIV RNA genotypes with those in current proviral HIV DNA genotypes among extensively treated patients with suppressed replication. HIV Med. 2012 Oct;13(9):517-25. doi: 10.1111/j.1468-1293.2012.01002.x. Epub 2012 Mar 14.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

De Castro N, Braun J, Charreau I, Pialoux G, Cotte L, Katlama C, Raffi F, Weiss L, Meynard JL, Yazdanpanah Y, Delaugerre C, Madelaine-Chambrin I, Aboulker JP, Molina JM; EASIER ANRS 138 study group. Switch from enfuvirtide to raltegravir in virologically suppressed multidrug-resistant HIV-1-infected patients: a randomized open-label trial. Clin Infect Dis. 2009 Oct 15;49(8):1259-67. doi: 10.1086/605674.


Responsible Party:	French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS) ( French National Agency for Research on AIDS and Viral Hepatitis )
ClinicalTrials.gov Identifier:	NCT00454337 History of Changes
Other Study ID Numbers:	2007-000162-20, ANRS 138 EASIER
Study First Received:	March 29, 2007
Last Updated:	November 6, 2012
Health Authority:	France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS):


HIV-1 infection enfuvirtide raltegravir treatment experienced

Additional relevant MeSH terms:


Emtricitabine Enfuvirtide Lopinavir Anti-HIV Agents Anti-Infective Agents Anti-Retroviral Agents Antiviral Agents	Enzyme Inhibitors HIV Fusion Inhibitors HIV Protease Inhibitors Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Protease Inhibitors Therapeutic Uses

ClinicalTrials.gov processed this record on March 03, 2015

Efficacy and Tolerance of the Switch From Enfuvirtine to Raltegravir in Antiretroviral Therapy Regimen in HIV Patients With Undetectable Viral Load (EASIER)