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

HIV Infections Clinical Trial

— EASIER  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00454337
• Other study ID #: 2007-000162-20
• Secondary ID: ANRS 138 EASIER
• Status: Completed
• Phase: Phase 3
• First received: March 29, 2007
• Last updated: November 6, 2012
• Start date: May 2007
• Est. completion date: September 2008

Study information

• Verified date: November 2012
• Source: French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
• Study type: Interventional

Clinical Trial Summary

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)

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 170
• Est. completion date: September 2008
• Est. primary completion date: September 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• HIV Infections

Intervention

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
• 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)

Locations

Country	Name	City	State
France	Service des maladies infectieuses et tropicales Hopital Saint Louis	Paris

Sponsors (2)

Lead Sponsor	Collaborator
French National Agency for Research on AIDS and Viral Hepatitis	Merck Sharp & Dohme Corp.

Country where clinical trial is conducted

France, 

References & Publications (7)

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 Ch — View Citation

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-infect — View Citation

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 pro — View Citation

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 ra — View Citation

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 patie — View Citation

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): — View Citation

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 su — View Citation

Outcome

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