Clinical trial NCT00454337: Efficacy and Tolerance of the Switch From Enfuvirtine to Raltegravir in Antiretroviral Therapy Regimen in HIV Patients With Undetectable Viral Load
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Infections
Keywords: HIV-1 infection
enfuvirtide
raltegravir
treatment experienced
Lead sponsor: ANRS, Emerging Infectious Diseases
Sponsor class: OTHER_GOV
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2007-03-30
Enrollment: 170
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: 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)

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 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.

Primary outcomes:
measure: 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
timeFrame: W24
Secondary outcomes:
measure: comparison of time to onset of virologic failure
timeFrame: W24 and W48
measure: proportions of pts with pVL under 50 and 400 cp per ml respectively at week 24 and week 48 ;
timeFrame: W24 & W48
measure: plasma viral mutations in the event of virologic failure, compared to HIV-DNA archived mutations at baseline;
timeFrame: virologic failure
measure: change in CD4 levels
timeFrame: between W0 and W48
measure: incidence of HIV-related events
timeFrame: between W0 and W48
measure: drug plasma and male genital tract pharmacokinetics;
timeFrame: W24 & W48
measure: incidence and type of adverse events, including adverse reactions
timeFrame: between W0 & W48
measure: proportions of discontinuing allocated treatment strategy
timeFrame: between W0 & W48
measure: quality of life and adherence
timeFrame: W4, W12, W24 and W48
measure: morphological and metabolic disorders outcome
timeFrame: between W0 & W48
Other outcomes:
Locations:
city: Paris
country: France
facility: Service des maladies infectieuses et tropicales Hopital Saint Louis
Study officials:
affiliation: AP-HP Hopital Saint Louis Paris
name: Nathalie De Castro, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: AP-HP Hopital saint Louis Paris
name: Jean M Molina, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: INSERM SC10 Villejuif France
name: Jean P Aboulker, MD
role: STUDY_CHAIR
References:
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 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.
citation: Barau C, Delaugerre C, Braun J, de Castro N, Furlan V, Charreau I, Gerard 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.
citation: Delaugerre C, Charreau I, Braun J, Nere 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.
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-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.
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):665-9. doi: 10.1097/QAD.0b013e3283445834.
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 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.
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 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.
citation: de Castro N, Braun J, Charreau I, Lafeuillade A, Viard JP, Allavena C, Aboulker JP, Molina JM; EASIER ANRS 138 study group. Incidence and risk factors for liver enzymes elevations in highly treatment-experienced patients switching from enfuvirtide to raltegravir: a sub-study of the ANRS-138 EASIER trial. AIDS Res Ther. 2016 Apr 2;13:17. doi: 10.1186/s12981-016-0101-3. eCollection 2016.
citation: 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.