Clinical trial NCT02273765: Raltegravir Versus Efavirenz in Naive HIV-1-infected Patients Receiving Rifampin for Active Tuberculosis
Official title: Phase III Open-label Randomized Multicenter Trial to Assess the Non-inferiority of Raltegravir Compared With EFavirenz, Both in Combination With LAmivudine and TEnofovir, in ART-naïve HIV-1-infected Patients Receiving Rifampin for Active TuBerculosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV-1 Infection
Tuberculosis
Lead sponsor: ANRS, Emerging Infectious Diseases
Sponsor class: OTHER_GOV
Collaborators: name: Merck Sharp & Dohme LLC
name: Ministry of Health, Brazil
First posted: 2014-10-24
Enrollment: 460
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: Phase III trial evaluating raltegravir as an alternative to efavirenz for antiretroviral treatment of HIV-infected patients with tuberculosis.

Detailed description: Phase III multicenter, international, open-label, randomized trial evaluating non-inferiority of raltegravir at dose of 400mg BID compared to efavirenz 600mg QD, both in association with tenofovir disoproxil fumarate and lamivudine in ART-naïve HIV-1 infected patients with active TB disease receiving a rifampin-based TB treatment initiated \<8 weeks before inclusion. Patients will be randomized between 2 arms: the raltegravir (RAL) 400 mg bid arm or the efavirenz (EFV) 600 mg qd arm, each in combination with tenofovir disoproxil fumarate (TDF) and lamivudine (3TC) and will be followed for 48 weeks after entry in the trial (ART initiation).

Eligibility criteria: Inclusion Criteria:

* Signed informed consent form
* Aged 18 years or more
* Confirmed HIV-1 infection as documented at any time prior to trial entry per national HIV testing procedures
* ART naïve
* For women of childbearing potential i.e. women of childbearing age who are not menopausal, or permanently sterilized (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy) or not refraining from sexual activity: negative urinary test for pregnancy and acceptance to use contraceptive methods
* Confirmed or probable active TB disease of any location, except neurological (meningitis or encephalitis), according to the following criteria based on WHO updated definitions:

  * Bacteriologically confirmed pulmonary TB (PTB) or extrapulmonary TB (EPTB), e.g. TB with a biological specimen positive by smear microscopy, culture or nucleic acid amplification test (such as Xpert MTB/RIF).
  * Clinically diagnosed PTB or EPTB with typical histological evidence of TB (caseous or granulomatous) on biopsy specimen or positive urinary LAM test OR a significant improvement on TB treatment
* Ongoing standard rifampin-containing TB treatment for ≤8 weeks at inclusion
* For French patients, affiliation to a Social Security program

Exclusion Criteria:

* HIV-2 co-infection
* Impaired hepatic function (icterus or ALT (SGPT) \> 5ULN)
* Hemoglobin \< 6.5 g/dl
* Creatinine clearance \<60ml/min (assessed by the Cockroft and Gault formula)
* Mycobacterium tuberculosis strain resistant to rifampin (current or past history).
* Neurological TB (meningitis or encephalitis)
* Severe associated diseases requiring specific treatment (including all specific AIDS defining illnesses other than TB, and any severe sepsis)
* Any condition which might, in the investigator's opinion, compromise the safety of treatment and/or patient's adherence to trial procedures including very severe TB-related clinical condition
* Concomitant treatments including phenytoin or phenobarbital (compounds interacting with UGT1A1)
* For HCV co-infected patients, need to start specific treatment for hepatitis during the trial duration
* For women of childbearing potential:

  * Pregnancy or breastfeeding
  * Refusal to use a contraceptive method
  * Any history of ARV intake for prevention of mother to child transmission of HIV (pMTCT)
* Subjects participating in another clinical trial evaluating therapies and including an exclusion period that is still in force during the screening phase
* Person under guardianship, or deprived of freedom by a judicial or administrative decision

Primary outcomes:
measure: Proportion of patients in virologic success
timeFrame: Week 48
Secondary outcomes:
measure: Time to death
timeFrame: Week 48
measure: Frequency, type and time to new or recurrent AIDS-defining illnesses
timeFrame: Week 48
measure: Frequency, type and time to severe HIV-associated non-AIDS defining illnesses
timeFrame: Week 48
measure: Frequency, type and time to grade 3 or 4 adverse events
timeFrame: Week 48
measure: Frequency, type and time to drug-induced clinical or biological adverse reactions of grade 3 or 4 or leading to treatment interruption
timeFrame: Week 48
measure: Change in plasma HIV-1 RNA from baseline to week 48
timeFrame: Week 48
measure: Proportion of patients in virologic success at each time point (HIV-1 RNA<50 copies/mL)
timeFrame: Week 48
measure: Time to virologic failure during follow-up
timeFrame: Week 48
measure: Frequency and time to new antiretroviral genotypic resistance in plasma RNA in patients with virologic failure
timeFrame: Week 48
measure: Change in CD4 cell counts from baseline to week 48
timeFrame: Week 48
measure: Frequency, type and time to Immune Reconstitution Inflammatory Syndrome
timeFrame: Week 48
measure: Frequency of tuberculosis treatment outcomes
timeFrame: Week 48
Other outcomes:
Locations:
city: Rio de Janeiro
country: Brazil
facility: Laboratory of clinical research on STD/AIDS - IPEC/FIOCRUZ
city: Abidjan
country: Côte D'Ivoire
facility: PACCI / CePReF Centre de Prise en charge de Recherche et de Formation
city: Paris
country: France
facility: Hôpital Saint Louis
city: Maputo
country: Mozambique
facility: Instituto Nacional de Saude / Hospital Geral de Machava
city: Ho Chi Minh City
country: Vietnam
facility: Pham Ngoc Thach Hospital
Study officials:
affiliation: Laboratory on Clinical research on DST/AIDS-IPEC FIOCRUZ Av Brasil, 4365 Manguinhos Rio de Janeiro, Brazil CEP 21040-900
name: Beatriz Grinsztejn, MD, PhD
role: STUDY_CHAIR
affiliation: AP-HP Hôpital Saint-Louis 1 avenue Claude Vellefaux, 75010 Paris, France
name: Nathalie De Castro, MD
role: STUDY_CHAIR
References:
citation: De Castro N, Marcy O, Chazallon C, Messou E, Eholie S, N'takpe JB, Bhatt N, Khosa C, Timana Massango I, Laureillard D, Chau GD, Domergue A, Veloso V, Escada R, Wagner Cardoso S, Delaugerre C, Anglaret X, Molina JM, Grinsztejn B; ANRS 12300 Reflate TB2 study group. Standard dose raltegravir or efavirenz-based antiretroviral treatment for patients co-infected with HIV and tuberculosis (ANRS 12 300 Reflate TB 2): an open-label, non-inferiority, randomised, phase 3 trial. Lancet Infect Dis. 2021 Jun;21(6):813-822. doi: 10.1016/S1473-3099(20)30869-0. Epub 2021 Mar 2.