Raltegravir Versus Efavirenz in Naive HIV-1-infected Patients Receiving Rifampin for Active Tuberculosis (REFLATE TB2)

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

Phase III trial evaluating raltegravir as an alternative to efavirenz for antiretroviral treatment of HIV-infected patients with tuberculosis.

Study Overview

• Status: Completed
• Conditions: Tuberculosis; HIV-1 Infection
• Intervention / Treatment: Drug: Tenofovir + lamivudine + raltegravir; Drug: Tenofovir + lamivudine + efavirenz

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).

• Study Type: Interventional
• Enrollment (Actual): 460
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Rio de Janeiro, Brazil
    • Laboratory of clinical research on STD/AIDS - IPEC/FIOCRUZ
• Côte D'Ivoire
  • Abidjan, Côte D'Ivoire
    • PACCI / CePReF Centre de Prise en charge de Recherche et de Formation
• France
  • Paris, France
    • Hopital Saint Louis
• Mozambique
  • Maputo, Mozambique
    • Instituto Nacional de Saude / Hospital Geral de Machava
• Vietnam
  • Ho Chi Minh City, Vietnam
    • Pham Ngoc Thach Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Raltegravir; Tenofovir 300mg QD + lamivudine 300mg QD + raltegravir 400mg BID	Drug: Tenofovir + lamivudine + raltegravir; In this arm, patients will receive the following medications : Tenofovir disoproxil fumarate (TDF) 300 mg / Lamivudine (3TC) 300 mg FDC once a day (1 tablet qd); Raltegravir (RAL) 400 mg (Isentress®): twice daily (1 tablet bid), with food In countries where TDF/3TC FDC is not available, the following separate drugs will be used: Tenofovir disoproxil fumarate (TDF) 300 mg (Viread® 245 mg): once a day (1 tablet qd); Lamivudine (3TC) : 300 mg once a day (300 mg, 1 tablet qd or 150 mg 2 tablets qd); Raltegravir (RAL) 400 mg (Insentress®): twice daily (1 tablet bid), with food
Experimental: Efavirenz; Tenofovir 300mg QD + lamivudine 300mg QD + efavirenz 600mg QD	Drug: Tenofovir + lamivudine + efavirenz; In this arm, patients will receive the following medications, in accordance with treatment guidelines in all countries: Tenofovir disoproxil fumarate (TDF) 300 mg / lamivudine (3TC) 300 mg FDC once a day (1 tablet qd); Efavirenz (EFV) 600 mg: once a day, at night (1 tablet qd) OR: • Tenofovir disoproxil fumarate (TDF) 245 300 mg / lamivudine (3TC) 300 mg / efavirenz (EFV) 600 mg: once a day (1 tablet qd), at night, if possible without food In countries where TDF/3TC FDC is not available, the following separate drugs will be used: Tenofovir disoproxil fumarate (TDF) 300 mg (Viread® 245 mg): once a day (1 tablet qd); Lamivudine (3TC): 300 mg once a day (300 mg, 1 tablet qd or 150 mg 2 tablets qd); Efavirenz (EFV) 600 mg: once a day, at night (1 tablet qd), if possible without food. The dose will not be adapted to the patient's body weight.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients in virologic success	Virologic success, defined as plasma HIV-1 RNA <50 copies/mL, at week 48 with a window period of 42 to 54 weeks (snapshot algorithm). Discontinuation of the strategy (ie. permanent discontinuation of EFV, RAL), missing values, loss to follow-up and death will be considered as failure.	Week 48

Secondary Outcome Measures

Outcome Measure	Time Frame
Time to death	Week 48
Frequency, type and time to new or recurrent AIDS-defining illnesses	Week 48
Frequency, type and time to severe HIV-associated non-AIDS defining illnesses	Week 48
Frequency, type and time to grade 3 or 4 adverse events	Week 48
Frequency, type and time to drug-induced clinical or biological adverse reactions of grade 3 or 4 or leading to treatment interruption	Week 48
Change in plasma HIV-1 RNA from baseline to week 48	Week 48
Proportion of patients in virologic success at each time point (HIV-1 RNA<50 copies/mL)	Week 48
Time to virologic failure during follow-up	Week 48
Frequency and time to new antiretroviral genotypic resistance in plasma RNA in patients with virologic failure	Week 48
Change in CD4 cell counts from baseline to week 48	Week 48
Frequency, type and time to Immune Reconstitution Inflammatory Syndrome	Week 48
Frequency of tuberculosis treatment outcomes	Week 48

Collaborators and Investigators

• Sponsor: ANRS, Emerging Infectious Diseases
• Collaborators: Merck Sharp & Dohme LLC; Ministry of Health, Brazil
• Investigators: Study Chair: Beatriz Grinsztejn, MD, PhD, Laboratory on Clinical research on DST/AIDS-IPEC FIOCRUZ Av Brasil, 4365 Manguinhos Rio de Janeiro, Brazil CEP 21040-900; Study Chair: Nathalie De Castro, MD, AP-HP Hôpital Saint-Louis 1 avenue Claude Vellefaux, 75010 Paris, France

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 11, 2015
• Primary Completion (Actual): November 28, 2018
• Study Completion (Actual): November 28, 2018

Study Registration Dates

• First Submitted: October 20, 2014
• First Submitted That Met QC Criteria: October 22, 2014
• First Posted (Estimate): October 24, 2014

Study Record Updates

• Last Update Posted (Actual): December 31, 2018
• Last Update Submitted That Met QC Criteria: December 28, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; HIV Integrase Inhibitors; Integrase Inhibitors; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Tenofovir; Raltegravir Potassium; Lamivudine; Efavirenz
• Other Study ID Numbers: ANRS 12300 REFLATE TB2