Efficacy and Safety of 2 Raltegravir Doses in Naive HIV-1-infected Patients Receiving Rifampin for Active Tuberculosis

Phase II Open-label Randomized Multicenter Trial to Compare the Efficacy and Safety of Two Different Doses of Raltegravir and Efavirenz, All in Combination With Tenofovir and Lamivudine, in Naive HIV-1-infected Patients Receiving Rifampin for Active Tuberculosis

Raltegravir is a potent antiretroviral agent that could be used as an alternative to efavirenz in HIV-1 infected patients with tuberculosis. However due to pharmacokinetic interactions, the optimal dose of raltegravir to be used in combination with rifampin is currently unknown.

This phase II open-label randomized multicenter trial is designed to estimate the antiviral efficacy of two doses of raltegravir and one dose of efavirenz at week 24, in HIV-1 naive patients co-infected with active tuberculosis (TB) treated with rifampin.

Study Overview

• Status: Completed
• Conditions: HIV Infections; Tuberculosis
• Intervention / Treatment: Drug: efavirenz; Drug: raltegravir; Drug: raltegravir

• Study Type: Interventional
• Enrollment (Actual): 155
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • Nova Iguaçu, Brazil
    • Hospital Genral de Nova Iguaçu
  • Porto Alegre, Brazil
    • Hospital Sanatorio Pertenon
  • Porto alegre, Brazil
    • Hospital Nossa Senhora da Coceiçao
  • Rio de Janeiro, Brazil
    • Ipec/Fiocruz
  • Salvador da Bahia, Brazil
    • Hospitral Universitario Pr Edgar Santos
  • Sao Paulo, Brazil
    • STD/AIDS department
• France
  • Paris, France, 75010
    • Hôpital Lariboisière
  • Paris, France, 75010
    • Hôpital Saint-Louis
  • Villeneuve Saint Georges, France, 94195
    • CHI Villeneuve Saint Georges

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:

• Adult patients (at least 18 years old)
• Plasma HIV RNA > 1000 copies/ml
• HIV-1-infection confirmed by ELISA and Western blot or Immunofluorescence
• ART naïve patients or
• ART for less than 3 months and more than 6 months ago ; an HIV resistance genotype at baseline showing no mutation to NNRTI and TDF or 3TC will be required
• For women of childbearing age, negative urinary test for pregnancy and to accept contraceptive methods: condom use and intra-uterine device when possible or declare no wish of pregnancy in the coming year.
• Confirmed or probable TB
• TB treatment including rifampin started since 2 to 8 weeks before randomisation
• Signed informed consent form
• For French patients, to be affiliated to the National Health Care System

Exclusion Criteria:

• HIV-2 infection (single or with HIV-1)
• Woman who is pregnant or likely to become so, is breastfeeding or refuses to use contraception
• ALT>2.5N, Hb <7g/dl, neutrophils < 750/mm3, platelet<50 000/mm3, bilirubin >5N, lipase >3N
• Creatinine clearance <60ml/min as assessed by the Cockcroft method
• Ongoing psychiatric pathology or 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
• Concomitant treatments including phenytoin or phenobarbital (compounds interacting with UGT1A1)
• Prior TB with a Mycobacterium tuberculosis strain resistant to rifampin
• TB treatment started for more than 8 weeks before randomisation

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 1; efavirenz	Drug: efavirenz; tenofovir 245 mg / lamivudine 300 mg / efavirenz 600 mg
Experimental: 2; raltegravir 400 mg	Drug: raltegravir; tenofovir 245 mg / lamivudine 300 mg / raltegravir 400 mg; Drug: raltegravir; tenofovir 245 mg / lamivudine 300 mg / raltegravir 800 mg
Experimental: 3; raltegravir 800 mg	Drug: raltegravir; tenofovir 245 mg / lamivudine 300 mg / raltegravir 400 mg; Drug: raltegravir; tenofovir 245 mg / lamivudine 300 mg / raltegravir 800 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Virologic success, using Time to Loss of Virologic Response (TLOVR) algorithm: -Plasma HIV RNA below 50 copies/ml at week 20, confirmed at week 24 -Absence of permanent treatment discontinuation -Absence of death -Still follow-up at week 24	24 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Proportion of patients with virologic response with the following definitions: - Plasma HIV RNA <50 copies/ml at week 24 - Rate of strategy discontinuation and treatment changes - Proportion of death - Proportion of patients loss to follow-up	24 weeks
Proportion of patients with virologic response with the following definitions: o Plasma HIV RNA <50 copies/ml o Plasma HIV RNA <400 copies/ml	24 and 48 weeks
Evolution in HIV RNA and HIV DNA (total and 2 LTR circular) from baseline to week 48	48 weeks
Rate of viral resistance mutations in the plasma at the time of virologic failure and in comparison with HIV-RNA mutations at W0	At the time of virologic failure
Evolution of CD4 cell counts from baseline to week 48	48 weeks
Frequency, type and time to a new AIDS-defining event or death	Through out the trial
Frequency, type, time to grade 3 or 4 adverse event	Through out the trial
Rate of success of TB treatment	48 weeks
Anti-TB resistance rate	48 weeks
Evolution of raltegravir and efavirenz trough concentration	Through out the trial

Collaborators and Investigators

• Sponsor: ANRS, Emerging Infectious Diseases
• Collaborators: Merck Sharp & Dohme LLC; Gilead Sciences
• Investigators: Study Chair: Beatriz Grinsztejn, MD, Fiocruz, Rio de Janiero, Brazil; Study Chair: Jean-Michel Molina, MD, Hôpital Saint-Louis, Paris, France

Publications and helpful links

General Publications

• Grinsztejn B, De Castro N, Arnold V, Veloso VG, Morgado M, Pilotto JH, Brites C, Madruga JV, Barcellos NT, Santos BR, Vorsatz C, Fagard C, Santini-Oliveira M, Patey O, Delaugerre C, Chene G, Molina JM; ANRS 12 180 Reflate TB study group. Raltegravir for the treatment of patients co-infected with HIV and tuberculosis (ANRS 12 180 Reflate TB): a multicentre, phase 2, non-comparative, open-label, randomised trial. Lancet Infect Dis. 2014 Jun;14(6):459-67. doi: 10.1016/S1473-3099(14)70711-X. Epub 2014 Apr 9. Erratum In: Lancet Infect Dis. 2014 Jun;14(6):448.

Study record dates

Study Major Dates

• Study Start: July 1, 2009
• Primary Completion (Actual): November 1, 2011
• Study Completion (Actual): May 1, 2012

Study Registration Dates

• First Submitted: January 13, 2009
• First Submitted That Met QC Criteria: January 13, 2009
• First Posted (Estimate): January 14, 2009

Study Record Updates

• Last Update Posted (Estimate): July 17, 2013
• Last Update Submitted That Met QC Criteria: July 16, 2013
• Last Verified: July 1, 2013

More Information

Terms related to this study

• Keywords: HIV; Pharmacokinetics; Tuberculosis; France; treatment naive; Brazil; Raltegravir
• 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; Raltegravir Potassium; Efavirenz
• Other Study ID Numbers: ANRS 12180 REFLATE TB