Clinical trial NCT00822315: Efficacy and Safety of 2 Raltegravir Doses in Naive HIV-1-infected Patients Receiving Rifampin for Active Tuberculosis
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Tuberculosis
Keywords: HIV
Tuberculosis
Pharmacokinetics
Raltegravir
France
Brazil
treatment naive
Lead sponsor: ANRS, Emerging Infectious Diseases
Sponsor class: OTHER_GOV
Collaborators: name: Gilead Sciences
name: Merck Sharp & Dohme LLC
First posted: 2009-01-14
Enrollment: 155
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: 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.


Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: 24 weeks
Secondary outcomes:
measure: 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
timeFrame: 24 weeks
measure: Proportion of patients with virologic response with the following definitions: o Plasma HIV RNA <50 copies/ml o Plasma HIV RNA <400 copies/ml
timeFrame: 24 and 48 weeks
measure: Evolution in HIV RNA and HIV DNA (total and 2 LTR circular) from baseline to week 48
timeFrame: 48 weeks
measure: Rate of viral resistance mutations in the plasma at the time of virologic failure and in comparison with HIV-RNA mutations at W0
timeFrame: At the time of virologic failure
measure: Evolution of CD4 cell counts from baseline to week 48
timeFrame: 48 weeks
measure: Frequency, type and time to a new AIDS-defining event or death
timeFrame: Through out the trial
measure: Frequency, type, time to grade 3 or 4 adverse event
timeFrame: Through out the trial
measure: Rate of success of TB treatment
timeFrame: 48 weeks
measure: Anti-TB resistance rate
timeFrame: 48 weeks
measure: Evolution of raltegravir and efavirenz trough concentration
timeFrame: Through out the trial
Other outcomes:
Locations:
city: Nova Iguaçu
country: Brazil
facility: Hospital Genral de Nova Iguaçu
city: Porto alegre
country: Brazil
facility: Hospital Nossa Senhora da Coceiçao
city: Porto Alegre
country: Brazil
facility: Hospital Sanatorio Pertenon
city: Rio de Janeiro
country: Brazil
facility: Ipec/Fiocruz
city: Salvador da Bahia
country: Brazil
facility: Hospitral Universitario Pr Edgar Santos
city: Sao Paulo
country: Brazil
facility: STD/AIDS department
city: Paris
country: France
facility: Hôpital Lariboisière
city: Paris
country: France
facility: Hôpital Saint-Louis
city: Villeneuve Saint Georges
country: France
facility: CHI Villeneuve Saint Georges
Study officials:
affiliation: Fiocruz, Rio de Janiero, Brazil
name: Beatriz Grinsztejn, MD
role: STUDY_CHAIR
affiliation: Hôpital Saint-Louis, Paris, France
name: Jean-Michel Molina, MD
role: STUDY_CHAIR
References:
citation: 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.