HIV-1 Infection, Tuberculosis
Conditions
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).
Interventions
DRUGTenofovir + 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
DRUGTenofovir + 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.
Sponsors
Merck Sharp & Dohme LLC
Ministry of Health, Brazil
ANRS, Emerging Infectious Diseases
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of patients in virologic success | Week 48 | 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. |
Secondary
| Measure | Time frame |
|---|---|
| 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 |
| Time to death | 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 |
| Proportion of patients in virologic success at each time point (HIV-1 RNA<50 copies/mL) | Week 48 |
Countries
Brazil, Côte d’Ivoire, France, Mozambique, Vietnam
Outcome results
None listed