HIV-1 Infection
Conditions
Keywords
HIV-1, Tuberculosis, Systematic empiric TB treatment, ART, TB diagnosis, Xpert MTB/RIF®, Urine LAM
Brief summary
In countries with a high tuberculosis (TB) prevalence, TB and invasive bacterial infections are leading causes of early death in patients who initiate antiretroviral therapy (ART) with advanced immunodeficiency. We hypothesize that a systematic 6-month empirical TB treatment initiated 2 weeks before the introduction of ART in HIV-infected adults with severe immunosuppression (CD4\<100/mm3) and no overt evidence of TB will reduce the risk of death and invasive bacterial infections. This strategy will be compared to one of extensive TB testing using point-of-care tests (Xpert MTB/RIF® and urine lipoarabinomanan LAM) and chest X-ray to identify and treat only patients with at least one positive test suggestive of TB.
Detailed description
Settings: Cambodia, Côte d'Ivoire, Uganda, Vietnam. Design: Multicentre, two-arm, unblinded randomized controlled superiority trial. Objective: To compare the 24-week risk of death and occurrence of invasive bacterial infection between two experimental strategies in HIV-1 infected adults who start ART with a CD4 count \<100/mm3: (i) continuous extensive TB screening during follow-up each time the patient present with symptoms, versus (ii) systematic empirical TB treatment started 2 weeks before ART initiation. Trial strategies: At inclusion, participants will be randomized 1:1 in two strategies of TB testing and treatment: extensive TB screening, or systematic empirical TB treatment. Extensive TB screening (arm 1): In this arm: * TB screening point-of-care tests (Xpert MTB/RIF®, urine LAM) and chest X-ray will be used extensively at randomisation (in all patients) and during follow-up (in patients with signs or symptoms suggestive of TB); * Only patients who meet standardized criteria for TB at inclusion or during follow-up will receive a standard TB treatment (2ERHZ/4RH); * ART (tenofovir(TDF)-lamivudine (3TC)/emtricitabine(FTC) or zidovudine (AZT)-lamivudine+ efavirenz) will be started immediately after randomization in patients not put on TB treatment, and 2 weeks after initiation of TB treatment in others. Systematic empirical TB treatment (arm 2): In this arm: * TB screening point-of-care tests will not be used; * All patients will start a 6-month standard TB treatment (2ERHZ/4RH) at randomization; ART (tenofovir-lamivudine/emtricitabine or zidovudine-lamivudine+ efavirenz) will be started 2 weeks after TB treatment initiation. Both strategies will apply to the first 24 weeks in the trial (intervention period). From week-24 to week-48, the choice of TB tests and the prescription of TB treatment will be left upon the decision of the investigator in both trial arms. Inclusion time: 24 months. Follow-up: each patient will be followed 48 weeks. Statistical analysis: the primary analysis will be intention to treat. It will compare the 24-week probability of death or invasive bacterial infection between arms. Sample size: 1050 participants. This will allow demonstration of a 40% reduction in the 24-week probability of death or invasive bacterial infection in arm 2, compared to arm 1 (α 5%; 1-β 80%).
Interventions
DRUGRifampin, isoniazid, pyrazinamide, ethambutol
Arm 1: Only patients who meet standardized criteria for TB at inclusion or during follow-up will receive a standard TB treatment (2ERHZ/4RH); Arm 2: • All patients will start a 6-month standard TB treatment (2ERHZ/4RH) at randomization
DEVICEXpert MTB/RIF®, Determine TB LAM, Chest X-ray
The following point-of-care TB tests will be systematically performed: Xpert MTB/RIF® on sputum (in all patients able to provide sputum; no sputum induction will be requested in others), Urine LAM (all patients). Depending on clinical presentation, Xpert MTB/RIF® will also be performed on any relevant extra-pulmonary specimen. TB treatment will depend on the result of the tests: Criteria met for confirmed or probable TB : TB treatment will be initiated immediately (Visit 1) followed by ART initiation 2 weeks later (Visit 2); No evidence of confirmed or probable TB: ART will be started immediately (Visit 1).
DRUGART (Atripla, Truvada, Efavirenz, Combivir)
* ART (TDF-3TC/FTC or AZT-3TC + efavirenz) will be started immediately after randomization in patients not put on TB treatment, and 2 weeks after initiation of TB treatment in others. * ART will be initiated 2 weeks after the onset of TB treatment (V2) for Arm 2
Sponsors
ANRS, Emerging Infectious Diseases
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥18 years; * HIV-1 infection as documented at any time prior to trial entry, as per national testing procedures; * CD4 \<100 cells/mm3; * No history of antiretroviral drug use (except transient ART for PMTCT); * Able to correctly understand the trial and to sign the informed consent.
Exclusion criteria
* HIV-2 co-infection; * Contra-indication to efavirenz; * Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) \>5 times the upper limit of normal; * Creatinine clearance \<50 ml/min; * Overt evidence that TB treatment should be started immediately; * History of TB treatment in the past 5 years; * Ongoing TB chemoprophylaxis (isoniazid preventive therapy); * Any condition that would lead to differ ART initiation (e.g. acute condition requiring investigations and/or treatment prior to ART initiation); * Current pregnancy or breastfeeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| All-cause mortality and incidence of invasive bacterial infections | 24 weeks | The primary endpoint is the composite of (i) 24-week all-cause mortality and (ii) 24-week incidence of invasive bacterial infections |
Secondary
| Measure | Time frame |
|---|---|
| Incidence of confirmed/probable/possible TB | 24 Weeks and 48 weeks |
| Incidence of grade 3 or 4 adverse events | 24 Weeks and 48 weeks |
Other
| Measure | Time frame |
|---|---|
| Incidence of TB-associated IRIS | 24 Weeks and 48 Weeks |
| Incidence of AIDS-defining diseases other than TB | 24 Weeks and 48 Weeks |
Countries
Cambodia, Côte d’Ivoire, Uganda, Vietnam
Outcome results
None listed