Systematic Empirical vs. Test-guided Anti-TB Treatment Impact in Severely Immunosuppressed HIV-infected Adults Initiating ART With CD4 Cell Counts <100/mm3

Study Overview
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Brief Summary
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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
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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%).

Official Title
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Systematic Empirical vs. Test-guided Anti-tuberculosis Treatment Impact in Severely Immunosuppressed HIV-infected Adults Initiating Antiretroviral Therapy With CD4 Cell Counts <100/mm3: the STATIS Randomized Controlled Trial

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Device: Xpert MTB/RIF®, Determine TB LAM, Chest X-ray
* Drug: ART (Atripla, Truvada, Efavirenz, Combivir)
* Drug: Rifampin, isoniazid, pyrazinamide, ethambutol


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Xpert MTB/RIF®, Determine TB LAM, Chest X-ray<br>Arm1 Extensive TB screening: In this arm, point-of-care tests for TB will be used at randomization (in all patients) and at each scheduled or unscheduled follow-up visit (in patients with signs or symptoms suggestive of TB and no clear alternative diagnosis); TB treatment will only be prescribed to patients with a diagnosis of TB | Device: Xpert MTB/RIF®, Determine TB LAM, Chest X-ray<br>* 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).<br>Drug: ART (Atripla, Truvada, Efavirenz, Combivir)<br>* 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<br>* Other names: ART;Drug: Rifampin, isoniazid, pyrazinamide, ethambutol<br>* 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<br>* Other names: Systematic Empiric treatment;|
| Experimental: Rifampin, isoniazid, pyrazinamide, ethambutol<br>Arm 2: Systematic Empiric treatment (Rifampicin,isoniazid, pyrazinamide, ethambutol) ART In this arm, all patients will start a systematic 6-month TB treatment at randomization. TB screening tests will not systematically be used neither at randomization nor while patients are on TB treatment. | Drug: ART (Atripla, Truvada, Efavirenz, Combivir)<br>* 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<br>* Other names: ART;Drug: Rifampin, isoniazid, pyrazinamide, ethambutol<br>* 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<br>* Other names: Systematic Empiric treatment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality and incidence of invasive bacterial infections | The primary endpoint is the composite of (i) 24-week all-cause mortality and (ii) 24-week incidence of invasive bacterial infections | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV-1, Tuberculosis, Systematic empiric TB treatment, ART, TB diagnosis, Xpert MTB/RIF®, Urine LAM