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

Purpose

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.

Condition	Intervention	Phase
HIV-1 Infection	Device: Xpert MTB/RIF®, Determine TB LAM, Chest X-ray Drug: ART (Atripla, Truvada, Efavirenz, Combivir) Drug: Rifampin, isoniazid, pyrazinamide, ethambutol	Phase 4


Study Type:	Interventional
Study Design:	Allocation: Randomized Intervention Model: Parallel Assignment Masking: None (Open Label) Primary Purpose: Prevention
Official Title:	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

Resource links provided by NLM:

MedlinePlus related topics: HIV/AIDS

Drug Information available for: Pyrazinamide

Genetic and Rare Diseases Information Center resources: Tuberculosis

U.S. FDA Resources

Further study details as provided by French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS):

Primary Outcome Measures:

All-cause mortality and incidence of invasive bacterial infections [ Time Frame: 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 Outcome Measures:

Incidence of confirmed/probable/possible TB [ Time Frame: 24 Weeks and 48 weeks ]
Incidence of grade 3 or 4 adverse events [ Time Frame: 24 Weeks and 48 weeks ]

Other Outcome Measures:

Incidence of TB-associated IRIS [ Time Frame: 24 Weeks and 48 Weeks ]
Incidence of AIDS-defining diseases other than TB [ Time Frame: 24 Weeks and 48 Weeks ]


Estimated Enrollment:	1050
Actual Study Start Date:	September 2014
Estimated Study Completion Date:	June 2018
Estimated Primary Completion Date:	November 2017 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Xpert MTB/RIF®, Determine TB LAM, Chest X-ray 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 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). Drug: ART (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 Other Name: ART Drug: Rifampin, 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 Other Name: Systematic Empiric treatment
Experimental: Rifampin, isoniazid, pyrazinamide, ethambutol 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) 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 Other Name: ART Drug: Rifampin, 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 Other Name: Systematic Empiric treatment

Arms

Assigned Interventions

Experimental: Xpert MTB/RIF®, Determine TB LAM, Chest X-ray

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

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).

Drug: ART (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

Other Name: ART

Drug: Rifampin, 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

Other Name: Systematic Empiric treatment

Experimental: Rifampin, isoniazid, pyrazinamide, ethambutol

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)

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

Other Name: ART

Drug: Rifampin, 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

Other Name: Systematic Empiric treatment

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%).

Eligibility

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02057796

Locations


Cambodia
Sihanouk Hospital Center of Hope
Phnom Penh, Cambodia, 2318
Côte D'Ivoire
CePReF Centre de Prise en charge de Recherche et de Formation
Abidjan, Yopougon, Côte D'Ivoire, 1954
Uganda
ISS ImmunoSuppression Service
Mbarara, Uganda, 1956
Vietnam
Pham Ngoc Thach Hospital
Ho Chi Minh City, Vietnam

Sponsors and Collaborators

French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)

Investigators


Principal Investigator:	François-Xavier Blanc, MD, PhD	Université de Nantes, Institut du thorax, CHU Nantes, France
Principal Investigator:	Kouao Médard Serge Domoua, MD	Service de Pneumologie, CHU de Treichville, Abidjan, Côte d'Ivoire

More Information


Responsible Party:	French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
ClinicalTrials.gov Identifier:	NCT02057796 History of Changes
Other Study ID Numbers:	ANRS 12290
First Submitted:	February 5, 2014
First Posted:	February 7, 2014
Last Update Posted:	July 12, 2017
Last Verified:	July 2017

Keywords provided by French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS):


HIV-1 Tuberculosis Systematic empiric TB treatment ART	TB diagnosis Xpert MTB/RIF® Urine LAM

Additional relevant MeSH terms:


Efavirenz Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination Lamivudine, zidovudine drug combination Rifampin Isoniazid Pyrazinamide Ethambutol Reverse Transcriptase Inhibitors Nucleic Acid Synthesis Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Anti-Retroviral Agents Antiviral Agents Anti-Infective Agents Cytochrome P-450 CYP2C9 Inhibitors	Cytochrome P-450 Enzyme Inhibitors Cytochrome P-450 CYP2C19 Inhibitors Cytochrome P-450 CYP2B6 Inducers Cytochrome P-450 Enzyme Inducers Cytochrome P-450 CYP3A Inducers Antibiotics, Antitubercular Antitubercular Agents Anti-Bacterial Agents Leprostatic Agents Cytochrome P-450 CYP2C8 Inducers Cytochrome P-450 CYP2C19 Inducers Cytochrome P-450 CYP2C9 Inducers Fatty Acid Synthesis Inhibitors Hypolipidemic Agents Antimetabolites

Efavirenz
Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
Lamivudine, zidovudine drug combination
Rifampin
Isoniazid
Pyrazinamide
Ethambutol
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP2C9 Inhibitors

Cytochrome P-450 Enzyme Inhibitors
Cytochrome P-450 CYP2C19 Inhibitors
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP3A Inducers
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Leprostatic Agents
Cytochrome P-450 CYP2C8 Inducers
Cytochrome P-450 CYP2C19 Inducers
Cytochrome P-450 CYP2C9 Inducers
Fatty Acid Synthesis Inhibitors
Hypolipidemic Agents
Antimetabolites

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