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

Sponsor

ANRS, Emerging Infectious Diseases (Other)

Overall Status

Completed

CT.gov ID

NCT02057796

Collaborator

(none)

1,050

Enrollment

Locations

Arms

Actual Duration (Months)

262.5

Patients Per Site

6.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	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

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%).

Study Design

Study Type:

Interventional

Actual Enrollment :

1050 participants

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

Actual Study Start Date :

Sep 1, 2014

Actual Primary Completion Date :

Apr 1, 2018

Actual Study Completion Date :

Apr 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
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 Names: 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 Names: 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 Names: 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 Names: Systematic Empiric treatment

Arm

Intervention/Treatment

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 Names:

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 Names:

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)

Other Names:

ART

Drug: Rifampin, isoniazid, pyrazinamide, ethambutol

Other Names:

Systematic Empiric treatment

Outcome Measures

Primary Outcome Measures

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 Outcome Measures

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 Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	Sihanouk Hospital Center of Hope	Phnom Penh		Cambodia	2318
2	CePReF Centre de Prise en charge de Recherche et de Formation	Abidjan	Yopougon	Côte D'Ivoire	1954
3	ISS ImmunoSuppression Service	Mbarara		Uganda	1956
4	Pham Ngoc Thach Hospital	Ho Chi Minh City		Vietnam

Sponsors and Collaborators

ANRS, Emerging Infectious Diseases

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