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

NCT ID: NCT02057796

Last Updated: 2020-10-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 1050 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-09-30
• Study Completion Date: 2018-04-30

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%).

Conditions

HIV-1 Infection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

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

Intervention Type: DEVICE

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).

ART (Atripla, Truvada, Efavirenz, Combivir)

Intervention Type: DRUG

• 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

Rifampin, isoniazid, pyrazinamide, ethambutol

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

ART (Atripla, Truvada, Efavirenz, Combivir)

Intervention Type: DRUG

• 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

Rifampin, isoniazid, pyrazinamide, ethambutol

Intervention Type: DRUG

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

Interventions

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).

Intervention Type: DEVICE

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

Intervention Type: 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

Intervention Type: DRUG

Other Intervention Names

ART; Systematic Empiric treatment

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

ANRS, Emerging Infectious Diseases

OTHER_GOV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

François-Xavier Blanc, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Université de Nantes, Institut du thorax, CHU Nantes, France

Kouao Médard Serge Domoua, MD

Role: PRINCIPAL_INVESTIGATOR

Service de Pneumologie, CHU de Treichville, Abidjan, Côte d'Ivoire

Locations

Sihanouk Hospital Center of Hope

Phnom Penh, , Cambodia

CePReF Centre de Prise en charge de Recherche et de Formation

Abidjan, Yopougon, Côte d’Ivoire

ISS ImmunoSuppression Service

Mbarara, , Uganda

Pham Ngoc Thach Hospital

Ho Chi Minh City, , Vietnam

Countries

Cambodia; Côte d’Ivoire; Uganda; Vietnam

References

Bonnet M, Gabillard D, Domoua S, Muzoora C, Messou E, Sovannarith S, Nguyen DB, Badje A, Juchet S, Bunnet D, Borand L, Natukunda N, Tran TH, Anglaret X, Laureillard D, Blanc FX; Systematic empirical vs. Test-guided Anti-tuberculosis Treatment Impact in Severely immunosuppressed HIV-infected adults initiating antiretroviral therapy with CD4 cell counts <100/mm3 (STATIS) Agence Nationale de Recherche sur le Sida et les hepatites virales (ANRS) 12290 Trial Team. High Performance of Systematic Combined Urine Liboarabinomannan Test and Sputum Xpert MTB/RIF for Tuberculosis Screening in Severely Immunosuppressed Ambulatory Adults With Human Immunodeficiency Virus. Clin Infect Dis. 2023 Jul 5;77(1):112-119. doi: 10.1093/cid/ciad125.

Reference Type: DERIVED

PMID: 36883573 (View on PubMed)

Blanc FX, Badje AD, Bonnet M, Gabillard D, Messou E, Muzoora C, Samreth S, Nguyen BD, Borand L, Domergue A, Rapoud D, Natukunda N, Thai S, Juchet S, Eholie SP, Lawn SD, Domoua SK, Anglaret X, Laureillard D; STATIS ANRS 12290 Trial Team. Systematic or Test-Guided Treatment for Tuberculosis in HIV-Infected Adults. N Engl J Med. 2020 Jun 18;382(25):2397-2410. doi: 10.1056/NEJMoa1910708.

Reference Type: DERIVED

PMID: 32558469 (View on PubMed)

Provided Documents

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

ANRS 12290

Identifier Type: -

Identifier Source: org_study_id