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

October 13, 2020 updated by: ANRS, Emerging Infectious Diseases

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

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.

Study Overview

Status

Completed

Conditions

Intervention / 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%).

Study Type

Interventional

Enrollment (Actual)

1050

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: PREVENTION
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
24 weeks

Secondary Outcome Measures

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

Other Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

September 1, 2014

Primary Completion (ACTUAL)

April 1, 2018

Study Completion (ACTUAL)

April 1, 2018

Study Registration Dates

First Submitted

February 5, 2014

First Submitted That Met QC Criteria

February 6, 2014

First Posted (ESTIMATE)

February 7, 2014

Study Record Updates

Last Update Posted (ACTUAL)

October 19, 2020

Last Update Submitted That Met QC Criteria

October 13, 2020

Last Verified

October 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ANRS 12290

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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