Clinical trial NCT02057796: Systematic Empirical vs. Test-guided Anti-TB Treatment Impact in Severely Immunosuppressed HIV-infected Adults Initiating ART With CD4 Cell Counts <100/mm3
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV-1 Infection
Keywords: HIV-1
Tuberculosis
Systematic empiric TB treatment
ART
TB diagnosis
Xpert MTB/RIF®
Urine LAM
Lead sponsor: ANRS, Emerging Infectious Diseases
Sponsor class: OTHER_GOV
First posted: 2014-02-07
Enrollment: 1050
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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%).

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.

Primary outcomes:
measure: All-cause mortality and incidence of invasive bacterial infections
timeFrame: 24 weeks
Secondary outcomes:
measure: Incidence of confirmed/probable/possible TB
timeFrame: 24 Weeks and 48 weeks
measure: Incidence of grade 3 or 4 adverse events
timeFrame: 24 Weeks and 48 weeks
Other outcomes:
measure: Incidence of TB-associated IRIS
timeFrame: 24 Weeks and 48 Weeks
measure: Incidence of AIDS-defining diseases other than TB
timeFrame: 24 Weeks and 48 Weeks
Locations:
city: Phnom Penh
country: Cambodia
facility: Sihanouk Hospital Center of Hope
city: Abidjan
country: Côte D'Ivoire
facility: CePReF Centre de Prise en charge de Recherche et de Formation
state: Yopougon
city: Mbarara
country: Uganda
facility: ISS ImmunoSuppression Service
city: Ho Chi Minh City
country: Vietnam
facility: Pham Ngoc Thach Hospital
Study officials:
affiliation: Université de Nantes, Institut du thorax, CHU Nantes, France
name: François-Xavier Blanc, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Service de Pneumologie, CHU de Treichville, Abidjan, Côte d'Ivoire
name: Kouao Médard Serge Domoua, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.