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

HIV-1 Infection Clinical Trial

— STATIS  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02057796
• Other study ID #: ANRS 12290
• Status: Completed
• Phase: Phase 4
• Start date: September 2014
• Est. completion date: April 2018

Study information

• Verified date: October 2020
• Source: French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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%).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1050
• Est. completion date: April 2018
• Est. primary completion date: April 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• HIV-1 Infection
• Tuberculosis

Intervention

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
• 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

Locations

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

Sponsors (1)

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

Countries where clinical trial is conducted

Cambodia,  Côte D'Ivoire,  Uganda,  Vietnam, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Incidence of TB-associated IRIS		24 Weeks and 48 Weeks
Other	Incidence of AIDS-defining diseases other than TB		24 Weeks and 48 Weeks
Primary	All-cause mortality and incidence of invasive bacterial infections	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	Incidence of confirmed/probable/possible TB		24 Weeks and 48 weeks
Secondary	Incidence of grade 3 or 4 adverse events		24 Weeks and 48 weeks