Systematic Empirical vs. Test-guided Anti-TB Treatment Impact in Severely Immunosuppressed HIV-infected Adults Initiating ART With CD4 Cell Counts <100/mm3 (STATIS)
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| ClinicalTrials.gov Identifier: NCT02057796 |
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Recruitment Status
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Active, not recruiting
First Posted
: February 7, 2014
Last Update Posted
: July 12, 2017
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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 |
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 (Clinical Trial) |
| Estimated 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 : | September 2014 |
| Estimated Primary Completion Date : | November 2017 |
| Estimated Study Completion Date : | June 2018 |
| Arm | Intervention/treatment |
|---|---|
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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).
Other Name: 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 Name: Systematic Empiric treatment
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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 Name: 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 Name: Systematic Empiric treatment
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- 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
- Incidence of confirmed/probable/possible TB [ Time Frame: 24 Weeks and 48 weeks ]
- Incidence of grade 3 or 4 adverse events [ Time Frame: 24 Weeks and 48 weeks ]
- Incidence of TB-associated IRIS [ Time Frame: 24 Weeks and 48 Weeks ]
- Incidence of AIDS-defining diseases other than TB [ Time Frame: 24 Weeks and 48 Weeks ]
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| Ages Eligible for Study: | 18 Years and older (Adult, Senior) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02057796
| Cambodia | |
| Sihanouk Hospital Center of Hope | |
| Phnom Penh, Cambodia, 2318 | |
| Côte D'Ivoire | |
| CePReF Centre de Prise en charge de Recherche et de Formation | |
| Abidjan, Yopougon, Côte D'Ivoire, 1954 | |
| Uganda | |
| ISS ImmunoSuppression Service | |
| Mbarara, Uganda, 1956 | |
| Vietnam | |
| Pham Ngoc Thach Hospital | |
| Ho Chi Minh City, Vietnam | |
| 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 |
| Responsible Party: | French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS) |
| ClinicalTrials.gov Identifier: | NCT02057796 History of Changes |
| Other Study ID Numbers: |
ANRS 12290 |
| First Posted: | February 7, 2014 Key Record Dates |
| Last Update Posted: | July 12, 2017 |
| Last Verified: | July 2017 |
Keywords provided by French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS):
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HIV-1 Tuberculosis Systematic empiric TB treatment ART |
TB diagnosis Xpert MTB/RIF® Urine LAM |
Additional relevant MeSH terms:
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Efavirenz Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination Lamivudine, zidovudine drug combination Rifampin Isoniazid Pyrazinamide Ethambutol Reverse Transcriptase Inhibitors Nucleic Acid Synthesis Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Anti-Retroviral Agents Antiviral Agents Anti-Infective Agents Cytochrome P-450 CYP2C9 Inhibitors |
Cytochrome P-450 Enzyme Inhibitors Cytochrome P-450 CYP2C19 Inhibitors Cytochrome P-450 CYP2B6 Inducers Cytochrome P-450 Enzyme Inducers Cytochrome P-450 CYP3A Inducers Antibiotics, Antitubercular Antitubercular Agents Anti-Bacterial Agents Leprostatic Agents Cytochrome P-450 CYP2C8 Inducers Cytochrome P-450 CYP2C19 Inducers Cytochrome P-450 CYP2C9 Inducers Fatty Acid Synthesis Inhibitors Hypolipidemic Agents Antimetabolites |