Systematic Empirical vs. Test-guided Anti-TB Treatment Impact in Severely Immunosuppressed HIV-infected Adults Initiating ART With CD4 Cell Counts <100/mm3
- Conditions
- HIV-1 Infection
- Interventions
- Device: Xpert MTB/RIF®, Determine TB LAM, Chest X-rayDrug: ART (Atripla, Truvada, Efavirenz, Combivir)Drug: Rifampin, isoniazid, pyrazinamide, ethambutol
- Registration Number
- NCT02057796
- Lead Sponsor
- ANRS, Emerging Infectious Diseases
- 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%).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 1050
- 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.
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Xpert MTB/RIF®, Determine TB LAM, Chest X-ray ART (Atripla, Truvada, Efavirenz, Combivir) 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 Rifampin, isoniazid, pyrazinamide, ethambutol ART (Atripla, Truvada, Efavirenz, Combivir) 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. Xpert MTB/RIF®, Determine TB LAM, Chest X-ray 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 Xpert MTB/RIF®, Determine TB LAM, Chest X-ray Rifampin, isoniazid, pyrazinamide, ethambutol 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 Rifampin, isoniazid, pyrazinamide, ethambutol 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.
- Primary Outcome Measures
Name Time Method All-cause mortality and incidence of invasive bacterial infections 24 weeks The primary endpoint is the composite of (i) 24-week all-cause mortality and (ii) 24-week incidence of invasive bacterial infections
- Secondary Outcome Measures
Name Time Method Incidence of confirmed/probable/possible TB 24 Weeks and 48 weeks Incidence of grade 3 or 4 adverse events 24 Weeks and 48 weeks
Trial Locations
- Locations (4)
Pham Ngoc Thach Hospital
🇻🇳Ho Chi Minh City, Vietnam
Sihanouk Hospital Center of Hope
🇰🇭Phnom Penh, Cambodia
ISS ImmunoSuppression Service
🇺🇬Mbarara, Uganda
CePReF Centre de Prise en charge de Recherche et de Formation
🇨🇮Abidjan, Yopougon, Côte D'Ivoire