Same-day Versus Rapid ART Initiation in HIV-positive Individuals Presenting With Symptoms of Tuberculosis

Study Overview
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Brief Summary
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SaDAPT is a pragmatic, randomized, therapeutic-use trial comparing two approaches (ART first versus TB results first) for the timing of ART initiation in PLHIV with presumptive TB, but no signs of central nervous system (CNS) disease, in a routine primary and secondary care setting in southern Africa with regard to HIV viral suppression (VL <400 copies/mL) 26 weeks after enrolment.

Detailed Description
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In this randomized controlled trial (RCT) two different, guideline-approved algorithms for antiretroviral therapy (ART) initiation in people living with HIV (PLHIV) with presumptive Tuberculosis (TB), but no signs of central nervous system (CNS) disease will be compared. In one arm, same-day initiation (SDI) of ART will be applied (ART first) for all participants independent of the status or results of initial TB investigations. In the other arm, an approach with deferral of ART initiation until TB is excluded or confirmed and TB treatment initiated will be applied (TB results first). The direct comparison of the two approaches in a pragmatic, two-country RCT conducted in a representative high-prevalence setting will provide evidence on the open question of optimal timing of ART initiation in the large subgroup of PLHIV with presumptive TB outside the CNS. Serum proteome sub- study: Prediction of clinical phenotypes in people living with HIV using the serum proteome. In a laboratory-based sub-study the plasma samples and clinical data collected as part of SaDAPT trial and ART initiation cohort at the study sites in Lesotho are used. The samples are screened for circulating inflammatory markers using proteomics in PLHIV with high risk of active TB and Immune reconstitution inflammatory syndrome (IRIS). The proteome will be deconvoluted using computational biology with the aim to develop diagnostics for active TB disease and predictors for IRIS.

Official Title
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Same-day Versus Rapid ART Initiation in HIV-positive Individuals Presenting With Symptoms of Tuberculosis: an Open-label Randomized Non-inferiority Trial in Lesotho and Blantyre District, Malawi

Conditions
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Human Immunodeficiency Virus (HIV) Infection

Intervention / Treatment
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* Other: ART first- Therapeutic use trial
* Other: TB results first- Therapeutic use trial


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 12 years or older HIV-positive Not taking ART (naïve or reported no ART intake since 90 days or more) Presenting with one or more TB symptoms according to W4SS Unknown TB status Planning to continue care at the study facility for at least 30 weeks Willing and able to consent (age 18 years or older) or assent with guardian consent (age 12 to 17 years) Exclusion Criteria: Medical condition requiring admission or referral to a higher level health facility at enrolment Symptoms or clinical signs suggestive for diseases of the CNS Positive cryptococcal antigen test (CrAg) Reporting to be pregnant Taking TB treatment, TB preventive therapy (TPT) or treatment against cryptococcal meningitis

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, parallel, open-label, 1:1 individually randomized, non-inferiority trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ART first arm<br>ART initiation on the day of enrolment independent of TB investigations | Other: ART first- Therapeutic use trial<br>* ART initiation on the day of enrolment independent of TB investigations in PLHIV with presumptive TB but no signs of CNS disease. The trial uses treatments and drug-doses as per international and national guidelines. All treatment components will be applied at standard dosage and no new substances or alternative indications will be tested.<br>|
| Active Comparator: TB results first arm<br>ART initiation only after active TB has been refuted or confirmed | Other: TB results first- Therapeutic use trial<br>* Deferral of ART initiation until active TB has been refuted or confirmed. PLHIV presenting with symptoms (cough, fever, night sweat, weight loss) are defined as presumptive TB, and should have microbiological TB investigations. Routine TB investigations in Malawi and Lesotho usually consist of two sputum bottles for analysis using nucleic acid amplification tests (Xpert MTB/RIF (Ultra)).The trial uses treatments and drug-doses as per international and national guidelines. All treatment components will be applied at standard dosage and no new substances or alternative indications will be tested.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HIV viral suppression <400 copies/mL | HIV viral suppression <400 copies/mL (obtained from routine laboratory reports at study facility, from laboratory reports of referral facility in case of transfer out, or from dried blood spot (DBS) sample for participants without documented clinic visit but found during home visit tracing) | 26 (22 - 40) weeks after enrolment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Retention in care | Retention in care, defined as a documented ART clinic visit between 22 and 30 weeks after enrolment | 26 (22 - 30) weeks after enrolment | 
| Engagement in care | Engagement in care, defined as reporting regular ART intake, irrespective if a documented visit took place between 22 and 30 weeks after enrolment | 26 (22 - 30) weeks after enrolment | 
| Disengagement from care | Disengagement from care, defined as non-engaged in care but reached through patient tracing | 26 (22 - 30) weeks after enrolment | 
| Lost to follow-up | Lost to follow-up, defined as non-retained in care and not reached through tracing | 26 (22 - 30) weeks after enrolment | 
| Non-traumatic mortality | Non-traumatic mortality | during the first 30 weeks after enrolment | 
| Serious adverse events (SAEs) | SAEs | during the first 30 weeks after enrolment | 
| TB-Immune reconstitution inflammatory syndrome (IRIS) | TB-Immune reconstitution inflammatory syndrome (IRIS) is defined as Adverse event of special interest (AESIs): AESIs | during the first 30 weeks after enrolment | 
| Incidence of TB disease (microbiologically confirmed and/or clinical diagnosis) | Incidence of TB disease (microbiologically confirmed and/or clinical diagnosis), defined as any TB diagnosis after enrolment not classified as prevalent TB at enrolment | during the first 30 weeks after enrolment | 
| HIV viral suppression | HIV viral suppression using different thresholds (<20 copies/mL; <100 copies/mL; <1000 copies/mL) | at 26 (22 - 40) weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tuberculosis (TB) infection, Acquired immunodeficiency syndrome, Antiretroviral therapy (ART), Immune reconstitution inflammatory syndrome, People living with HIV (PLHIV), Same-day initiation (SDI) of ART, TB preventive treatment, Sub-Saharan African countries, HIV/TB-coinfection, immune reconstitution inflammatory syndrome (IRIS)