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

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

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

Swiss National Science Foundation, SolidarMed Lesotho, Kamuzu University of Health Sciences, Malawi, Swiss Tropical & Public Health Institute, Malawi-Liverpool-Wellcome Trust Clinical Research Programme, London School of Hygiene and Tropical Medicine

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.

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.

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)

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.

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.

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)

Engagement in care, defined as reporting regular ART intake, irrespective if a documented visit took place between 22 and 30 weeks after enrolment

TB-Immune reconstitution inflammatory syndrome (IRIS) is defined as Adverse event of special interest (AESIs): AESIs

Incidence of TB disease (microbiologically confirmed and/or clinical diagnosis), defined as any TB diagnosis after enrolment not classified as prevalent TB at enrolment

Prevalence of active TB, defined as TB diagnosed clinically or microbiologically through the TB investigations at enrolment

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