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: an Open-label Randomized Non-inferiority Trial in Lesotho and Blantyre District, Malawi

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Human Immunodeficiency Virus (HIV) Infection
• Intervention / Treatment: Other: ART first- Therapeutic use trial; Other: TB results first- Therapeutic use trial

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 611
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Niklaus Labhardt, Prof. Dr. DTM&H, MIH; Phone Number: +41 79 870 18 59; Email: Niklaus.Labhardt@usb.ch
• Study Contact Backup: Name: Felix Gerber, M Med; Email: felix.gerber@swisstph.ch

Study Locations

• Lesotho
  • Maseru, Lesotho
    • SolidarMed Lesotho, Premium House #224, Kingsway, Maseru West
• Malawi
  • Blantyre, Malawi
    • Kamuzu University of Health Sciences, Helse Nord Tuberculosis Initiative

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: "ART first" arm; ART initiation on the day of enrolment independent of TB investigations	Other: ART first- Therapeutic use trial; 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.
Active Comparator: "TB results first" arm; ART initiation only after active TB has been refuted or confirmed	Other: TB results first- Therapeutic use trial; 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.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevalence of active TB diagnosed at enrolment (exploratory endpoint)	Prevalence of active TB, defined as TB diagnosed clinically or microbiologically through the TB investigations at enrolment	up to a maximum of 28 days after enrolment

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Collaborators: London School of Hygiene and Tropical Medicine; Swiss National Science Foundation; Swiss Tropical & Public Health Institute; SolidarMed Lesotho; Malawi-Liverpool-Wellcome Trust Clinical Research Programme; Kamuzu University of Health Sciences, Malawi
• Investigators: Principal Investigator: Rachael Mary Burke, BMBCh, MSc, DTM&H, London School of Hygiene and Tropical Medicine; Principal Investigator: Niklaus Labhardt, Prof. Dr. DTM&H, MIH, Division of Clinical Epidemiology, University Hospital Basel

Study record dates

Study Major Dates

• Study Start (Actual): October 19, 2022
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: July 6, 2022
• First Submitted That Met QC Criteria: July 6, 2022
• First Posted (Actual): July 11, 2022

Study Record Updates

• Last Update Posted (Actual): March 8, 2024
• Last Update Submitted That Met QC Criteria: March 7, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: TB preventive treatment; Antiretroviral therapy (ART); Tuberculosis (TB) infection; Acquired immunodeficiency syndrome; Immune reconstitution inflammatory syndrome; People living with HIV (PLHIV); Same-day initiation (SDI) of ART; Sub-Saharan African countries; HIV/TB-coinfection; immune reconstitution inflammatory syndrome (IRIS)
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immune System Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Slow Virus Diseases; Urogenital Diseases; Genital Diseases; HIV Infections; Tuberculosis; Acquired Immunodeficiency Syndrome; Immunologic Deficiency Syndromes
• Other Study ID Numbers: AO_2022-00031; am22Labhardt

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No