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 Malawi (SaDAPT)
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Date
2022-06-06
Authors
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Journal ISSN
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Publisher
Kamuzu University of Health Sciences
Abstract
Sponsor-Investigator Prof. Dr. Niklaus Labhardt, MD, DTM&H, MIH
Swiss Tropical and Public Health Institute & University Hospital Basel
Study Title: Same-day versus rapid ART initiation in HIV-positive individuals presenting with symptoms of tuberculosis: an open-label, randomized, controlled clinical trial in Lesotho and Malawi
Short Title / Study ID: SaDAPT Trial (“Same-Day ART initiation in Presumptive TB”)
Protocol Version and Date: Version 2.0, 05.06.2022
Trial registration: Registration is planned on clinicaltrials.gov as soon as this version of the protocol has been approved by the Independent Ethics Committees (IECs)
Study category and Rationale
Risk category A. The SaDAPT trial entails the comparison of two different algorithms for the timing of ART initiation in people living with HIV (PLHIV) presenting with symptoms of a possible tuberculosis (TB) infection but no signs of central nervous system (CNS) disease. Both approaches are in line with current national or international guidelines.
Clinical Phase: Therapeutic use trial. 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.
Background and Rationale
HIV remains a major cause of morbidity and premature death in many sub-Saharan African countries including Lesotho and Malawi. Globally, 680’000 lives were lost in 2020 in association with HIV despite the availability of effective and low-cost antiretroviral therapy (ART).1 The most important opportunistic infection associated with HIV is TB, accounting for over 200’000 HIV-related deaths worldwide, mainly in low-income settings, where prevalence of HIV/TB-coinfection is highest.2 WHO recommends a four-symptom screening (W4SS) approach including cough, fever, night sweat and weight loss for clinical routine TB screening among PLHIV. 3–6 PLHIV presenting with at least one of the four symptoms are defined as having presumptive TB. The prevalence of presumptive TB among PLHIV not taking ART has been estimated at 71% in a systematic review.
4 An important approach to improve access to ART—and thereby reduce HIV transmission as well as AIDS related morbidity and mortality—is the implementation of rapid, and if possible same-day initiation (SDI) of ART.7 PLHIV with opportunistic infections may benefit particularly from rapid ART initiation and the subsequent suppression of HIV replication and reconstitution of CD4-cell mediated immunity. At the same time, they are at risk of developing immune reconstitution inflammatory syndrome (IRIS) after initiation of ART.8–10 The risk for development of IRIS increases with earlier initiation of ART.8,10–13 Until the release of a guideline update in 2021,3,14 WHO had recommended to delay initiation of ART in case of presumptive TB until TB has been investigated and TB treatment initiated if TB disease has been confirmed in order to reduce the risk of IRIS.15 The 2021 guideline update contains for the first time a “clinical consideration” to start ART in PLHIV with presumptive TB but no signs of central nervous system (CNS) disease while rapidly investigating for TB, thus allowing SDI for this subgroup of PLHIV. However, a systematic review on the effect of SDI for PLHIV with presumptive TB but no signs of CNS disease, that was conducted to inform this guideline update came to the conclusion that “there is insufficient evidence
about whether presence of TB symptoms should lead to ART start being deferred or not”.16 Accordingly, the guidelines emphasize the need for further research on the impact of SDI in PLHIV with presumptive TB on various health outcomes including mortality, HIV and TB outcomes, retention in care, adverse events and IRIS.14
Overall objective: To compare two approaches for the timing of ART initiation in PLHIV with presumptive TB but no signs of CNS disease (“ART first” versus “TB results first”) with regard to HIV viral suppression, engagement in care, serious adverse events (SAEs) and adverse events (AEs) consistent with TB-IRIS in a pragmatic randomized trial reflecting routine primary and secondary care setting in southern Africa.
Hypothesis For PLHIV with presumptive TB, but no signs of CNS disease, same day ART (“ART first”) is non-inferior to rapid ART (“TB results first”) for being retained in care with suppressed HIV viral load (VL) 26 weeks after enrolment.
Endpoints: Primary endpoint
- HIV viral suppression (VL <400 copies/mL) 26 (range 22 – 40) weeks after
enrolment
Secondary and safety endpoints
- Retention in care 26 (22 – 30) weeks after enrolment
- Engagement in care 26 (22 – 30) weeks after enrolment
- Disengagement from care 26 (22 – 30) weeks after enrolment
- Lost to follow-up 26 (22 – 30) weeks after enrolment
- Non-traumatic mortality, Serious Adverse Events (SAEs), and Adverse Events of
Special Interest (AESIs) during the first 30 weeks after enrolment
- Incidence of TB disease (microbiologically confirmed and/or clinical diagnosis)
during the first 30 weeks after enrolment
- HIV viral suppression at 26 (22 – 40) weeks using different thresholds (<20
copies/mL; <100 copies/mL; <1000 copies/mL)
- ART initiation within 7 and within 28 days after enrolment
Study design: Prospective, parallel, open-label, 1:1 individually randomized, non-inferiority trial
Inclusion / Exclusion criteria:
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 W4SS4
- 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 or TB preventive therapy (TPT)
ART initiators cohort In parallel to the the SaDAPT trial, we will observationally follow-up all PLHIV (re)initiating ART at the study sites in a prospective ART initiation cohort,
independent of whether they are eligible for participation in the SaDAPT trial.
Description
Keywords
Same-day versus rapid ART initiation in HIV-positive individuals presenting with symptoms of tuberculosis