[FG] Labhardt Niklaus

SaDAPT is a randomized controlled trial in Lesotho and Malawi investigating when to start antiretroviral therapy in persons testing positive for HIV and simultaneously showing symptoms of a possible TB infection.

Rapid, if possible same-day initiation (SDI) of antiretroviral therapy (ART) is recommended for all persons living with HIV (PLHIV) without contraindication who are ready to start treatment. A possible contraindication to initiating ART is the presence of an untreated tuberculosis (TB) infection as it increases the risk of TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) after ART initiation. In case of TB symptoms (presumptive TB), previous guidelines recommended to postpone ART initiation until investigations for active TB infection have been completed to avoid initiating ART in presence of untreated TB and thus reduce the risk of TB-IRIS. However, the 2021 guidelines of the World Health Organization (WHO) changed to recommending rapid or SDI even in case of TB symptoms without awaiting results of TB diagnostic tests based on the assumption that TB tests often unnecessarily delay ART initiation increasing the risk for pre-ART attrition from care while the clinical relevance of TB-IRIS outside the central nervous system remains unclear. To date, there is no conclusive evidence about whether SDI of ART or TB test results should be prioritized in PLHIV with presumptive TB.

SaDAPT is a two arm, individually randomized, pragmatic trial comparing two approaches for the timing of ART initiation in PLHIV with presumptive TB (“ART first” versus “TB results first”). PLHIV in Lesotho and Malawi, aged 12 years and older (re)initiating ART who have at least one of TB symptom (cough, fever, night sweats or weight loss) and who do not have signs of meningitis are eligible. Participants in the “ART first” arm will be offered SDI of ART while those in the “TB results first” arm will be offered ART only after results of TB tests are available.

We hypothesize that the “ART first” approach is safe and non-inferior to the “TB results first” approach with regard to HIV viral suppression (<400 copies/ml) six months after enrollment. Secondary outcomes include retention in care and adverse events consistent with TB-IRIS.

Improving the HIV care cascade in Lesotho: Towards 90-90-90 - A research collaboration with the Ministry of Health

Background: Despite enormous progress in the last decade, HIV/AIDS remains the most important cause of morbidity and mortality in most countries of Southern Africa and a central contributor to economic underdevelopment and poverty in many societies. The 2014 UNAIDS "90-90-90" targets for 2020 represent an important step towards an AIDS-free generation by 2030. The targets emphasize the importance of antiretroviral therapy (ART) to prolong the life of people living with HIV and as the most effective preventative measure for reducing the spread of new infections through better virus control. The three key targets of "90-90-90" are: - 90% of all people living with HIV will know their HIV status. - 90% of all people with diagnosed HIV infection receive treatment. - 90% of all people receiving therapy will have their virus suppressed.

This project represents a collaboration between the Research Coordination Unit (RCU) of the Ministry of Health (MoH) of Lesotho, the District Health Management Team (DHMT) of Butha-Buthe, SolidarMed (Lesotho-based Swiss organization for health in Africa), the Swiss Tropical and Public Health Institute (SwissTPH) and the Molecular Virology unit at the Department of Biomedicine (DBM) of the University of Basel. The project combines epidemiological, operational and clinical research to address key questions related to reaching 90-90-90 targets in rural Lesotho, a country with the second-highest HIV prevalence in the world, high transmission rates and low ART coverage.

Methods: The proposed project is planned in Butha-Buthe district, Northern Lesotho, involving 2 hospitals and 10 health centers. As a crucial first step, the project has established the technical basis for the intended studies. As part of Lesotho's national viral load (VL) roll-out plan, the country's first decentralized VL monitoring platform was installed in the district laboratory of Butha-Buthe by the end of October 2015. Two randomized controlled trials (RCTs) and additional observational studies are planned within the proposed project.

RCT-1 (CASCADE-trial; NCT02692027, www.visibleimpact.org/projects/1197-cascade-trial) addresses the care-cascade from HIV-test to linkage to care to retention in care and achievement of viral suppression in the era of test-and-treat. Individuals who are newly tested HIV-positive during home-based HIV testing and counseling (HTC) are randomized into 2 groups. The control group provides standard of care with post-test counseling and a referral letter for enrolment in pre-ART care at the nearest facility. In the intervention-group, baseline laboratory testing and adherence counseling is provided after a positive HIV test at the participant's home with the option to start ART on the same day. The first primary endpoint is linkage to care at the facility within 3 months. The secondary endpoint is retention in care and viral suppression 12 months after HIV diagnosis. This trial has two nested observational studies. The first examines HTC-coverage achieved through home-based HTC while recruiting trial-participants. The second examines glucose- and lipid-profiles pre-ART and after ART initiation.

RCT-2 (SAVIR-trial): A culturally adapted, short, standardized adherence intervention for patients on ART with unsuppressed VL will be rolled out to the facilities in the district using a step-wedged design with the primary endpoint of VL re-suppression at follow-up determination. Establishing routine viral load monitoring will be linked to a database, a plasma-bank and introduction of genotypic sequencing in the district. This will allow observational studies on roll-out of viral load monitoring, treatment failure, switch to second-line ART and HIV resistance. Based on these observational data, a protocol for a third RCT will be elaborated by end of 2016. This RCT will address challenges identified in the field of treatment failure and switch to second-line ART.