Kiekens et al. BMC Public Health (2022) 22:455 https://doi.org/10.1186/s12889-022-12738-4 RESEARCH ARTICLE Exploring the mechanisms behind HIV drug resistance in sub-Saharan Africa: conceptual mapping of a complex adaptive system based on multi-disciplinary expert insights Anneleen Kiekens 1* , Bernadette Dierckx de Casterlé 2 , Giampietro Pellizzer 3 , Idda H. Mosha 4 , Fausta Mosha 5 , Tobias F. Rinke de Wit 6 , Raphael Z. Sangeda 7 , Alessio Surian 8 , Nico Vandaele 9 , Liesbet Vranken 10 , Japhet Killewo 11 , Michael Jordan 12,13,14 and Anne‑Mieke Vandamme 1,15 Abstract Background: HIV drug resistance (HIVDR) continues to threaten the efectiveness of worldwide antiretroviral therapy (ART). Emergence and transmission of HIVDR are driven by several interconnected factors. Though much has been done to uncover factors infuencing HIVDR, overall interconnectedness between these factors remains unclear and African policy makers encounter difculties setting priorities combating HIVDR. By viewing HIVDR as a complex adap‑ tive system, through the eyes of multi‑disciplinary HIVDR experts, we aimed to make a frst attempt to linking diferent infuencing factors and gaining a deeper understanding of the complexity of the system. Methods: We designed a detailed systems map of factors infuencing HIVDR based on semi‑structured interviews with 15 international HIVDR experts from or with experience in sub‑Saharan Africa, from diferent disciplinary back‑ grounds and afliated with diferent types of institutions. The resulting detailed system map was conceptualized into three main HIVDR feedback loops and further strengthened with literature evidence. Results: Factors infuencing HIVDR in sub‑Saharan Africa and their interactions were sorted in fve categories: biology, individual, social context, healthcare system and ‘overarching’. We identifed three causal loops cross‑cutting these layers, which relate to three interconnected subsystems of mechanisms infuencing HIVDR. The ‘adherence motivation’ subsystem concerns the interplay of factors infuencing people living with HIV to alternate between adherence and non‑adherence. The ‘healthcare burden’ subsystem is a reinforcing loop leading to an increase in HIVDR at local popu‑ lation level. The ‘ART overreliance’ subsystem is a balancing feedback loop leading to complacency among program managers when there is overreliance on ART with a perceived low risk to drug resistance. The three subsystems are interconnected at diferent levels. Conclusions: Interconnectedness of the three subsystems underlines the need to act on the entire system of factors surrounding HIVDR in sub‑Saharan Africa in order to target interventions and to prevent unwanted efects on other © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Open Access *Correspondence: Anneleen.kiekens@kuleuven.be 1 Department of Microbiology, Immunology and Transplantation, Clinical and Epidemiological Virology, Institute for the Future, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium Full list of author information is available at the end of the article