The HIV epidemic has dramatically changed over the past 30 years; there are now fewer newly infected people (especially children), fewer AIDS-related deaths, and more people with HIV (PWH) receiving treatment. However, the HIV epidemic is far from over. Despite the tremendous advances in anti-retroviral therapies (ART) and the implementation of ART regimens, HIV incidence (number of new infections over a defined period of time) and prevalence (the burden of HIV infection) in certain regions of the world and socio-economic groups are still on the rise. HIV continues to disproportionally affect highly marginalized populations that constitute higher-risk and stigmatized groups, underserved and/or neglected populations. In addition, it is not uncommon for PWH to suffer enhanced debilitating conditions resulting from the synergistic interactions of both communicable diseases (CDs) and non-communicable diseases (NCDs). While research utilizing only a comorbidities framework has advanced our understanding of the biological settings of the co-occurring conditions from a molecular and mechanistic view, harmful interactions between comorbidities are often overlooked, particularly under adverse socio-economical and behavioral circumstances, likely prompting disease clustering in PWH. Synergistic epidemics (syndemics) research aims to capture these understudied interactions: the mainly non-biological aspects that are central to interpret disease clustering in the comorbidities/multi-morbidities only framework. Connecting population-level clustering of social and health problems through syndemic interventions has proved to be a critical knowledge gap that will need to be addressed in order to improve prevention and care strategies and bring us a step closer to ending the HIV epidemic.