Since the beginning of the antiretroviral therapy (ART) era, its extraordinary effect in terms of morbidity and mortality has been linked to a three-drug combination HIV treatment strategy, which has been perceived as a constant paradigm for many years. However, epidemiological studies over the past decade have clearly shown that ART does not result in complete normalization of all biomarkers, and some degree of systemic immune activation and inflammation, including endothelial dysfunction, persist. It is generally accepted that these pathophysiological processes are the cause of non-AIDS diseases, which are clinically manifested in people living with HIV on average 10 years earlier than in the general HIV-negative population. HIV treatment is not eradicative but only inhibitive and requires regular daily medication. This increases the risk of the cumulative impact of side effects and drug toxicity. In addition, it is expected that there will be a significant increase in the number of patients with various other non-AIDS comorbidities that will require multiple medication in the coming years. In particular, the higher genetic barrier of the new generation of drugs and an improved safety profile have raised the question of the effectiveness of two-drug combination regimens with the fundamental goal of reducing the burden on the human body by different drugs while maintaining high efficacy fully comparable to the current three-drug combination strategy. However, the question of whether dual combination regimens can sufficiently suppress the persistence of chronic inflammation and immune activation remains unanswered. To answer such a question, robust data from large prospective randomized studies are needed, which are still lacking. This review discusses the principle of systemic immune activation, its regenerative potential in ART, the expected causes leading to systemic immune activation, intervention options to influence it, as well as the limitations of studies to date.