Metabolic complications in people living with HIV: the role of obesity, inflammation, lipid metabolism, and directions for future interventions

Cardiometabolic comorbidities constitute a substantial health burden for people living with HIV (PLWH) in the modern antiretroviral treatment (ART) era. Prevalence of obesity, defined as a body mass index (BMI) ≥30 kg/m2, is rising in PLWH, as a consequence of multiple factors, including weight gain associated with ART, traditional risk factors, and virus-induced alterations in adipose tissue biology and metabolism. Both obesity and HIV infection are characterized by a state of persistent inflammation, which ultimately contributes to the development of non-AIDS related comorbidities in PLWH. The specific aspects of the interaction between obesity and HIV on the immune system, as well as the clinical implications, are poorly understood. This PhD thesis aimed at increasing our understanding of the following key aspects of metabolic health in PLWH: The epidemiology of and risk factors of obesity in PLWH: PLWH in Ireland and England have a lower prevalence of obesity than HIV-negative controls, but obesity was associated with a substantial burden of co-morbidities in PLWH, especially in terms of cardiovascular disease (CVD), hypertension, and diabetes. Factors associated with obesity in PLWH include female sex, black African ethnicity, and older age. Pathogenesis of inflammation in obesity and HIV: Pathogenesis of obesity and its associated inflammation derives from disturbances in adipose tissue immune function, which is characterised mostly by alterations in T-cell and macrophage activation, with a switch to pro-inflammatory immune phenotype and resulting increases in pro-inflammatory chemokines, which contribute to the development of metabolic syndrome. There is a lack of human studies looking at adipose tissue inflammation in PLWH and of the specific pathways associated with inflammation in PLWH. Identification of specific pathways of inflammation in PLWH with obesity: obesity in PLWH was associated with activation of systemic inflammatory, endothelial, atherosclerosis and coagulation pathways, rather than those linked with innate immune activation and gut microbial translocation. These associations suggest an unfavourable cardiovascular profile in PLWH with obesity, with a potential impact on clinical outcomes, which will have to be explored in further research. Characterisation of lipid and body composition abnormalities in PLWH on modern ART: PLWH from a contemporary cohort had lower pro-atherogenic lipid parameters compared to HIV-negative controls, suggesting the possible influence of older ART on previously reported lipid abnormalities. There were also no differences in body composition parameters between PLWH and controls. These findings suggest that traditional risk factors for CVD might not explain the higher incidence of cardiac events in PLWH, which might be influenced by HIV-related factors, such as inflammation. Assessment of the effect of pharmaceutical weight loss strategies in PLWH: the SWIFT study was designed to assess the impact of pharmaceutical interventions for weight loss in PLWH. The primary objective was to assess for the first time the efficacy of semaglutide as an adjunct to diet and exercise in achieving greater weight loss in obese PLWH as compared to diet and exercise alone. The secondary objectives were to explore the effect of semaglutide on the following outcomes: markers of immune function and HIV viral reservoirs; markers of glucose and lipid metabolism; markers of inflammation and gut microbial translocation. In conclusion, the results of this thesis add to the current body of literature and fill some of the research gaps on metabolic health in PLWH, setting the way to explore the impact of specific interventions not only on metabolic health, but also on immune activation and quality of life in PLWH.