Weight Gain After HIV Therapy Initiation: Pathophysiology and Implications

Abstract

Rapid advances in potency, safety, and availability of modern HIV antiretroviral therapy (ART) have yielded a near-normal life expectancy for most people living with HIV (PLWH). Ironically, considering the history of HIV/AIDS (initially called “slim disease” due to associated weight loss), the latest dilemma faced by many people starting HIV therapy is weight gain and obesity, particularly Black people, women, and those who commenced treatment with advanced immunodeficiency. We review the pathophysiology and implications of weight gain among PLWH on ART and discuss why this phenomenon was only recognized recently, despite the availability of effective therapy for nearly 30 years. We comprehensively explore the theories of the causes, from initial speculation that weight gain was simply a return to health for people recovering from wasting to comparative effects of newer regimens versus prior toxic agents, to direct effects of agents on mitochondrial function. We then discuss the implications of weight gain on modern ART, particularly concomitant effects on lipids, glucose metabolism, and inflammatory markers. Finally, we discuss intervention options for PLWH and obesity, from the limitations of switching ART regimens or specific agents within regimens, weight-gain mitigation strategies, and potential hope in access to emerging anti-obesity agents, which are yet to be evaluated in this population.

Exercise to Prevent Accelerated Vascular Aging in People Living With HIV

“…248,249 However, older nucleoside reverses transcriptase inhibitors (eg, abacavir, zidovudine, and lamivudine) and the non-nucleoside inhibitor efavirenz may increase CVD risk, although associations between these specific drugs and CVD risk is also inconsistent across studies. 116,123,248,[250][251][252][253] Moreover, contemporary ART drugs such as tenofovir and integrase strand transfer inhibitors cause significant fat mass gain, particularly among women, 254,255 and although the degree to which this contributes to long-term CVD risk is presently unclear, 253,256 modeling studies predict an increase in CVD risk. 257 The protease inhibitors such as ritonavir-boosted darunavir, lopinavir, and atazanavir are largely considered to be the most cardiotoxic, causing hyperlipidemia, insulin resistance, oxidative stress, and cellular senescence that together contribute to increased CVD risk with long-term use.…”

Expanding the human gut microbiome atlas of Africa

“…In turn, HIV infection can diminish epithelial barrier integrity 58 , allowing for microbial translocation that promotes immune activation and chronic inflammation 59,60 . Moreover, obesity has become a major problem for individuals on the latest generation of ART such as dolutegrevir 61 . Very few studies have measured associations between the gut microbiome and HIV status in African populations 13,[62][63][64] , where baseline microbiome composition and disease profiles are distinct from those observed in HICs.…”

Intersections between HIV and obesity in emerging economies

“…Current cardiovascular disease risk calculators underestimate the risk in PWH because they fail to take this into account [19,20]. Noncommunicable diseases including cardiovascular conditions are now also leading causes of mortality for PWH, threatening the near-normal life expectancy that PWH should otherwise experience with effective ART [21 ▪▪ ,22]. However, caution is needed when applying this narrative in some emerging economy settings.…”

“…The relative impact of ART exposure as an independent driver of weight change is therefore a pertinent and dynamic field of investigation [21 ▪▪ ]. Pharmaceutical manufacturers have much to lose if newer ART drugs under patent monopoly prices are identified as causing obesity.…”