Since the introduction of combined antiretroviral therapy (cART) and more effective treatments for AIDS, there has been a dramatic shift from the weight loss and wasting that characterised HIV/AIDS (and still does in countries where cART is not readily available or is initiated late) to healthy weight, or even overweight and obesity at rates mirroring those seen in the general population. These trends are attributable to several factors, including the “return to health” weight gain with reversal of the catabolic effects of HIV-infection following cART-initiation, strategies for earlier cART-initiation in the course of HIV-infection which have prevented many people living with HIV-infection from developing wasting, in addition to exposure to the modern obesogenic environment. Older cART regimens were associated with increased risk of body fat partitioning disorders (lipodystrophy) and cardiometabolic complications including atherothrombotic cardiovascular disease (CVD) and diabetes mellitus. Whilst cART now avoids those medications implicated in causing lipodystrophy, long-term cardiometabolic data on more modern cART regimens are lacking. Longitudinal studies show increased rates of incident CVD and diabetes mellitus with weight gain in treated HIV-infection. Abdominal fat gain, weight gain, and rising body mass index (BMI) in the short-term during HIV treatment was found to increase incident diabetes risk. Rising BMI was associated with increased risk of incident CVD, however the relationship varied depending on pre-cART BMI category. In contrast, a protective association with mortality is evident, predominantly in the underweight and in resource-poor settings, where weight gain reflects access to cART and virological suppression. The question of how to best evaluate, manage (and perhaps constrain) weight gain during HIV treatment is of clinical relevance, especially in the current climate of increasingly widespread cART use, rising overweight, and obesity prevalence and growing metabolic and cardiovascular disease burden in people living with HIV-infection. Large prospective studies to further characterise the relationship between weight gain during HIV treatment and risk of diabetes, CVD and mortality are required.

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