Addressing excess visceral abdominal fat and cardiometabolic risk in people with HIV

In the mid-1990s, clinicians treating people with HIV began to notice a syndrome characterized by loss of limb fat, facial wasting and accumulation of abdominal fat in individuals on early combination antiretroviral therapy regimens.

Initially known as lipohypertrophy, the phenomenon eventually assumed the broader definition of clinically apparent lipodystrophy, which, at its height, affected roughly half of people with HIV (PWH) on combination antiretroviral therapy (ART). With the incorporation of thymidine analogs and first-generation protease inhibitors into early combination ART regimens, clinicians increasingly recognized the metabolic consequences of the lipodystrophy phenotype: high rates of insulin resistance, dyslipidemias and elevated risk for diabetes and cardiovascularevents.

That recognition sharpened clinicians’ understanding of how the difference between metabolically healthy obesity and its metabolically unhealthy counterpart is largely driven by where fat is stored in the body. The accumulation of visceral fat is considered one of the hallmarks of metabolically unhealthy obesity, a complex syndrome characterized not just by fat deposition in the viscera, but also the often concomitant deposition of fat in the liver, heart and skeletal muscle. Metabolically unhealthy obesity has been associated with a range of cardiometabolic conditions including hyperglycemia, insulin resistance, accelerated frailty, coronary artery disease and CV events. Its prevalence among PWH in the early combination ART era was a nagging concern for patients and clinicians alike.

Excess visceral abdominal fat in the modern ART era

As second-generation protease inhibitors and integrase inhibitors anchored various new combinations in the so-called “modern” ART era, many in the HIV treatment community came to think of lipodystrophy as a thing of the past, or as limited to individuals who had been on treatment for decades. But even today, lipodystrophy remains highly prevalent in PWH taking modern ART regimens.

It has become apparent that the elevated levels of visceral adiposity seen in many PWH are not solely due to the toxicity or other lingering effects of the newer ART agents; in fact, much of the lipid repositioning into the viscera results from the virus itself. Around 2015, when the study of adipose tissue came back into vogue, researchers realized that subcutaneous fat can be a reservoir for HIV, and that changes in subcutaneous immune cell populations as a result of HIV infection appear to drive fat accumulation in other depots. Some in the field believe this phenomenon is a reaction to changes in subcutaneous fat, and that the body simply needs another place to store the energy in those lipids. The implication is that no matter how much we improve the tolerability and adverse event profile of any ART agent, lipodystrophy will never entirely go away in the presence of HIV infection itself.

Unsurprisingly, as the population living with HIV ages, we see increased prevalence of excess visceral abdominal fat among older individuals on modern ART therapy. This has been accompanied by a constellation of related conditions, including an accelerated frailty phenotype that is thought to result from excessive deposition of lipid in skeletal muscles (termed myosteatosis). Similarly, whereas insulin resistance and accumulation of liver fat are more common in older people, these pathologies appear to be accelerated in the presence of excess visceral abdominal fat. Additionally, PWH have a roughly twofold increased risk for CV events compared with the general population, which is heightened further in those with excess visceral abdominal fat.

Lessons from the VAMOS study

Enhancing awareness of excess visceral abdominal fat is crucial because many health care professionals underappreciate its contribution to heightened risk for CV events such as myocardial infarction. As PWH today increasingly resemble the general population, particularly the high prevalence of being overweight or obese, excess visceral abdominal fat has in many ways become a hidden phenomenon. Moreover, with modern ART regimens, we see little limb wasting. Whereas longtime HIV practitioners may be more attuned to the pernicious effects of fat redistribution, fewer providers today consider excess visceral abdominal fat a potential contributor to the adverse metabolic and CV events seen in PWH. Although there are abundant data on these phenomena dating back to the early protease inhibitor era, data from the modern ART area are sparse.

That data gap was a major impetus for the Visceral Adiposity Measurement and Observations Study (VAMOS), results of which we presented at IDWeek 2024. This cross-sectional, multicenter observational study enrolled 170 PWH who had virologic suppression on ART for at least 1 year, and BMI between 20 kg/m² and 40 kg/m². The primary objective of this analysis was to assess how excess visceral abdominal fat impacts traditional CVD risk factors and overall CV risk in PWH in the modern ART era.

In VAMOS, we first found that the prevalence of excess visceral abdominal fat was 58%, demonstrating how excess visceral abdominal fat is still common even in today’s PWH on modern ART. We found that higher levels of visceral abdominal fat in PWH are associated with:

• increases in the homeostasis model assessment for insulin resistance (HOMA-IR) and triglyceride-HDL ratios (an alternative measure of insulin resistance, and a broad marker of dyslipidemia in aging PWH) (Figure 1); and
• higher 10-year atherosclerotic CVD risk scores (Figure 2).

We also explored growth hormone levels as a potential driver behind the relationship between EVAF and CV risk. This area of investigation revealed an inverse correlation between growth hormone levels and visceral fat area levels in PWH (Figure 3), a finding that supports targeting excess visceral abdominal fat reduction via the growth hormone axis.

Our hope is that the VAMOS outcomes enhance provider awareness of the prevalence of excess visceral abdominal fat across a wide range of patient populations, even those with no exposure to early ART regimens. These results implore intensified efforts to identify individuals at risk for excess visceral abdominal fat, such as by assessing the waist circumference and waist-to-hip ratio, which is an effective and cost-efficient way to measure visceral fat accumulation. Additionally, when evaluating people for CV risk, clinicians should consider the potential contributions of excess visceral abdominal fat to CVD, and that attention should be given to targeting excess visceral abdominal fat when considering CVD risk management.

Potential therapeutic interventions

Tesamorelin (Egrifta, Theratechnologies), a growth hormone-releasing factor analog, has previously been shown to reduce excess visceral abdominal fat in PWH in randomized controlled trials. Therefore, one could speculate that tesamorelin may impact 10-year ASCVD risk scores. In fact, in an analysis of pooled outcomes data from two phase 3 randomized studies involving 543 PWH presented at IDWeek 2024, treatment with tesamorelin was associated with a reduction in 10-year ASCVD risk scores. Given that 44% of these patients were already treated with lipid-lowering medications, these data provide evidence of the importance of reducing excess visceral abdominal fat when aiming to lower long-term CV risk.

There is also evidence that GLP-1receptor agonistss — a class that has raised public awareness of obesity and the benefits of weight loss — can markedly reduce visceral fat and liver fat. However, there are questions about the suitability of GLP-1ss in PWH, many of whom also have sarcopenia, myosteatosis and increased risk for frailty. One concern is whether the concomitant lean mass reductions observed with some of these agents are potentially detrimental to this population, particularly individuals initiating treatment with high levels of myosteatosis and declining muscle mass. This is in direct contrast to tesamorelin, whose specific effect on visceral fat is associated with no impact on lipoatrophy and a concomitant increase in lean body mass. More data are needed to determine whether GLP-1 agents may accelerate frailty in this group.

Enhancing awareness

Enhancing awareness of excess visceral abdominal fat is crucial, as few health care professionals fully appreciate its CV implications. As if that knowledge gap were not challenging enough, the high prevalence of overweight and clinical obesity among PWH — a feature that blurs the distinction between visceral and subcutaneous fat accumulation — has made excess visceral abdominal fat a well-masked phenomenon.

The hidden nature of excess visceral abdominal fat does not mean it is not there. The rising rates of CV events and metabolic disease in PWH should prompt clinicians to suspect excess visceral abdominal fat as a contributing factor. Similarly, PWH should not merely accept excess visceral abdominal fat as a condition they need to endure, not when there are targeted interventions for this population. Just as statins have been shown to have a dramatic effect on reducing CV events and mortality in PWH, therapeutic tools like tesamorelin can significantly reduce excess visceral abdominal fat in PWH, and may be associated with decreased ASCVD risk scores. To the extent that we can enhance health care professional and patient awareness of the risks associated with excess visceral abdominal fat and the importance of addressing them, we will have done the PWH community a great service in promoting their healthy aging.

By John R. Koethe, MD, MSCI

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