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CROI 2015: Does HIV Make You Fat? Study Connects Viral Load with Fat Gains

HIV infection or inflammatory changes associated with it may be responsible for fat accumulation and body fat redistribution, rather than antiretroviral drugs, according to a study presented at the recent 2015 Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.


[Produced in collaboration with Aidsmap]

Grace McComsey of Case Western University in Cleveland said that although the association of subcutaneous fat loss (lipoatrophy) with mitochondrial damage caused by certain HIV drugs is well-established -- and most of the world no longer uses the drugs like stavudine (d4T) that are most strongly associated with it -- 2 decades of research had failed to establish a cause for the distinctive fat gain(lipohypertrophy), especially in the trunk and within the abdomen, seen in some people with HIV on antiretroviral therapy (ART).

Initially these fat gains were associated with protease inhibitors (PIs) but switching from PIs to non-nucleoside reverse transcriptase inhibitors (NNRTIs) or to integrase inhibitors did not reverse fat gains. One study found greater fat gain in people taking boosted atazanavir (Reyataz) rather than efavirenz (Sustiva), but a general association with any drug or class of drugs had not been demonstrated. Given that untreated HIV infection usually results in weight loss, fat gains when people started ART, once it became available, may have understandably been associated with treatment rather than HIV.

The study McComsey presented, ACTG A5260s, compared changes in limb fat, trunk fat, visceral adipose tissue (central abdominal fat), and lean muscle mass in 1809 ART-naive patients starting either of the 2 boosted PIs atazanavir or darunavir (Prezista), or the integrase inhibitor raltegravir (Isentress), all combined with tenofovir/emtricitabine (Truvada).

DEXA and CAT scans measured fat and muscle distribution at baseline and nearly 2 years (96 weeks) later. They were then assessed for associations with drug regimen, baseline HIV viral load, Framingham risk score (a measure of the likelihood of cardiovascular disease), and a number of hormones, cytokines (cell messenger chemicals), and markers of inflammation: leptin (higher in obese people), adiponectin (lower in obese people), D-dimer (a coagulation marker), C-reactive protein (an inflammation indicator), and the cytokines or cytokine receptors interleukin 6 (IL-6), CD14, and CD163.

In terms of demographics, the study participants' average age was 36, 90% were men, and 44% were white (slightly more taking atazanavir). Their average pre-ART viral load was 34,150 copies/mL and their average CD4 count was 351 cells/mm3.  Those taking atazanavir had slightly, but not significantly, more limb and trunk fat, but not more visceral fat or muscle.

Limb, trunk, and visceral fat all increased during the 96 weeks on ART. Limb fat increased by 15% (20% on raltegravir), trunk fat by 22% (16% on atazanavir and 29% on raltegravir), and visceral fat by 31%; the differences between drugs were not statistically significant. Lean muscle mass increased slightly, by 2%, in people on atazanavir or raltegravir, and by 1.2% in patients taking darunavir; this was a significant difference but probably does not reflect any real difference between the drugs.

Increases in visceral fat were associated with lower leptin and higher adiponectin levels, but this probably is effect rather than cause, as adiponectin is secreted by fatty tissue. Subcutaneous limb fat gain was also associated with higher IL-6 and lean body mass gain with higher D-dimer and lower baseline CD4 -- the latter not unexpected, as lean body mass falls with AIDS.

However by far the strongest association with fat gain was with high viral load. There were mean increases of at least 25% and up to 35% in both subcutaneous and visceral fat in people who had a baseline viral load over 100,000 copies/mL, whichever drug they were taking. In patients with a baseline viral load below 100,000 copies/mL, the fat gains were below 10%, apart from a gain in visceral fat of about 14% in people taking raltegravir. She noted that even when adjusted for inflammatory markers, HIV viral load was still significantly associated with fat gain.

McComsey said that the fat gains observed were not necessarily those associated with health improvement due to control of HIV. "A 30% gain in visceral adipose tissue in just 2 years is pretty bad," she said. "Even limb fat increased by 1.5 kilos from a baseline of 7 kilos (21%). There was an average increase in 3.0 to 3.5 in people’s BMI [body mass index] score." Although people in general may be getting fatter, it does not happen as fast as this, she added.



GA McComsey, C Moser, JS Currier, et al. Body Composition Changes After Initiation of Raltegravir or Protease Inhibitors. 2015 Conference on Retroviruses and Opportunistic Infections. Seattle, February 23-24, 2015. Abstract 140.

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Growth Hormone Releasing Factor Tesamorelin Reduces Visceral Fat in HIV Positive People with Lipodystrophy

The growth hormone releasing factor tesamorelin (brand name Egrifta, formerly TH9507)reduced the amount of visceral abdominal fat in HIV positive people with central fat accumulation and led to improved feelings about body image, researchers reported in the March 1, 2010 Journal of Acquired Immune Deficiency Syndromes. Tesamorelin lowered total cholesterol and did not cause significant side effects, including blood glucose abnormalities.

Abdominal fat accumulation -- an aspect of lipodystrophy syndrome -- is a concern for many HIV positive people, both in terms of body image and cardiovascular risk. Administration of human growth hormone has been shown to reduce visceral adipose tissue (fat deep within the abdomen), but it can lead to side effects including elevated blood glucose, swelling, bone pain, and carpal tunnel syndrome.

In contrast to administering growth hormone directly, tesamorelin is a growth hormone releasing factor that stimulates the pituitary gland in the brain to secrete more growth hormone. Investigators hypothesized that it might provide similar benefits with fewer adverse effects, and this was supported by initial studies.

Julian Falutz from McGill University School of Medicine and colleagues investigated the effects of tesamorelin in 404 HIV positive participants on antiretroviral therapy (ART) who had excess abdominal fat.

This double-blind Phase 3 trial consisted of 2 sequential parts. During the first 6 months, patients were randomly assigned (2:1) to receive daily subcutaneous injections of 2 mg tesamorelin or placebo. In the extension phase (months 6-12), participants initially receiving tesamorelin were randomly assigned (1:1) to either continue on the same tesamorelin regimen or switch to placebo, while patients initially randomized to placebo switched to tesamorelin.

The primary endpoint was changes in visceral adipose tissue, assessed with both CT and DEXA scans. Secondary endpoints included other body composition measurements, body image, levels of insulin-like growth factor-1 (a protein produced in response to growth hormone stimulation), and safety parameters.


  • Visceral adipose tissue decreased by 10.9% (21 cm2 or about 1 kg) on average in the tesamorelin group versus a 0.6% (1 cm2 or about 0.2 kg) decrease in the placebo group during the first 6 months (P < 0.0001).
  • Trunk fat (P < 0.001), waist circumference (P = 0.02), and waist-to-hip ratio (P = 0.001) all improved significantly, with no changes in limb or subcutaneous abdominal fat.
  • Patients reported significantly less distress about belly appearance in the tesamorelin group compared with the placebo group (P = 0.02).
  • Physicians' ratings of patient belly appearance also improved significantly (P = 0.02).
  • Among participants who continued on tesamorelin for 12 months, visceral adipose tissue decreased by 17.5% (P < 0.001).
  • However, the visceral adipose tissue improvements of the first 6 months were rapidly lost in patients who switched from tesamorelin to placebo.
  • Patients receiving tesamorelin did not experience a significant decrease in triglycerides compared with placebo (as was seen in a prior Phase 3 study), but there was a trend in this direction.
  • Participants who received tesamorelin for 12 months experienced a significant decrease in total cholesterol.
  • Tesamorelin was well-tolerated overall.
  • Levels of insulin-like growth factor-1 increased significantly, but there was no apparent change in glucose parameters.
  • About 4% of participants experienced hypersensitivity reactions, which were generally mild; a few discontinued therapy prematurely for this reason.

Based on these findings, the study authors concluded, "Tesamorelin reduces visceral fat by approximately 18% and improves body image distress in HIV-infected patients with central fat accumulation. These changes are achieved without significant side effects or perturbation of glucose."

With these new data, they added, "there are now consistent results from two large Phase 3, randomized, placebo-controlled studies to suggest that [tesamorelin] is a potentially useful clinical strategy to selectively reduce visceral adipose tissue and improve body image among HIV-infected patients with abdominal fat accumulation in the context of antiretroviral therapy."

Montreal-based developer Theratechnologies has requested approval of tesamorelin from the U.S. Food and Drug Administration; and the agency will told a public meeting on May 27, 2010 to discuss the topic.

Affiliations: Department of Medicine, Montreal General Hospital and McGill University School of Medicine, Montreal, Canada; Massachusetts General Hospital and Harvard Medical School, Boston, MA.



J Falutz, D Potvin, JC Mamputu, and others. Effects of Tesamorelin, a Growth Hormone-Releasing Factor, in HIV-Infected Patients With Abdominal Fat Accumulation: A Randomized Placebo-Controlled Trial With a Safety Extension. Journal of Acquired Immune Deficiency Syndromes 53(3): 311-322. March 1, 2010.