A Potential Treatment for HIV-Related Abdominal Obesity
In a placebo-controlled trial, daily tesamorelin injections reduced visceral adiposity and improved lipid profiles; however, the drug also led to a higher rate of treatment discontinuation because of adverse events than did placebo.
The accumulation of visceral fat is one of the most vexing morphologic abnormalities associated with HIV infection and antiretroviral therapy (ART). Such fat deposits are uncomfortable and disfiguring and may the raise the risk for cardiovascular disease. Might tesamorelin, a growth hormone-releasing factor, be a potential treatment for this condition?
To address this question, investigators conducted an industry-funded, multisite, clinical trial among 412 HIV-infected patients who were receiving ART and had accumulations of abdominal fat (defined, for men, as a waist circumference ≥95 cm and a waist-to-hip ratio ≥0.94, and, for women, as a waist circumference ≥94 cm and a waist-to-hip ratio ≥0.88). Patients were randomized in a 2:1 ratio to receive daily subcutaneous injections of tesamorelin (2 mg) or placebo for 26 weeks. The primary endpoint was the absolute change in visceral adipose tissue area, as measured by single-slice, cross-sectional computed tomography scans.
From baseline to 26 weeks, the tesamorelin group experienced a significantly greater mean change in visceral adipose tissue than did the placebo group (a decrease of 27.8 cm vs. an increase of 5.1 cm). The tesamorelin group also reported greater subjective improvements in appearance, as measured by validated surveys. Lipid-profile changes further favored tesamorelin, with significant reductions in mean triglyceride level, total cholesterol level, and total-to-HDL cholesterol ratio. Mean fasting blood glucose levels, 2-hour glucose levels, and insulin levels did not differ between the groups at week 26. Treatment discontinuation because of adverse events was more common with tesamorelin than with placebo (12.1% vs. 2.9%; P<0.002), mostly due to arthralgias, swelling, and injection-site reactions. Antibodies to tesamorelin developed in nearly half the patients who received the drug; six of these patients also developed urticaria reactions that extended beyond the injection site. Development of antibodies did not alter the drug’s effectiveness.
More than a decade has passed since patients first complained about "protease paunch," and, thus far, we have relatively little to offer them. The use of pharmacologic doses of recombinant growth hormone for this indication — a non-FDA-approved use — has been fraught with side effects, and few other promising treatments have emerged. The current results with tesamorelin are therefore encouraging, but many questions remain: Who are the appropriate candidates for this investigational product? How long should it be given? What is the significance of developing antibodies to the product? What is the potential for overstimulation of the pituitary gland and induction of neoplasms or neurobehavioral changes? Finally, how much will the drug cost? Recombinant growth hormone is extraordinarily expensive, and one suspects that tesamorelin also will be costly. Although the data presented here are no doubt favorable, a daily injectable growth-hormone analogue is unlikely to become a regular component of HIV therapy.
— Paul E. Sax, MD
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In a placebo-controlled trial, daily tesamorelin injections reduced visceral adiposity and improved lipid profiles; however, the drug also led to a higher rate of treatment discontinuation because of adverse events than did placebo.
Summary
The accumulation of visceral fat is one of the most vexing morphologic abnormalities associated with HIV infection and antiretroviral therapy (ART). Such fat deposits are uncomfortable and disfiguring and may the raise the risk for cardiovascular disease. Might tesamorelin, a growth hormone-releasing factor, be a potential treatment for this condition?
To address this question, investigators conducted an industry-funded, multisite, clinical trial among 412 HIV-infected patients who were receiving ART and had accumulations of abdominal fat (defined, for men, as a waist circumference ≥95 cm and a waist-to-hip ratio ≥0.94, and, for women, as a waist circumference ≥94 cm and a waist-to-hip ratio ≥0.88). Patients were randomized in a 2:1 ratio to receive daily subcutaneous injections of tesamorelin (2 mg) or placebo for 26 weeks. The primary endpoint was the absolute change in visceral adipose tissue area, as measured by single-slice, cross-sectional computed tomography scans.
From baseline to 26 weeks, the tesamorelin group experienced a significantly greater mean change in visceral adipose tissue than did the placebo group (a decrease of 27.8 cm vs. an increase of 5.1 cm). The tesamorelin group also reported greater subjective improvements in appearance, as measured by validated surveys. Lipid-profile changes further favored tesamorelin, with significant reductions in mean triglyceride level, total cholesterol level, and total-to-HDL cholesterol ratio. Mean fasting blood glucose levels, 2-hour glucose levels, and insulin levels did not differ between the groups at week 26. Treatment discontinuation because of adverse events was more common with tesamorelin than with placebo (12.1% vs. 2.9%; P<0.002), mostly due to arthralgias, swelling, and injection-site reactions. Antibodies to tesamorelin developed in nearly half the patients who received the drug; six of these patients also developed urticaria reactions that extended beyond the injection site. Development of antibodies did not alter the drug’s effectiveness.
Comment
More than a decade has passed since patients first complained about "protease paunch," and, thus far, we have relatively little to offer them. The use of pharmacologic doses of recombinant growth hormone for this indication — a non-FDA-approved use — has been fraught with side effects, and few other promising treatments have emerged. The current results with tesamorelin are therefore encouraging, but many questions remain: Who are the appropriate candidates for this investigational product? How long should it be given? What is the significance of developing antibodies to the product? What is the potential for overstimulation of the pituitary gland and induction of neoplasms or neurobehavioral changes? Finally, how much will the drug cost? Recombinant growth hormone is extraordinarily expensive, and one suspects that tesamorelin also will be costly. Although the data presented here are no doubt favorable, a daily injectable growth-hormone analogue is unlikely to become a regular component of HIV therapy.
— Paul E. Sax, MD
Click here for AIDS Clinical Care subscription information.
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