New Drug Being Studied for Lipodystrophy

In high-income countries, the availability of highly active antiretroviral therapy (HAART) has led to dramatic declines in deaths due to AIDS-related infections. However, the use of HAART is associated with a group of side effects called the lipodystrophy syndrome. Features of this syndrome include the following:

• Increased levels of fatty substances -- cholesterol and triglycerides -- in the blood.

• Fat gain (and possibly redistribution) in the belly and, in women, increased breast size.
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• Loss of fat just under the skin (subcutaneous fat) in the arms, legs and face.

Another possible side effect from combination therapy is problems in the way the body processes sugar. This could lead to having higher-than-normal levels of sugar in the blood for prolonged periods. As a response to this, the pancreas gland releases increased amounts of the hormone insulin, to help lower blood sugar levels. However, in some PI users, it seems that the body resists the effect of insulin (insulin resistance) and even more insulin is produced. Over time, insulin resistance can grow worse and, in rare cases, diabetes may develop.

The precise cause of these strange changes seen in some HAART users is not clear, but researchers are trying to understand why lipodystrophy occurs. For more information about treatment options for managing drug-related side effects please see CATIE's Practical Guide to HIV Drug Side Effects at www.catie.ca/sideeffects_e.nsf.

Hormone Zaps Fat

Because one of the body's hormones, growth hormone (GH), has been found to help "burn" fat, there is a lot of interest in using growth hormone injections for the treatment of fat accumulation in people with HIV/AIDS (PHAs). In HIV positive people who have fat redistribution, one research team found that the production of GH is about 40% less than that in otherwise healthy HIV positive people and in healthy HIV negative people. So it is possible that PHAs with fat redistribution are not producing enough GH or the hormone is not working properly.

The good news is that in at least one study of people with HIV, injections of growth hormone were found to significantly reduce fat accumulation in the belly. Subcutaneous fat also decreased, but to a lesser extent than the fat deposited deeper in the belly (visceral fat).

Drawbacks of this therapy include the relatively high levels of growth hormone used (4-6 mg/day), side effects such as joint pain, and increased risk of diabetes. Also, fat previously deposited in the belly tends to return once GH therapy is stopped. There may be an increased risk of cancer with the use of growth hormone, however, this has only been documented in one person. The main factor holding doctors back from prescribing GH more frequently (and holding PHAs back from using it) is its high cost. Another drawback is that the drug must be injected. One way around the problem of injecting GH is to get the body to produce more of its own GH -- something researchers are struggling to do.

Peptide Stimulates Production of GH

Researchers at a Montreal company called Theratechnologies have been studying a small compound, or peptide, called TH9507 since the mid-1990s. This peptide helps to stimulate the production of growth hormone by the body. In theory, increased levels of growth hormone produced because of stimulation from TH9507 should speed up fat loss, increase muscle buildup, hasten recovery from bone damage such as hip fractures, and improve the immune response to vaccines. TH9507 is not the only peptide that can stimulate GH release. However, what makes this drug unique is that it lasts longer in the body than many other similarly designed peptides.

TH9507 in the Body

Theratechnologies has funded research with their peptide in elderly people and in people with diabetes. In these populations, the drug appears to be safe. This is not surprising, as the amount of GH produced in response to the peptide is similar to low, natural levels. To find out if TH9507 has any side effects and benefits in HIV positive people with lipodystrophy, the company plans to sponsor clinical trials. The company hopes to enroll 60 volunteers who will be randomly assigned to receive two different doses of the peptide or fake peptide (placebo). In the study, the drug will be taken twice daily by injection for three months. The sites for this initial study, called a Phase II trial, are all in North America:

• Montreal: Clinique L'Actuel, Clinique du Quartier-Latin and Montreal General Hospital (HIV metabolic clinic)

• Atlanta: AIDS Research Consortium of Atlanta (ARCA)

• Boston: Massachusetts' General Hospital

• New York: St. Luke-Roosevelt Hospital

Because lipodystrophy is so common among people with HIV who are on HAART and the trial is enrolling such a limited number of volunteers, we expect that study sites will quickly meet their enrollment targets.

References

1. Engelson E.S., Glesby M.J., Mendez D., et al. Effect of recombinant human growth hormone in the treatment of visceral fat accumulation in HIV infection. Journal of Acquired Immune Deficiency Syndromes 2002;30(4):379-391.

2. Pantanowitz L., Garcia-Caballero T. and Dezube B.J. Growth hormone receptor (GH)-expressing carcinoid tumors after recombinant human GH therapy for human immunodeficiency virus-related lipodystrophy. Clinical Infectious Diseases 2003;36(3):370-372.

3. He Q., Engelson E.S., Albu J.B., et al. Preferential loss of omental- mesenteric fat during growth hormone therapy of HIV-associated lipodystrophy. Journal of Applied Physiology 2003;94(5):2051-2057.

4. Anonymous. Theratechnologies initiates Phase II clinical trial in Canada and the U.S. for ThGRF in HIV-related lipodystrophy. Press release. 22 May 2003.