Therapeutic Trial of Growth Hormone Releasing Factor in HIV patients

Abstract & Commentary

By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University School of Medicine, Section Editor, HIV, is Associate Editor for Infectious Disease Alert.

Synopsis: In this study, 412 HIV-infected patients with abdominal visceral fat accumulation as a major manifestation of lipodystrophy were randomized to tesamorelin 2 mg SQ daily or placebo for 26 weeks. Patients receiving tesamorelin decreased visceral fat and improved lipid profiles.

Source: Falutz J, et al. Metabolic effects of a growth hormone-releasing factor in patients with HIV. N Engl J Med. 2007;357:2359-2370.

This multicenter, randomized, placebo-controlled trial of a synthetic GHRH analogue, tesamorelin (1-44 amino acids from the amino terminal of GHRH with a trans-3-hexenoyl group added to the amino terminal to increase the half-life over native GHRH), randomized 412 patients (86% male) to daily subcutaneous tesamorelin vs placebo for 26 weeks. Inclusion criteria included the receipt of at least 8 weeks prior antiretroviral (ARV) therapy and excessive abdominal visceral fat, as defined by various objective morphometric criteria. Use of stable lipid lowering regimen and testosterone replacement within 3 and 6 months of entry, respectively, was permitted.

The tesamorelin regimen was well-tolerated, with only a modest increase in treatment related side effects seen in the tesamorelin arm. Peripheral edema, myalgia, hypoesthesia, paresthesia, rash, and injection site reactions were the only remarkable events that seemed to be associated with active drug, but all of these were encountered in less than 10% of patients.

Bottom line results showed that tesamorelin therapy resulted in a 15.2% decrease in abdominal visceral fat vs an increase of 5% in the placebo group. Serum triglycerides decreased by 50 mg/dL in the tesamorelin group vs an increase of 9 mg/dL in the placebo group. Similarly, the total/HDL cholesterol ratio decreased by 0.31 in the treated vs increased by 0.21 in the placebo group. Levels of insulin-like growth factor (IGF-I), which mediates the effect of hGH on tissue, increased by 81% in the tesamorelin group and decreased by 5% in the placebo group. No differences in glycemic measurements were observed between the groups.

Commentary

Despite the use of newer antiretroviral agents (which are less likely to produce nucleoside analogue-related lipoatrophy and protease inhibitor-related fat accumulation), these dysmorphic changes, which were frequently induced by older agents, are distressing to patients and unfortunately persist following change to new ARV regimens. This study shows that a 26-week course of tesamorelin administered SQ daily can produce a reduction in visceral abdominal fat and is potentially a therapeutic option. However, caution is definitely warranted at this early date. It is known from experience with the therapeutic use of growth hormone in HIV patients that while use of hGH improved strength and lean body mass, side effects with prolonged use included salt and water retention, glucose intolerance, insulin resistance, and carpal tunnel syndrome. Longer-term studies of the safety and efficacy of GHRH analogue therapy will need to be conducted before this treatment modality should be considered standard of care. (It is intuitively evident to most internists that deliberately altering the hypothalamic-pituitary axis is not something to be done casually!) Even if shown to be well-tolerated in longer-term studies, use of daily milligram amount doses of a recombinant protein, such as tesamorelin, are likely to be quite expensive.