Recombinant human growth hormone reduces visceral fat in two randomised studies

A large double-blind, randomised placebo-controlled study has demonstrated that a daily dose of recombinant human growth hormone can significantly reduce visceral fat accumulation that occurs in people receiving antiretroviral therapy. However, during the lower dose maintenance phase, almost half of those treated experienced substantial re-accumulation of visceral fat. The results of the phase III study, sponsored by manufacturer Serono, were presented last month at the Sixteenth International AIDS Conference in Toronto.

A second open-label study, reported in the September edition of HIV Medicine, also observed a significant reduction after 24 weeks of induction and maintenance treatment. In this study, visceral fat reduction appeared to be sustained to week 24 with no rebound.

Visceral fat accumulation has been noted in up to one-third of people receiving potent antiretroviral therapy, and causes concern for several reasons:

• Visceral fat accumulation in adults is associated with the development of a metabolic syndrome of high lipid levels, insulin resistance and diabetes, all of which carry a heightened risk for cardiovascular disease.
• Visceral fat accumulation is stigmatising for people with HIV who suffer from it.
• There are few reports of reversal of fat accumulation, following switches in antiretroviral therapy, and its relationship to specific antiretroviral drugs is less well understood than is the case for subcutaneous fat loss (lipoatrophy), which has been strongly associated with d4T (stavudine, Zerit) and to a lesser extent, AZT (zidovudine, Retrovir).

Individuals with obesity are known to have blunted growth hormone secretion and low serum-insulin growth factor-I secretions. Studies have therefore been undertaken into the effectiveness of recombinant human growth hormone (often abbreviated as r-HGH) as a treatment for lipodystrophy-associated fat accumulation.

But the optimum dose of recombinant human growth hormone as a treatment for visceral adiposity has not been determined, and its durability is unknown. In addition, there are concerns that treatment with rHGH could cause fat loss from the face, limbs and buttocks, another symptom of lipodystrophy.

Study 24380 randomised 325 HIV-positive individuals with excess visceral adipose tissue to receive either 4mg of recombinant human growth hormone (n=243) or placebo daily for twelve weeks (n=79). All participants were receiving antiretroviral therapy and 62% were receiving a protease inhibitor. Ninety-seven per cent of patients in the rHGH arm were receiving at least one nucleoside analogue. Both classes have been associated with visceral fat accumulation in HIV-positive people.

Participants had a median body mass index of 27 and a body fat percentage of 22% - not high by North American standards. In order to be included in the study, male participants were required to have a waist circumference of at least 88cm (34in)

After twelve weeks of daily treatment participants in the rHGH arm were randomised to receive a maintenance dose of 2mg rHGH or placebo every other day until week 36. Follow-up data on the maintenance phase in the group initially randomised to placebo were not presented.

After twelve weeks visceral fat, as measured by CT scan, and total trunk fat, as measured by DEXA scan, had both declined in the rHGH group by approximately 20%, and this difference was significant when compared to the placebo group, in which a slight increase in visceral and trunk fat was measured (+4%) (p=.001).

However subcutaneous adipose tissue levels declined by around 7%, whether measured by CT scan or by DEXA scan of limb fat, and these declines were significant when compared to the placebo group (P

Modest declines in non-HDL cholesterol were also reported in the rHGH group, but these changes were confounded by a 3% reduction in LDL cholesterol in the placebo group too, and maintenance phase results were not reported, making it difficult to draw any strong conclusions about the metabolic effects of rHGH.

Although rHGH showed an effect on visceral adipose tissue during the induction phase almost half (40.3%) of patients who had lost visceral fat saw the majority of their visceral fat come back. The study’s secondary endpoint was to show that less than half of patients regained half of the visceral fat lost during the study, so from this point of view, the study achieved a successful outcome. However, the study’s design is likely to provoke questions from regulators about the durability of rHGH as a treatment for visceral fat accumulation in HIV lipodystrophy when the data are submitted to support a license application for use of rHGH as a lipodystrophy treatment.

Side-effects of rHGH during the induction phase were predominantly mild to moderate, and consisted most frequently of peripheral oedema (swollen ankles and limbs) (46%) and arthralgia (joint pain)(39%). Headache, reduced sensitivity to touch and aching muscles were also more frequently reported in the rHGH group. Increased blood glucose levels were also more common in the rHGH group (14% vs 3%, p=0.003).

A second study of rHGH, carried out in Germany, did not report the same incidence of re-accumulation of visceral fat during the maintenance phase, perhaps due to a difference in the studied dosing regimen.

German investigators led by Marcus Bickel designed an open-label study involving 26 HIV-positive patients who were taking potent anti-HIV therapy and had experienced fat accumulation. They were randomised to receive 4mg of rHGH once-daily for twelve weeks, or 4mg of rHGH three times a week for twelve weeks. After twelve weeks, patients in both arms of the study received 2mg of rHGH once-daily for a further twelve weeks.

All but one of the patients was male and had a median age of 45 years. HIV was well controlled in the majority of patients, 80% having a viral load below 50 copies/ml and the median CD4 cell count was 500 cells/mm³.

Body composition was measured by MRI scan in this study.

Compared to baseline, overall there was a significant reduction in visceral adipose tissue by week twelve (30%) and a further reduction by week 24 (40%, p

Although, compared to baseline, facial fat tissue was reduced by 3.2 cm² by week 24 in the patients taking once-daily treatment, and 2.4 cm² in patients who took thrice-weekly treatment, these reductions were not considered significant by the investigators (p = 0.91).

The investigators also recorded a significant reduction in waist-to-hip circumference in both arms of the study at weeks twelve and 24 (p

Total cholesterol fell by 31mg/dl in the once-daily treatment arm by week twelve and by 8.1mg/dl in the thrice-weekly arm. These reductions were statistically significant (p = 0.046) and the reductions were maintained to week 24. However, patients taking once-daily recombinant human growth hormone had a greater increase in their HDL, often called “good” cholesterol (p = 0.03).

Fasting glucose and insulin levels did not change in either arm of the study.

Although 67% of patients taking the study medication once-daily and 29% of those taking it three times a week reported side-effects, none of the side-effects were considered serious and all resolved once treatment was discontinued.