Background: Some HIV-infected patients develop fat maldistribution with visceral adipose tissue (VAT) accumulation and metabolic abnormalities. No medical treatment is approved by the US Food and Drug Administration to reduce VAT.
Methods: In this double-blind trial, 245 HIV-infected patients with excess VAT were randomized to receive placebo (PL), recombinant human growth hormone (r-hGH) at a dose of 4 mg daily (DD) or 4 mg on alternate days (AD) for 12 weeks. For weeks 12 to 24, DD patients were rerandomized to PL (DD-PL) or AD (DD-AD), AD patients continued on AD (AD-AD), and PL patients were switched to DD (PL-DD).
Results: From baseline to week 12, VAT decreased significantly compared with PL in DD (-8.6%, P < 0.001) but not in AD (-4.2%, P = 0.052). Trunk-to-limb fat ratio decreased significantly in both (P < 0.001) compared with PL, as did total cholesterol and non-high-density lipoprotein (HDL) cholesterol (-4.5% and -7.5% in DD, -4.3% and -6.2% in AD). At week 24, all groups displayed significant (P < 0.05) reductions in VAT (-5.3% to -9.5%) and trunk fat (-7.8% to -22.8%). DD-AD and AD-AD also displayed significant (P < 0.05) reductions in non-HDL cholesterol.
Conclusions: These results suggest that r-hGH dosed at 4 mg daily for 12 weeks decreases VAT and cholesterol concentrations in HIV-infected patients with excess VAT. The optimal regimen to sustain these effects awaits determination.
Use of highly active antiretroviral therapy (HAART) has markedly decreased the morbidity and mortality of HIV infection, 1 but many patients treated with HAART develop fat maldistribution (accumulation and/or depletion), dyslipidemia, insulin resistance, and other abnormalities. 2-4 In aggregate, these changes are termed HIV lipodystrophy.2,5,6 Although knowledge in this area is rapidly emerging, causal relationships among the various abnormalities are uncertain, as are pathogenic mechanisms. 4,6 Fat maldistribution can be disfiguring, debilitating, and stigmatizing 2,3,7-9 and may lead to nonadherence to antiretroviral therapy. 10,11 Another concern is that fat maldistribution, particularly visceral adipose tissue (VAT) accumulation and associated abnormalities, may promote premature atherogenesis. 2-4,6,12-17
Current data indicate that excess VAT is not substantially reversed by discontinuation or switching of antiretroviral therapy. 18 Diet and exercise interventions may reduce adiposity and metabolic risk factors in HIV patients 3,19,20 as they do in some obese patients without HIV, 21 but responses may not be sustained. 22 No medical therapies are presently approved by the US Food and Drug Administration (FDA) to reduce excess VAT in patients with HIV-1 infection.
It is well known that recombinant human growth hormone (r-hGH) reduces VAT and improves lipid levels in HIV-negative patients with growth hormone (GH) deficiency. 23,24 Excess VAT is associated with reduced GH secretion in both HIV-infected 25 and -noninfected persons. 26 In preliminary studies, r-hGH, given at doses ranging from 3 to 6 mg daily for 12 to 24 weeks, reduced abdominal and dorsocervical fat 27-33 and improved the lipid profile 32,33 in HIV-infected nonwasting patients with abnormal fat accumulation. At a dose of 6 mg daily, which is approved by the FDA to treat HIV-associated wasting, 34,35 r-hGH reduced VAT substantially in 2 studies of patients with HIV and excess VAT 32,33 but resulted in adverse events of greater severity and frequency than expected based on use in HIV-associated wasting. 30,33 One study 33 also found that most of the VAT reduction took place by week 12 and that most VAT reaccumulated after treatment cessation.
The present double-blind, placebo-controlled trial was designed to further evaluate the efficacy and safety of r-hGH therapy, at doses of 4 mg every other day and 4 mg daily for a period of 12 weeks, as a treatment of abnormal central (including visceral) adipose tissue accumulation and dyslipidemia in HIV-infected patients with excess VAT. There have not been any previous placebo-controlled trials of r-hGH in this population using a dose of 4 mg daily. This trial also explored the efficacy of r-hGH, dosed at 4 mg every other day, as an effect-maintenance strategy and compared induction-maintenance to continuous 4-mg AD therapy. Because r-hGH can increase insulin resistance, patients with glucose intolerance were excluded from this study, and insulin and glucose parameters were evaluated throughout the study. Data from this trial on effects of r-hGH on subjects' quality of life (QOL) and body image are reported elsewhere. 36