August 17, 2006 (AIDSmeds)—Following on the heels of a published clinical trial showing that recombinant human growth hormone (rhGH) treatment is associated with reductions in unhealthy fat seen in HIV-positive people lipodystrophy,encouraging results from a second study were reported today at the XVIInternational AIDS Conference (IAC) in Toronto. The new data suggestthat an initial 12-week induction course of rhGH, followed bylower-dose maintenance therapy, results in notable drops in visceralfat.

HIV-associated lipodystrophy generally involves twodifferent types of body-fat changes. First there is a buildup of fat.Some people see the amount of visceral fat – fat deep within the body –around their gut increase significantly (lipohypertrophy). Some peoplesee the fat in their legs, arms, buttocks, or face diminish (lipoatrophy). These complications are associated with the use of HIV treatment, notably protease inhibitors and the nucleoside reverse transcriptase inhibitors Zerit® (stavudine) and Retrovir® (zidovudine).

Whilethere are emerging therapeutic choices for lipoatrophy – facial fillershave become popular, albeit pricey, options – there has not yet been aclinically proven (or approved) therapy for lipohypertrophy.

When rhGH was being evaluated in clinical trials for HIV-associated wasting syndrome– it is approved by the U.S. Food and Drug Administration (FDA) andsold as Serostim® for this indication – the study investigators notedthat the injectable hormone significantly reduced body fat (whileincreasing muscle mass). Based on this observation, rhGH was furtherexplored in studies involving patients with lipodystrophy.

A study published in a March 2004 issue of the Journal of Acquired Immune Deficiency Syndromesindicated that 12 weeks of rhGH therapy at a daily dose of 4mg wasassociated with significant decreases in visceral fat compared topre-treatment levels.

In the phase III follow-up studyreported by Carl Grunfeld, MD, of the University of California, SanFrancisco, 325 HIV-positive people with lipodystrophy were randomizedto receive either 4mg daily injections of rhGH or placebo for 12 weeks– the induction phase of the study.  For the next 24 weeks, patientswho initially received induction therapy with rhGH were againrandomized to take 2mg rhGH on alternate days or placebo – themaintenance phase of the study. Patients originally randomized toplacebo continued for 24 weeks and then later received 4mg rhGH.

After12 weeks induction treatment, patients in the rhGH group experienced anaverage decrease in visceral fat of 32 centimeters squared (cm2),compared to an average increase in visceral fat of 0.5 cm2 in theplacebo group. This difference between the rhGH group and the placebogroup was statistically significant, meaning that it was not due tochance.

By the end of the maintenance phase of thestudy, Dr. Grunfeld reported, reductions in visceral fat were generallymaintained among patients who remained on rhGH during the entire 36weeks of the study. Among those who continued on alternate-day 2mg rhGHdosing, approximately 40% regained at least 50% of the visceral fatthey had lost during the induction phase of the study. This, however,was considered a success according to the way the study was designed.Among those who were on rhGH induction therapy and then switched toplacebo, 53.7% regained at least 50% of the visceral fat they had lost.This was considered a failure.

There has been someconcern that rhGH would also reduce limb fat – such as in the arms,legs, and face – which could be problematic for people alreadysuffering from lipoatrophy. After 12 weeks of induction treatment,limb fat did decrease in the rhGH group compared to those who tookplacebo, with statistically significant differences between the twogroups.  However, by week 36, limb fat measurements were again similarto those seen before treatment with rhGH was started. 

Ofnote, levels of non-HDL cholesterol – so-called "bad" cholesterol –decreased in response to rhGH treatment. However, it should be notedthat patients were permitted to take lipid-lowering statins whileparticipating in the rhGH study.

No unexpected sideeffects were reported.  Muscle and joint pain, as well as tissueswelling, were common. For example, tissue swelling was seen inapproximately 46% of patients receiving rhGH during the induction phaseof the study. But by the end of the maintenance phase of the study,tissue swelling was only seen in 7% of patients on low-dose rhGH.

Anotherconcern surrounding rhGH therapy is its potential to cause glucoseintolerance, a potentially serious problem for people who are alreadydiabetic or pre-diabetic due to the HIV medications they take. In thisstudy, glucose levels increased during the first few weeks of theinduction phase of the study, but were back down to pre-rhGH treatmentlevels by the time maintenance therapy was started.

Dr.Grunfeld concluded that 4mg rhGH induction therapy for 12 weeks,followed by 24 weeks of 2mg rhGH every-other-day maintenance treatment,achieves significant and lasting reduction in visceral fat and isrelatively well tolerated. 

An application requesting approval ofrhGH for lipodystrophy has been submitted to the U.S. Food and DrugAdministration by Serono and is currently being reviewed.