Lipodystrophy treatment under investigation by US Attorney

Serono, manufacturer of the human growth hormone drug Serostim, is being investigated by the U.S. Attorney's office for possible improper billing and inducements to sell the drug, which is approved in the US for HIV-related wasting.

"Serono has received an administrative subpoena," spokeswoman Carolyn Castel told The Boston Globe on Thursday. "The company is cooperating with the government in the context of the subpoena."

Human growth hormone (HGH) - a natural hormone produced in the pituitary gland which has been genetically engineered as recombinant human growth hormone (rHGH) by Serono and other biotechs - is also one of the most promising therapies for lipodystrophy, and researchers into treatments for the syndrome - lipohypertrophy (fat accumulation) and lipoatropy (fat loss) - are hoping that it may be the 'holy grail'; a therapy that ameliorates both types of symptoms.

In the US, where accelerated approval was granted in 1996 for the treatment of HIV-related wasting, Serostim is the lipodystrophy treatment drug of choice for those who can obtain it, according to sources contacted this week by aidsmap, despite the fact it is not licensed for that indication and therefore cannot be reimbursed for when used explicitly for lipodystrophy treatment.

Several small-scale studies (including those by Lo, Engelson, Furrer and

Torres) have already shown that rHGH can reduce both buffalo hump size and visceral fat and researchers in London are hoping to show that at lower doses, and in combination with other drugs, it can restore lost fat. According to several sources approached by aidsmap, the drug is commonly being used off-label in the States, as patients self-report a ten percent weight loss that they may or may not actually have, which gives the clinician a justification to prescribe the drug and get it covered by insurance.

"Lots of HIV clinicians are writing scripts for it for those with big bellies and buffalo humps, etc., but doing it relatively quietly so as not to draw attention to the fact that it's being used for lipodystrophy-associated fat accumulation instead of for traditional wasting," says Lark Lands, Science Editor of POZ magazine, who adds that "there's absolutely no way to know how many patients are accessing it for lipodystrophy since no one has records on that."

US treatment activist, Michael Mooney, who runs the website medibolics.com and is co-author of the book Built To Survive: a comprehensive guide to the medical use of anabolic steroids, nutrition and exercise for HIV+ men and women confirms that in his experience "doctors were quite willing to co-operate" in writing prescriptions for human growth hormone, fully aware that patients "hadn't really lost a full amount, or they really didn't fit the typical definition of someone who would be approved."

According to the Boston Globe about 6,000 people currently use Serostim in the US. Given the high cost of the drug, and the availability of other much cheaper therapies for wasting, it is unlikely that many patients are currently taking Serostim for its approved use. As a treatment for wasting, Schambelan and others showed that over 12 weeks 178 patients gained an average of 6.6 lbs. of lean body mass using 6 mg Serostim daily. According to US online pharmacy drugstore.com the monthly cost of this treatment would be $6917.40 (£4717.91). As a comparison, Strawford and others showed that over 12 weeks 18 patients gained an average of 6.6 lbs. of lean body mass using 200 mg of the anabolic steroid nandrolone every two weeks. According to drugstore.com the monthly cost would be $56.70 (£38.67).

"On a cost basis it's quite simply ridiculous and there's little basis for any real discussion," says Mooney, who has written extensively about the use of steroids and Serostim for wasting. "Serostim growth hormone may have value in therapy for lipodystrophy because of its potential for improving lipid oxidation (fat burning) in HIV, and while data from several studies by Mulligan and others show that HGH can increase lean body mass, lean body mass does not always mean muscle tissue," he says. Other components of lean body mass can include water, bone connective tissue and organs.

Los Angeles-based MD, Tony Mills, who sees many patients with HIV, confirms that both he and his colleagues are using Serostim to treat lipodystrophy. "I think the majority of physicians in the US who are on the cutting edge of HIV care believe in growth hormone as the treatment-of-choice for the fat accumulation we see in HIV-related lipodystrophy," says Mills. "The preliminary data has been convincing and my personal experience has been

confirmatory: growth hormone works. Now if we could just get the FDA to give growth hormone its indication for lipodystrophy, we would be ready to fight this disfiguring and often crippling condition."

Serostim is not the only promising treatment for fat accumulation: the anti-diabetes drug metformin, liposuction and anabolic steroids have all been used to varying degrees of success. The lack of large-scale trials and its side-effect profile - which can include headache, muscle pain, swelling of the joints and rarer instances of carpal tunnel syndrome and increased insulin sensitivity - explain why human growth hromone is not yet approved in the US for lipodystrophy. Serono is currently carrying out these studies in the US and Europe.

In the EC, where Serono has exclusive rights to market rHGH and where the only approved growth hormone so far is Serono's Saizen - used to treat children with growth deficiency, with similar NHS costs to Serostim in the US - Serostim's reputation as an expensive treatment for HIV wasting appears to be its greatest hurdle for consideration as a legitimate treatment for HIV-associated lipodystrophy. aidsmap spoke to a number of HIV clinicians with an interest in metabolic disorders, and all had varying concerns about the potential high cost of rHGH in clinical practice.

"Human growth hormone does have this horrible cost issue hanging over it," admits Derek Macallan of St. George's Hospital, London, one of two trial sites for the HALT (HIV-associated lipodystrophy treatment) study that includes Serostim in two of its five treatment arms. "It's a complete obstacle," adds Graeme Moyle of Chelsea and Westminster Hospital, London, - the other HALT site - who designed the study with Macallan. "But I think that's a decision that's up to NICE (the National Institute of Clinical Excellence, the government body which decides which drugs the NHS should pay for)." But, as Duncan Churchill of the Royal Sussex County Hospital, points out, "six months of growth hormone treatment for one patient could pay the year's salary of a badly-needed admin worker."

George Scullard, who runs the metabolic clinic at St. Mary's Hospital, London, recently approached Serono to supply Serostim for a trial that would have combined rHGH with exercise as a potential treatment for fat accumulation. "They said they would help with research costs but they would like us to buy rHGH, and even at reduced rates, it was out of the question," he says. "We couldn't afford that."

But, adds Scullard, even if cost issues were overcome, rHGH has a long way to go before being accepted as a standard treatment for fat accumulation in HIV-associated lipodystrophy. "The studies have all been fairly small and they are so transient. It doesn't matter what the cost is. If you've spent six months on rHGH and two months later you're back to baseline, then it doesn't seem to be worth it."

Both Macallan and Moyle appear to be rather more upbeat about rHGH's prospects as a lipodystrophy treatment. Their HALT study is testing Serostim alongside the anti-diabetes drug rosiglitazone, the fat-lowering drug pravastatin, diet and exercise in a five-arm, randomised open-label study. The trial has been open for six months and has currently enrolled just over half of its 60 places. Participants will undergo full CT and DEXA scans as well as 3D facial photographs in order to gain a complete picture of fat distribution throughout the 12 months of the trial.

"We are looking for restoration of fat mass in people with lipodystrophy," says Moyle of the study, which uses 2 mg/daily of rHGH, one-third of the approved dose for HIV wasting. The idea is to restore rHGH levels to normal in people with lipodystrophy, since Hadigan et al have shown that "levels of growth hormone are low in people with lipodystrophy," says Moyle, "or at least the pulse amplitude of rHGH is lower, which is consistent with other data from people with central fat accumulation". Furthermore, one of the arms combines Serostim with rosiglitazone "which may counteract any potential for insulin resistance, and secondly improve the quality of fat storage and glucose storage peripherally," adds Moyle. "The intention is to see whether combining the two leads to different effects of the rHGH than what would normally happen."

According to Lark Lands, community activists in the US have been using lower dose Serostim for some time, seeing good fat-reducing results and less side-effects. "I suspect that lower doses are a very good idea that will eventually become the norm," says Lands, "And, of course, they have the other very significant benefit of sharply reducing the total cost of the drug."

It is difficult to gauge at this stage how significant the US investigation into Serostim's marketing and billing practices will be on the approval of the drug as a treatment for lipodystrophy. Data from Serono's own 9037 multicentre study, to be reported in July at a satellite meeting of the International AIDS Conference in Barcelona, is expected to provide much more information on the use of rHGH, both for wasting and in lipodystrophy treatment. The drug has already been tarnished by several previous controversies: there has been concern from both AIDS activists and government officials that Serostim and other rHGH products are priced artificially high; and last year, fake copies of Serostim were found to be being circulated in the US after illegal purchases by athletes created a black market for growth hormone drugs.