Drug Watch: TH9507 -- An Experimental Treatment for Lipodystrophy
- Treating Lipodystrophy with Growth Hormone Products
- TH9507: A New Treatment Option?
- Selected Sources
As the use of highly active antiretroviral therapy (HAART) became widespread, HIV positive individuals and their physicians began to notice changes in body fat distribution, with excess fat or fat loss noted in different areas. These body shape changes are sometimes accompanied by metabolic abnormalities, such as insulin resistance and elevated blood fats. Collectively, these changes are known as lipodystrophy syndrome.
Treatment options for lipodystrophy are somewhat limited. Growth hormone has been used with success in clinical trials to reduce visceral adipose tissue, fat that collects around the abdominal organs. A new product, TH9507, a synthetic growth hormone releasing hormone analog made by the Canadian pharmaceutical company Theratechnologies, is currently showing promise in clinical trials and may represent a new treatment option for people with some types of lipodystrophy.
Lipodystrophy is a broad term that refers to a variety of body shape changes and metabolic abnormalities associated with the treatment of HIV infection. Lipoatrophy, one form of lipodystrophy, is fat loss from the face, upper and lower extremities, and buttocks, and loss of subcutaneous fat of the abdomen. Lipoatrophy differs from AIDS wasting in that it is associated with HAART and immune reconstitution, not progression of disease. In addition, lipoatrophy does not include loss of lean tissue mass.
Fat accumulation, the other half of lipodystrophy syndrome, can occur in the upper back and neck (sometimes called "buffalo hump"), around the abdominal organs as visceral adipose tissue (VAT), and in the breasts. Fat accumulation around the abdominal organs can occur with normal or decreased amounts of subcutaneous abdominal fat.
The causes of lipodystrophy syndrome are still unclear. Lipoatrophy is associated with use of non-nucleoside reverse transcriptase inhibitors (NRTIs), especially d4T (stavudine; Zerit) and AZT (zidovudine; Retrovir), but not with abacavir (Ziagen) or tenofovir (Viread). Body shape changes develop after several years of use of the drugs and are attributed to mitochondrial toxicity (damage to the energy-producing organs in the body's cells). Risk factors associated with lipoatrophy include higher viral load and lower nadir CD4 cell count.
Many risk factors for fat accumulation have been identified, including patient factors like older age and baseline body composition, disease factors like progression to AIDS and more robust immune reconstitution, and medication factors like increased length of treatment. The prevalence of fat accumulation among HIV positive people is estimated at 40%.
Lipoatrophy and fat accumulation can be difficult to diagnose based solely on patient perception and clinical exam. In research studies, whole-body dual-energy X-ray absorptiometry (DEXA) scanning is used to confirm abnormal distribution of fat, and computed tomography (CT) and/or magnetic resonance imaging (MRI) scans are used to document visceral fat accumulation.
There are important reasons to develop and study treatments for lipodystrophy. First, the metabolic abnormalities associated with lipodystrophy (hyperlipidemia and impaired metabolism of glucose, or blood sugar) can contribute to diabetes and heart disease. Second, fear of developing lipodystrophy may keep some people from starting an antiretroviral drug regimen or taking their medications consistently; relieving distress related to body shape changes may remove an obstacle to treatment and dramatically improve adherence to antiretroviral therapy.
Tactics to treat fat accumulation have included exercise and various medical and surgical therapies. Also successful in clinical trials are growth hormone products and related agents.
Growth hormone, produced by the pituitary gland, breaks down fat tissue and stimulates gluconeogenesis (production of glucose by the liver). Growth hormone also stimulates the secretion of insulin-like growth factor-1 (IGF-1) from the liver. The production of IGF-1 leads to the muscle-building and bone-growth properties of growth hormone.
When compared with HIV negative men and HIV positive men without lipodystrophy, HIV positive men with VAT tend to have lower growth hormone concentration. When exogenous (not produced by the body) growth hormone is provided, visceral fat decreases.
Recombinant human growth hormone (rhGH) has been marketed under various brand names. Serostim, one growth hormone product, has been used to treat AIDS wasting, and it was observed that patients treated with Serostim gained lean body mass while losing fat.
For example, in the STARS (Serostim in the Treatment of Adipose Redistribution Syndrome) trial, daily growth hormone therapy was associated with an 8.6% reduction in VAT from baseline -- a significant decrease over placebo at week 12. (Serostim administered every other day was associated with a VAT decrease of 4.2% from baseline, which was not a statistically significant change.) Reductions in trunk-to-limb-fat ratio were significant in both Serostim dosing groups. The effect on VAT was maintained to the trial's end at week 24, even in a study group that was rerandomized from daily therapy to placebo at week 12.
In addition to changes in VAT, decreased levels of low-density lipoprotein (LDL, or "bad") cholesterol and increased levels of high-density lipoprotein (HDL, or "good") cholesterol were seen in the daily-treatment group at week 12. No significant change in triglycerides was observed. One potentially negative side effect seen in the Serostim groups was an increase in fasting blood glucose levels. However, the higher levels remained within normal limits in all study participants. Other bothersome side effects of Serostim included fluid retention and muscle and joint aches.
A smaller study by Polyxeni Koutkia, MD, of the Massachusetts General Hospital Program in Nutritional Metabolism and colleagues tested growth hormone releasing hormone (GHRH, marketed as Geref) for the treatment of fat accumulation. Thirty-one patients with increased waist-to-hip ratio were randomized to receive GHRH or placebo for 12 weeks. Lab tests and DEXA/CT scanning were employed to track the change in levels of IGF-1 (used to detect overall changes in levels of growth hormone in response to GHRH), as well as the secondary study endpoints of change in body composition and other lab values.
Concentrations of IGF-1 increased significantly in the GHRH group. Lean body mass also increased significantly, and total fat mass did not change significantly. DEXA scans indicated significant decreases in trunk fat, and CT scans showed that abdominal VAT decreased 9% on average in the GHRH group and increased by 1% in the placebo group.
|Lipodystrophy and Cardiovascular Risk|
Lipodystrophy is often associated with metabolic abnormalities, including hypertriglyceridemia (elevated levels of certain blood fats), decreased HDL cholesterol levels, and high serum glucose levels and accompanying insulin resistance. These abnormalities, along with increased visceral fat, are associated with increased cardiovascular risk.
HIV infection was associated with hypertriglyceridemia and low levels of HDL and LDL cholesterol prior to the introduction of HAART. With HAART, increases in triglycerides and LDL cholesterol with persistently low HDL levels have been observed. This change is worrisome because of the increased risk of cardiovascular disease associated with hyperlipidemia.
Lipid abnormalities should be treated following guidelines for HIV negative individuals and by watching for interactions between antiretrovirals and cholesterol-lowering agents. For treating high cholesterol, pravastatin (Pravachol) is the preferred statin drug in terms of interactions with HAART drugs.
In a large, global case-control study of cardiovascular risk factors, Dr. Salim Yusuf and colleagues from the Population Health Research Institute assessed the effect of various risk factors on cardiovascular disease in HIV negative participants. Abnormal lipids was one of the two most important risk factors for cardiovascular disease worldwide (the other was smoking). Abdominal obesity was associated with increased risk of cardiovascular disease even when adjusted for other risk factors.
TH9507 is a synthetic analog of GHRH and triggers the release of growth hormone in a similar way. Growth hormone is usually released from the pituitary in "pulses" based on stimulation by GHRH. Administration of TH9507 results in similar pulsatile secretion of growth hormone.
A Phase II study of TH9507, described in the August 12, 2005, issue of the journal AIDS, enrolled 61 patients in three groups (placebo or 1 mg or 2 mg TH9507 daily). The primary outcome measure was change in abdominal fat. Trunk fat (assessed by DEXA scanning) decreased by 9% in the 2-mg treatment group at 12 weeks -- a significant decline. Visceral fat decreased by 15% in the 2-mg treatment group, and lean body mass increased in the treatment groups compared with the placebo arm. There was no change in limb fat. Decreased cholesterol and triglyceride levels were observed in the treatment group. TH9507 was generally well tolerated, with no effect on blood glucose levels.
Building on these results, a study presented at the 2007 Conference on Retroviruses and Opportunistic Infections examined the effect of TH9507 on HIV-associated abdominal fat accumulation. This randomized, double-blind, placebo-controlled trial enrolled over 400 participants at sites throughout the United States. In a press conference, investigator Steven Grinspoon, MD, of Harvard Medical School's Division of Nutrition emphasized the importance of developing agents to reverse fat accumulation as a means of improving the cardiovascular disease risk profiles of individuals living with HIV.
In the Phase III study, 412 participants were randomized in a 2:1 ratio to receive 2 mg TH9507 or placebo. Eligibility requirements included CD4 cell count greater than 100 cells/mm3, abdominal fat accumulation in the setting of HIV therapy, large waist circumference and high waist-to-hip ratio, and a fasting glucose level below 150 mg/dL (normal is up to 100 mg/dL). Patients could be on stable treatment with a lipid-lowering agent. Most participants (84%) were male.
The primary study endpoint was decreased VAT as measured by CT scan. Secondary endpoints included improved lipid profile (triglycerides and total cholesterol:HDL ratio), improved production of IGF-1, patient perception of body shape, and safety data (blood glucose level, hyperinsulinemia). The study was powered to detect an 8% difference between the two groups.
At 26 weeks, a 15% reduction in VAT was seen in the treatment group, compared with a 5% increase in VAT in the placebo group, for a net effect of 20%. The treatment did not increase subcutaneous adipose tissue. Waist circumference decreased three centimeters on average in the treatment group -- roughly a pants size, Dr. Grinspoon observed.
Lipid profiles improved in the treatment vs placebo group, and no increase in fasting glucose was noted in the treatment group. Additionally, there was no effect on immune parameters -- TH9507 did not appear to either raise or lower CD4 cell counts in either group. Side effects included headaches and arthralgias in more than 10% of participants in both groups. There were slightly more events of extremity swelling, muscle aches, and urticarial (allergic) rash in the treatment group.
A theoretical safety concern with both Serostim and TH9507 is that increased levels of IGF-1 caused by increased growth hormone may contribute to tumorgenesis. Individuals with active malignancies are advised to avoid either agent, although no increase in cancer incidence or risk has been observed to date.
In conclusion, the investigators stated that TH9507 appears to decrease VAT and improve cardiovascular disease risk, but noted that more safety data and data on the durability of the treatment effect are needed. The study is ongoing to one year, with the participants who were originally randomized to receive TH9507 re-randomized to receive either continued treatment or placebo to assess the durability of the drug's effect. Another Phase III trial is also now underway in North America and Europe (see "Open Clinical Trials," in this issue).
Interestingly, in addition to undergoing studies of its application in HIV-associated lipodystrophy, TH9507 is also in a Phase II trial to assess the cognitive effects of GHRH in patients ages 55-80 with mild cognitive impairment. This study is based on preliminary indications that GHRH improves cognitive function in healthy older people.
|Other Treatment Options|
A small study by Dr. Gilles Thoni and colleagues of the Sports, Performance, Health Laboratory at the University of Montpellier, France, showed loss of visceral fat with individualized, supervised exercise. In a small study with 19 participants, VAT was assessed by CT scan at baseline and after four months of regular aerobic exercise. There was a 12.8% reduction of total adipose tissue, with a 12% reduction in VAT and improvement in lipid parameters.
Metformin, a drug used to treat diabetes, reduces hepatic gluconeogenesis, decreases absorption of glucose from the gastrointestinal tract, and increases insulin sensitivity, resulting in increased peripheral glucose uptake.
Metformin was tested in a randomized, placebo-controlled study by Dr. Colleen Hadigan of Massachusetts General Hospital and colleagues involving 26 HIV positive participants with abnormal glucose tolerance, high waist-to-hip ratios, and fat redistribution. Participants in the treatment group experienced decreased insulin resistance with reduction in insulin levels. There was significant reduction in weight and a 6% decrease in VAT in the treatment group, with an 8% increase in the placebo group. However, metformin is not currently recommended for patients who are not diabetic because the evidence to date is insufficient to support its use for treating fat accumulation.
Lipodystrophy diagnosis and management remains a major challenge in HIV clinical care. Growth hormone has been used successfully to treat fat accumulation, and TH9507 appears to hold promise for the management of HIV- and HAART-associated fat accumulation and metabolic abnormalities with fewer side effects than previous treatments. "If you look at [our] data compared to data on growth hormone," Grinspoon stated at the Retrovirus Conference, TH9507 is "much more palatable, yet you get the same thing for the buck. You get the same about 15 to 20 percent reduction in visceral fat, with an improvement across lipids, but without toxicity in terms of glucose."
A new, affordable, and more tolerable lipodystrophy treatment option is needed to decrease cardiovascular risk factors in HIV positive individuals -- and to improve self-perception and quality of life. Unfortunately, a major issue with TH9507, if approved, will be cost of therapy. Currently, the growth hormone product Serostim is only approved for treatment of HIV wasting and is prohibitively expensive for most patients. A sustained benefit must be demonstrated by TH9507 in order to justify the cost to insurers, and this evidence will take time to accumulate. TH9507 is one to watch as it progresses in the clinical development pipeline.
Anne Monroe, M.D., is a resident in Internal Medicine at Jackson Memorial Hospital in Miami, Florida. She has a long-standing interest in HIV clinical trials and women's health.
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