Treatment of hiv-associated dysmorphia/dysmetabolic syndrome (HADDS) with or without lipodystrophy

a technology of lipodystrophy and hiv, applied in the direction of metabolism disorder, drug composition, peptide/protein ingredient, etc., can solve the problems of affecting the clinical outcome of patients with hiv. the effect of reducing fat mass and urinary nitrogen excretion, increasing lean body mass and improving clinical outcom

Inactive Publication Date: 2008-01-03
LAB SA (FR) +1
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  • Abstract
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  • Application Information

AI Technical Summary

Benefits of technology

RhGH therapy effectively reduces fat accumulation in areas like buffalo hump and truncal adiposity, increases lean body mass, and improves metabolic parameters without significant adverse effects, offering a promising treatment for HADDS.

Problems solved by technology

However, in addition to developing abnormal adipose accumulation, some HADDS patients develop abnormally depleted subcutaneous adipose tissue, termed “peripheral lipodystrophy” (or lipoatrophy) at other specific sites.
However, it is unclear which, if any, of the patients in the two aforementioned preliminary reports were HADDS patients, and what percentage of HADDS patients have preclinical indicators of abnormal endothelial function.
However, it may take years before well-designed, prospective, observational cohort studies precisely quantify the risk of premature coronary artery disease in patients with HADDS.
As discussed further below, excess accumulation of visceral adipose tissue has been associated with adverse clinical outcomes.
The physical manifestations of HADDS are also of public health significance because these manifestations are perceived by many patients to be disturbing, disfiguring, appalling, stigmatizing, and / or threatening loss of privacy.
Concerns about health, appearance, potential stigmatization and loss of privacy in the workplace and elsewhere, may lead some patients with HADDS to discontinue otherwise effective antiretroviral therapy (Struble and Piscitelli, 1999).
These concerns may also lead other HIV patients to refuse to initiate medically necessary antiretroviral therapies for fear of developing the syndrome and the increased medical risks associated with it (Cheng, 1999).
This could eventually lead to increased HIV infectivity, more opportunistic complications, and increased medical costs.
These risk factors include abnormally accumulation of visceral adipose tissue, hyperlipidemia, hyperinsulinemia, and premature atherosclerotic changes associated in HADDS, may result in increased risk for cardiovascular disease and stroke (Henry et al, 1998).
Other metabolic manifestations associated with HADDS syndrome also have the potential to become medically significant problems warranting therapeutic intervention.
It is difficult to pharmacologically manage hyperlipidemia and hyperinsulinemia in HIV patients receiving combination antiretroviral therapy because the antiretroviral agents typically interact with anti-hyperlipidemics (statins, fibrates) and anti-hyperglycemic agents (thiazides and glitazones), which also undergo significant hepatic metabolism (Henry et al, 1998).
These abnormalities include hypertension, hypogonadism, impaired sexual function (decreased, erectile dysfunction), menstrual irregularities, hair loss, dry skin, and ingrown toenails that can become infected, peripheral neuropathy, liver steatosis, osteoporosis with bone fractures and avascular necrosis of the hips, and derangement of the complement system with coagulation disorders, leading to increased bleeding in hemophiliacs.
These results tend to implicate the protease inhibitors themselves in the development of this problem.
However, other researchers have found that the protease inhibitors per se are not always associated with the morphologic and metabolic abnormalities of lipodystrophy syndrome and HADDS (Lo et al, 1998; Kotler et al, 1998; Brinkman 1999; Carr, 1999b; Gervasconi, 1999; Hadigan et al, 1999).
Despite advances in treating the retrovirus infection and the complications of AIDS, some HIV-infected patients still develop overt AIDS wasting (or cachexia), which involves profound depletion of weight and lean body mass.
However, this non-HIV related syndrome typically develops over many years.
However, the potential for reduction of the abnormal adipose tissue accumulation is uncertain.
Since visceral adiposity, buffalo hump, and other fat accumulation in HIV-1-infected individuals with HADDS does not the result from Cushing's Syndrome (Lo et al, 1998), it would be unwise to treat it as such.
Dietary modification and exercise are of limited success in reducing abnormally distributed regional fat accumulation such as buffalo hump and visceral adiposity (Kotler et al, personal communication).
As described above, antiretroviral switch strategies have been disappointing at best.
However, because of its adverse effect profile, metformin may not be the best therapeutic agent to offer to most patients with HADDS.
Surgical interventions, such as liposuction and surgical excision, have been used with limited success to treat abnormally accumulated adipose tissue in the dorsocervical, submandibular, breast areas, or as lipomas.
It is not feasible to liposuction abnormally accumulated visceral adipose tissue due to the risk of bowel perforation.
Windisch et al (1998) reported that AIDS-associated wasting was characterized by weight loss, depletion of lean body mass and preservation of body fat, leading to muscle weakness and organ failure.

Method used

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[0120] Examples of production of amino acid substitutions in proteins which can be used for obtaining analogs of the hGH for use in the present invention include any known method steps, such as presented in U.S. Pat. RE 33,653; 4,959,314; 4,588,585 and 4,737,462, to Mark et al; U.S. Pat. No. 5,116,943 to Koths et al; U.S. Pat. No. 4,965,195 to Namen et al; and U.S. Pat. No. 5,017,691 to Lee, et al, and lysine substituted proteins presented in U.S. Pat. No. 4,904,584 (Shaw et al).

[0121] Among the substances which bind to and initiate signalling of the human growth hormone receptor which may be used in accordance with the present invention are all of those growth hormone analogs and mimetics already known in the literature, such as, for example, are disclosed in U.S. Pat. Nos. 5,851,992; 5,849,704; 5,849,700; 5,849,535; 5,843,453; 5,834,598; 5,688,666; 5,654,010; 5,635,604; 5,633,352; 5,597,709; and 5,534,617.

[0122] Preferably, the hGH variant or analog will have a core sequence, whi...

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Abstract

Pathological regional adipose tissue accumulation associated with HIV-associated dysmorphic / dysmetabolic syndrome (HADDS) which may occur with or without subcutaneous adipose tissue lipodystrophy (and which is also described as HIV-associated adipose redistribution syndrome or HARS and other specific medical terms), is treated by administering an effective amount of human growth hormone or other substance which binds to and initiates signalling of the hGH receptor. Alternatively, a substance which stimulates production of endogenous hGH, such as human growth hormone releasing hormone, may be administered. HADDS and related syndromes include abnormal adipose tissue accumulation in the visceral, submandibular, supraclavicular, pectoral, mammary and / or dorsocervical (buffalo hump) area, and / or with subcutaneous lipomas, with or without associated metabolic or other physiologic abnormalities.

Description

CROSS-REFERENCE TO RELATED APPLICATION [0001] The present application is a continuation of application Ser. No. 10 / 725,484, filed Dec. 3, 2003, which is a division of application Ser. No. 09 / 475,989, filed Dec. 30, 1999, now issued as U.S. Pat. No. 6,696,063, which claims the benefit of priority from provisional application No. 60 / 114,389, filed Dec. 30, 1998, the entire contents of these applications being hereby incorporated herein by reference.FIELD OF THE INVENTION [0002] The present invention is directed to a method for treating HIV-associated dysmorphia / dysmetabolic syndrome or HIV-associated adipose redistribution syndrome, and related syndromes. BACKGROUND OF THE INVENTION [0003] Advances in antiviral treatment of HIV infection, along with developments in the prophylaxis and therapy of opportunistic infections, have greatly improved the long-term health of HIV-infected individuals. However, along with improved antiretroviral therapy a new syndrome has developed, which is ide...

Claims

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Application Information

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Patent Type & AuthorityApplications(United States)
IPC IPC(8): A61K38/25A61P3/00A61P31/18A61K38/27
CPCA61K38/27A61K38/25A61P3/00A61P31/18
InventorTORRES, RAMON A.
OwnerLAB SA (FR)