CA2257804A1 - Treatment of hiv-associated dysmorphia/dysmetabolic syndrome - Google Patents

Abstract

HIV-associated dysmorphic/dysmetabolic syndrome (HADDS) and related syndromes are 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. The HADDS may include dorsocervical fat pads (buffalo hump) and truncal adiposity (crix belly), particularly in AIDS patients undergoing protease inhibitor therapy.

Description

JAN-04-1999 16:26 FROM BRO~JDY AND NEIMRRK TO COWLING&HENDERS P.03i45 TREATJMENT OF HIV-ASSOCIATED DXSMORPHIA/DXSMETABOLIC SYNDROME
Fz_e_ld of the Invention The present invention is directed to a method for treating HIV-associated dysmorphia/dysmetabolic syndrome and S related syndromes.
Background of the Invention 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-0 positive individuals. However, despite these advances in treating the underlying retrovirus infection and the complications of I~.IDS, there are still patients who have lost lean body mass, either from malnutrition or from other causes. While several clinical studies have associated malnutrition ~,aith decreased caloric intake, therapies designed to increase caloric intake have not proven effective in replacing lean body mass.
A Condition identified herein as HIV-associated dysmorphia-dysmetabolic syndrome, or HADDS, or alternatively, fat maldistribution syndrome, FMS, has been noted in patients suffering from chronic HIV infection, often in conjunction with the use of highly active combination antiretroviral therapies 'that include an HIV protease-inhibiting agent (Carr et al, 1998; Lo et al, 1998). It is a multisystemic, gender dimorphic disorder associated with HIV infection which includes (Z) abnormalities of body composition or habitus, (2) metabolic alterations, and (3) possibly other abnormal physiology.

JAN-04-1999 16:27 FROM BROWDY AND NEIMARK TO COWLING&HENDERS P.04i45 The syndrome is relatively new, and, consequently, there is not yet a standardized name for the syndrome. Names other than those noted above include HIV-associated adipose redistribution syndrome CHARS); protease paunch, although the syndrome may not be directly related to protease inhibitors; HIv-related Buffalo Hump;
HIV-related breast enlargement; HIV-related symmetric lipomatosis;
HIV-associated Lipodystrophy Syndrome (HALS); and HIV-associated Dysmorphia/Metabolic Syndrome (HARMS).
The complex syndrome, involving rapid (within weeks to months) fat accumulation with limb wasting, facial wasting, and concomitant hyperlipidemia and hyperinsulinemia, in the absence of hypercortisolism, is unique in the history of medicine. Its etiology is unknown. The bodily manifestations of the syndrome have important public health significance. The body habitus changes are frightening, disfiguring, and stigmatizing to patients. These changes may lead to physical discomfort and disability and could lead to discontinuation of otherwise effective antiretroviral therapy or refusal to initiate medically necessary antiretroviral therapies for fear of developing the syndrome. This could lead to increased HIv infectivity, more opportunistic complications, and increased medical costs.
These medical complications are occurring with increased frequency in patients with HIV/AIDS_ It is unclear if the syndrome is drug-related. Although it is more prevalent in HIV/AIDS patents who have received antiretroviral medications (highly active antiretroviral therapy with protease inhibitors), in some cases the syndrome or some of JRN-04-1999 16:2'7 FROM BROIJDY RND NEIMARK TO COWLING&HENDERS P.05i45 its manifestations have been observed in, patients who have never received antiretrovirals (Lo et al, 1998; Carr et al, 1998).
Manifestations of the syndrome sometimes partially abate when antiretroviral medications are discontinued or changed, but the manifestations often do not abate completely or resolve relatively quickly. This raises a concern that the syndrome might occur in conjunction with immune reconstitution or autoirnmune phenomena associated with chronic suppression of HIV-1. There is no currently known effective medical therapy for this syndrome.
In HADDS there appears to be fat cell proliferation or hypertrophy in several areas of the body: the omental or visceral region, in the dorsocervical fat (which creates the "buffalo hump"), and elsewhere, including breast fat accumulation and occasionally multiple lipomatosis and bilateral asymmetric lipomatosis. Muscle or lean tissue is abnormally distributed, as there may be muscle depletion in the limbs, and abnormalities of the genitalia resembling Peyronie's Disease. There may be other alterations in body composition, such as cutaneous manifestations:
thinning hair, dry skin, abnormal nails, and prominent vei.ns_ This condition may or may not be associated with osteoporosis or avascular necrosis of the hips.
The body habitus changes are frightening and disfiguring, and may result in psychological or physical discomfort that lead to body image disturbance, depression, and agoraphobia; decreased mobility from buffalo hump or truncal obesity; ventral hernias, possibly related to rapid accumulation of abdominal fat; and respiratory insufficiency, possibly due to - _ CA 02257804 1999-O1-OS
JAN-04-1999 16:28 FROM BROWDY AND NEIMARK TO GOSLING&HENDERS P.06i45 excess accumulation of abdominal fat. These changes can also be socially stigmatizing because they may reveal that the patient has HIV/AIDS-Moreover, the metabolic manifestations of the syndrome may contribute to the development of medically serious problems, such as sudden and severe hyperglycemia, new-onset diabetes mellitus, difficult to treat hyperlipidemia, premature coronary artery disease, gout, and osteoporosis with bone fractures and avascular necrosis of the hips. Other typical metabolic or 7 physiological abnormalities may include elevated triglycerides and cholesterol abnormalities, including elevated total cholesterol, elevated LDL cholesterol, and'decreased HDL-cholesterol. Less common metabolic or physiologic abnormalities appear to include hypertension, hormonal abnormalities, or other abnormalities such as derangement of the complement system or coagulation disorders, leading to increased bleeding in hemophiliacs.
The changes in body composition Which may be related to antiretroviral treatment of HIV infection are more related to the regional distribution of fat than to the absolute amounts of fat 0 and lean tissue. The most visible regional alteration is an increase in waist size. Kotler et al (1998) reported finding increased visceral fat along with pelvic and perinephric fat using a whole body MRI technique. Carr et al (1998) observed peripheral HADDS in HIV-positive patients receiving protease inhibitors 5 which, together with the known side effects of protease inhibitors, e.g., hvperlipidemia and diabetes mellitus, suggests that protease inhibitors cause metabolic perturbations leading to J~1N-04-1999 16: 28 FROM BROLJDY AND NE I MRRK TO GOL.IL I NG&HENDERS P. 07145 insulin resistance. Carr et al (1998) documented increased truncal fat in a majority (64%) of their protease inhibitor-treated subjects using the technique of dual-energy X-ray absorptiometry. They also found evidence of insulin resistance, although clinically apparent diabetes mellitus was very uncommon.
An amino acid sequence in the catalytic site of HIV protease was found to have a significant homology with a low density lipoprotein receptor-like protein. These results would tend to implicate the protease inhibitors themselves in the development of 7 this problem, but other researchers have found that the protease inhibitors pez se axe not responsible for these symptoms.
Other visible body changes in patients which have been reported in the literature include thinning of the skin on the arms and legs, and increased wrinkling of the face, especially in S the nasolabial folds. A buffalo hump (dorsocervical fat pad) may be present, as well as enlargement of the supraclavicular fat pads with apparent bulging. This condition also affects females, with the most notable changes, in addition to increased waist size, being narrowing of the hips and enlargement of the breasts.
Viraben et a1 (1997) reported a case study involving eight patients who developed either partial or generalized lipodystrophy after protease inhibitor therapy. In four of these patients, either diabetes or insulin resistance was also discovered. While two patients developed progressive loss of subcutaneous fat from both legs, excess fat deposition in the unaffected buttocks and abdomen gave an impression of obesity. In six cases, a cachetic appearance was observed resulting from the JRN-04-1999 16:29 FROM BROODY RND NEIMARK TO GOOLING&HENDERS P.08i45 loss of buccal, parotid and preauricular fat pads. Two patients exhibited a generalised loss of fatty tissue from the face.
Lo et al (1998) reported the results of studies done in eight HIV-1-positive patients referred for investigation of buffalo hump. Only four of these patients were on triple antiretroviral regimens that included a pxotease inhibitor. No other signs of Cushing's Syndrome were present in the patients.
The fact that four of the patients with buffalo hump had no history of protease-inhibitor use indicates that development of non-Cushingoid buffalo hump is not unique to protease-inhibitor therapy. The mechanism of further increase in triglyceride values in patients with buffalo hump is not certain, although a possible relation between increased triglyceride concentration and atypical body-fat distribution should be considered. For example, central fat accumulation may lead to the metabolic syndrome of insulin resistance, hypertriglyceridemia and hypertension if the major component gained is visceral fat.
Miller et al (1998) reported that some patients experienced an increase in abdominal girth with symptoms of 0 abdominal fullness, distension, ox bloating after adding indinavir, a protease inhibitor, to combination drug regimens for HIV-1 infection. In several patients with these symptoms, abdominal computed-tomography (CT) scans suggested an excess amount of intra-abdominal fat and a relative paucity of 5 subcutaneous fat. There were no relationships among visceral fat, hypertriglyceridemia, and hypercholesterolemia.

JAN-04-1999 16:29 FROM BRO~IDY AND NEIMARK TO GOSLING&HENDERS P.09i45 Additional reports of HADDS were presented at the 5th Conference on Retroviruses and Opportunistic Infections February 1-5, 1998, at Chicago, IL. Mulligan et al (1998) compared results obtained in patients before and after beginning an antiretroviral regimen that included a protease inhibitor or lamivudine. No significant changes in total or regional fat or lean body mass were found by dual-energy X-ray absorptiometry in any group over the short time period of about four months.
Keruly et al (1998) reported on short-term protease 7 inhibitor use in relation to hyperglycemia and diabetes. They calculated an incidence of 0.35 per 100 person-months for severe hyperglycemia and 0.52 for any degree of hyperglycemia. The median time of onset after first use of a protease inhibitor (ritonavir, saquinavir and indinavir) was 53 days. Thus, it appears that metabolic changes are seen early in the course of PI
therapy, while the morphological changes may take longer.
However, Dong et al (1998) reviewed all cases of diabetes associated with the use of protease inhibitors and found six cases of hyperglycemia from across the U.S. which were related to the 0 use of protease inhibitors, and concluded that protease inhibitor-induced hyperglycemia appears to be a rare occurrence.
Bjorntop (1996) found a similar syndrome of truncal obesity and metabolic abnormalities, including insulin resistance in HIV-negative subjects. This non-HIV related syndrome is known 5 as Syndrome X.
The FDA reported that there were reports of peripheral insulin resistance due to alterations in fat metabolism in JAN-04-1999 16:30 FROM BROODY RND NEIMARK TO GOWLING&HENDERS P.10i45 patients receiving protease inhibitors for treatment of their HIV
infection, and some of these diabetic patients were found to have truncal obesity. Other patients were found to have hypertriglyceridemia, even though this abnormality was first reported and associated with HIV infection, in the presence or absence of disease complications. Patients with hypertriglyceridemia prior to starting therapy appear to have an exacerbation of the condition while on therapy and do not return to their previous state. In other patients, serum cholesterol 7 concentrations rise, though rarely to dangerously high levels.
Some patients developed hypertension and, in others, low serum testosterone concentrations developed or pre-existing hypogonadism persisted.
From the above, it is unclear if administration of protease inhibitors results in HADDS or if the H.A.DDS results from the antiviral effect of the protease. The changes are not seen consistently in protease inhibitor-treated patients, and many patients have only certain elements of the syndrome. In some cases the syndrome or its manifestation have been observed in 0 patients who have never received antiretrovirals. The potential for reversal of the altered fat distribution is uncertain. What is suggested by the reports is that buffalo hump in HIV-1-infected individuals is not necessarily associated with Cushing's Syndrome or hyperglycemia. There is also evidence that raised triglyceride 5 concentrations may occur with visceral fat accumulation or buffalo humps.
- g JAN-04-1999 16:30 FROM BROWDY AND NEIMARK TO COWLING&HENDERS P.11i45 As noted above, serum abnormalities occur with variable frequency in patients with truncal obesity. Serum cortisol concentration typically is normal, although 24-hour urinary-free cortisol may be moderately elevated. Other studies have found no increase in cortisol secretive. Due to alterations in fat distribution, some patients appeared to have a phenotype reminiscent of Cushing's Syndrome, but this was ruled out in all reported cases.
Several studies have documented insulin resistance as a 0 result of protease inhibitor therapy, and the incidence of clinical diabetes mellitus in patients receiving protease inhibitors appears to be low and the severity varies.
SEROSTIM" recombinant human growth hormone (rhGH) produced by Serono Laboratories, Inc., has recently been given accelerated FDA approval fox treating weight loss and wasting in patients with AIDS.
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 0 ~ organ failure. Although the FDA has approved recombinant growth hormone for treating AIDS-associated wasting, the adverse event profile is similar to that of other recombinant growth hormone products. Trials of recombinant growth hormone on the control of wasting in patients with AIDS have been encouraging. Post-s marketing experience with. over 10,000 AIDS wasting patients receiving SEROSTIM since 1995 indicates that a three-month course was effective in 98~ of the patients.
_ g _ JAN-04-1999 16-30 FROM BRO~JDY AND NEIMARK TO GOWLING&HENDERS P.12i45 Schambelan et al (1996) and Krent2 et al (1993) compared metabolic and anthropometric changes induced by pharmacological versus physiological doses (5.0 vs. 2.5 mg, every other day) of recombinant human growth hormone in 7.0 HIV-positive patients with AIDS or AIDS-related complex. During treatment, insulin-like growth factor-7. (IGF-1) levels increased significantly in the pharmacological rhGH treatment group, whereas no significant change was observed in IGF-1 in the group receiving a physiological dose of rhGH. In the group treated with 0 pharmacologic hGH, weight loss preceding the study was reversed in each of the four patients who completed the study. This weight gain was associated~with increases in lean body mass and total body water, with concomitant decreases in fat mass and urinary nitrogen excretion. Significant positive changes in body composition were also observed in the pharmacological dose hGH
group, and these changes correlated with improvements in physical function (treadmill performance). The pharmacological dose of rhGH was associated with minor increments in fasting plasma glucose, insulin and C-peptide concentrations, which were of 0 negligible clinical significance.
To date, no treatment other than surgical liposuction of the fat pad or plastic surgery has shown to be effective in treating some features of HADDS. However, these methods do not affect the underlying metabolic abnormalities observed in HADDS.
5 Moreover, while liposuction may decrease abnormal fat deposits, liposuction does not restore fat to the areas from which fat has been lost. Furthermore, these techniques present the risks of JAN-04-1999 16:31 FROM BROI~DY AND NEIMARK TO GO~JLING&HENDERS P.13i45 anesthesia and scarring. Also, it is not feasible to liposuction visceral omental fat because of the risk of bowel perforation.
S mma of the Inve tlon It is an object of the present izwention to overcome the aforementioned deficiencies in the prior art.
It is another object of the present invention to treat any type of HADDS and related syndromes, including excess dorsocervical fat accumulation, breast fat accumulation and 0 truncal adiposity, with recombinant human growth hormone (rhGH) or any other substance which binds to and initiates signalling of the human growth hormone receptor or which stimulates release of or potentiates the activity of endogenous hGH.
According to the present invention, human growth hormone (hGH) is administered to treat HADDS and related syndromes, such as Syndrome X (also known as Metabolic Syndrome X) and hereditary lipodystrophy. The human growth hormone administered is preferably recombinant human growth hormone (rhGH).
Alternatively, a substance which stimulates release of endogenous 0 growth hormone, such as growth hormone releasing hormone (GHRH) or other substances which agonize the GHRH receptor, may be used.
Any HADDS patient can be treated by means of the present invention.
r~ra; 1 Pct nPgcrivtion of tk~e Present Invention 5 The present invention relates to the discovery that HIV-associated dysinorphia/dysmetabolic syndrome (HADDS) may be treated by the administration of an effective amount of human growth JAN-04-1999 16:31 FROM BROWDY AND NEIMARK TO COWLING&HENDERS P.14i45 hormone. The HADDS which may be treated in accordance with the present invention may present itself as, for example, dorsocervical fat pads ("buffalo hump"), visceral adiposity ("truncal obesity", "omental fat accumulation", "Crix belly" ox "protease paunch"), abnormal breast fat accumulation, and other abnormal fat accumulation (including single or multiple lipomas and bilateral symmetric lipomatoses).
Human growth hormone, also known as somatotropin, is a protein hormone produced and secreted by the somatotropic cells of 0 the anterior pituitary. Secretion is regulated by a releasing factor, i.e., the growth hormone-releasing hormone (GHRH), and by an inhibitory factor, somatostatin. Human growth hormone plays a key role in somatic growth through its effects on the metabolism of proteins, carbohydrates and lipids.
5 Human growth hormone is a single polypeptide chain of 191 amino acids (Bewley et al, 1972) having two disulfide bands, one between Cys-53 and Cys-165, forming a large loop in the molecule, and the other between Cys-182 and Cys-189, forming a small loop near the C-terminus. The DNA sequence that confirmed 0 the amino acid sequence was reported by Martial et al (1979).
Purified hGH is a white amorphous powder in its lyophilized form.
It is readily soluble (concentrations >10 mg/L) in dilute aqueous buffers at pH greater than 7.2.
In solution, hGH exists predominantly as a monomer, with 5 a small fraction as dimers and higher molecular' weight oligomers.
Under certain conditions, hGH can be induced to form larger amounts of dimers, trimers and higher oligomers.

JRN-04-1999 16:32 FROM BRO~JDY RND NEIMRRK TO GOIJLING&HENDERS P.15i45 Several derivatives of hGH are known, including naturally-occurring derivatives, variants anal metabolic products, degradation products primarily of biosynthetic hGH and engineered derivatives of hGH produced by genetic methods. One example of a naturally-occurring derivative of hGH is GH-V, a variant of growth hormone found in the placenta. Other members of the gene locus are described in Chen et al (1989). Any derivative of hGH, including derivatives designed to be long-lasting in the body, can be used fox the purpose of the present invention as long as it 0 retains the biological activity of hGH.
Methionyl hGH was the first form of hGH to be produced through recombinant DNA technology. This compound is actually a derivative of hGH having one additional methionine residue at its N-terminus (Goeddel et al, 199).
.A naturally-occurring variant of hGH called 20-K-hGH has been reported to occur in the pituitary as well as in the bloodstream (Lewis et al, 1978; Lewis et al, 1980). This compound, which lacks the 15 amino acid residues from Glu-32 to Gln-46, arises from an alternative splicing of the messenger 0 ribonucleic acid (DeNoto et al, 1981). This compound shares many, but not all of the biological properties of hGH.
20-K-HGH is made in the pituitary and secreted into the blood- It makes up about 5~ of growth hormone output of adults, and about 20% of growth hormone output of children. It has the same growth promoting activity as 22 kD growth hormo~.e, and has been reported to have equal to or greater the amount of lipolytic activity as the 22 kD form. It binds to growth hormone receptors JRN-04-1999 16:32 FROM BROWDY RND NEIMARK TO GOWLING&HENDERS P.16i45 with equal affinity as the 22 kD growth hormone, and has one tenth the lactogenic (prolactin-like) bioactivity as the 22 kD hormone.
Unlike 22 kD, the 20-k-HGH has weak anti-insulin activity.
A number of derivatives of hGH arise from prvteolytic modifications of the molecule. The primary pathway for the metabolism of hGH involves proteolysis. The region of hGH around residues 130-150 is extremely susceptible to proteolysis, and several derivatives of hGH having nicks or deletior~s in this region have been described (Thorlacius-Ussing, 1987). This region 0 is in the large loop of hGH, and cleavage of a peptide bond there results in the generation of two chains that are connected through the disulfide bond at Cys-53 and Cys-165. Many of these two-chain forms are reported to have increased biological activity (Singh et al, 1974). Many derivatives of human growth hormone have been generated artificially through the use of enzymes. The enzymes trypsin and subtilisin, as well as others, have been used to modify hGH at various points throughout the molecule (Lewis et al, 1977; Graff et al, 1982). One such derivative, called two-chain anabolic protein (2-CAP), was Formed through the controlled 0 proteolysis of hGH using trypsin (Becker et al, 1989). 2-CRP was found to have biological properties very distinct from those of the intact hGH molecule, in that the growth-promoting activity of hGH Was largely retained and most of the effects on carbohydrate metabolism were abolished.
5 Asparagine and glutamine residues in proteins are susceptible to deamidation reactions under appropriate conditions.
Pituitary hGH has been shown to undergo this type of reaction, JAN-04-1999 16:33 FROM BRObIDY AND NEIMARK TO GO~JLING&HENDERS P.17i45 resulting in conversion of Asn-152 to aspartic acid and also, to a lesser extent, conversion of Gln-137 to glutamic acid (Lewis et al, 1981). Deamidated hGH has been shown to,have an altered susceptibility to proteolysis with the enzyme subtilisin, suggesting that deamidation may have physiological significance in, directing proteolytic cleavage of hGH. Biosynthetic hGH is known to degrade under certain storage conditions, resulting in deamidation at a different asparagine (Asn-149). This is the primary site of deamidation, but deamidation at Asn-152 is also 7 seen (Becker et al, 1988)_ Deamidation at Gln-137 has not been reported in biosynthetic hGH.
Methionine residues in proteins are susceptible to oxidation, primarily to the sulfoxide. Both pituitary-derived and biosynthetic hGH undergo sulfoxidations at Met-14 and Met-125 (Becker et al, 1988). Oxidation at Met-170 has also been reported in pituitary but not biosynthetic hGH_ Both desamide hGH and Met-14 sulfoxide hGH have been found to exhibit full biological activity (Becker et al, 1988).
Truncated forms of hGH have been produced, either 0 through the actions of enzymes or by genetic methods. 2-CAP, generated by the controlled actions of trypsin, has the first eight residues at the N-terminus of hGH removed. Other truncated versions of hGH have been produced by modifying the gene prior to expression in a suitable host. The first 13 residues have been 5 removed to yield a derivative having distinctive biological properties (Gertler et al, 1985) in which the polypeptide chain is not cleaved.

J~1N-04-1999 16:33 FROM BROWDY RND NEIMARK TO GO~JLING&HENDERS P.18i45 Although human growth hormone was originally obtaizzed from pituitary glands of cadavers, these preparations were not electorphoretically homogeneous, and antibodies appeared in the serum of patients treated with preparations of the order of 500 purity, the immunogezzicity being attributed to inactive components. Recombinant DNA technology permitted production of an unlimited supply of hGkl in a number of different systems.
Purification of hGH from the culture medium is facilitated by the presence of only low amounts of contaminating proteins. In fact, it has been shown that hGH can be purified on a laboratory scale by a single purification step on a reversed-phase HPLC column (Hsiung et al (1989).
Recombinant human growth hormone, rhGH, is produced by Serono Laboratories, Inc., as SEROSTIM" which product has been given accelerated FDA approval for treating weight loss and wasting in AIDS patients. PROTROPIN" produced by Genentech, Inc. (South San Francisco, CA), differs slightly in structure from natural sequence hGH, having an additional methionine residue at the N-terminus. Recombinant hGH is generally marketed as vials containing hGH plus additional.excipients, e.g., glycine and mannitol, in a lyophilized form. A companion diluent vial is provided, allowing the patient to reconstitute the product to the desired concentration prior to administration of the dose.
Recombinant hGH can also be marketed in other well-known manners, such as prefilled syringES, etc.
After intravenous administration, the elimination of hGH
is described by first-order kinetics with a serum half-life of 7.2-JRN-04-1999 16:34 FROM BROWDY RND NEIMRRK TO GOWLING&HENDERS P.19i45 30 minutes in both animals and humans (Moors et al, 1988;
Hendricks et al, 1985). Traditionally, intramuscular injection has been the method of choice as the preferred route of delivery.
In humans, absorption of exogenous hGH appears to be more rapid from the intramuscular site, with a time to maximum concentration of two to three hours, compared to four to six hours after subcutaneous administration. The disappearance phase from serum has been reported to range from 12-20 hours for intramuscular administration, and 20-24 hours after subcutaneous administration (Albertsson-Wikland et al, 1986; Jorgensen et al, 1987). In general, no significant differences have been observed in the pharmacokinetics or biological activities of recombinant natural sequence hGH, recombinant N-methion.yl-hGH, or pituitary-derived material in humans (Moors et al, 1988; Jorgensson et al, 1988).
The term "human growth hormone", as used in the present invention, is intended to include the naturally-occurring derivatives, as noted above, including, without limitation, both the 20 kD and the 22 kD human growth hormone, GH-v, and other members of the growth hormone gene locus as described in Chen et al (1989). The term also includes functional derivatives, fragments, variants, analogs, or salts which retain the biological activity of growth hormone, i.e., Which act as agonists to the growth hormone receptor. In other words, they are capable of binding to the growth hormone receptor to initiate the signaling activity of the receptor.
"Functional derivatives" as used herein covers derivatives which may be prepared from the fux~,ctioxnal groups which JAN-04-1999 16:34 FROM BROWDY AND NEIMRRK TO COWLING&HENDERS P.20i45 occur as side chains on the residues or the N- or C-terminal groups, by means known. in the art, and axe included in the invention as long as they remain pharmaceutically acceptable, i.e., they do not destroy the biological activity of hGH as described herein, i.e., the ability to bind the hG8 receptor and initiate receptor signalling, and do not confer toxic properties on compositions containing it. Derivatives may have chemical moieties, such as carbohydrate or phosphate residues, provided such a derivative retains the biological activity of hGH and 0 remains pharmaceutically acceptable.
For example, derivatives may include aliphatic esters of the carboxyl groups, amides of the carboxyl groups by reaction with ammonia or with primary or secondary amines, N-acyl derivatives or free amine groups of the amino acid residues formed 5 with acyl moieties (e.g., alkanoyl or carbocyclic aroyl groups) or O-acyl derivatives of free hydroxyl group (e.g., that of seryl or threonyl residues) formed with acyl moieties. Such derivatives may also include for example, polyethylene glycol side-chains which may mask antigenic sites and extend the residence of the p molecule in body fluids.
Of particular importance is a growth hormone that has been derivatized or combined with a complexing agent to be long lasting. For example, pegylated versions, or growth hormones genetically engineered to exhibit long lasting activity in the S body, can be used to treat HADDS according to the present invention.

JAN-04-1999 16:35 FROM BROIJDY RND NEIMARK TO GOWLING&HENDERS P.21i45 HGH that is acetylated at the N-terminus has been isolated and identified (Levels et al, 1979). It is not clear if acylation serves a regulatory role or is simply an artifact o~ the purification. However, it is expected that this the molecule exhibits anti-HADDS activity in a similar fashion to other hGH
derivatives.
The term "derivatives" is intended tv include only those derivatives that do not change one amino acid to another of the twenty commonly-occurring natural amino acids.
The term "salts" herein refers to both salts of carboxyl groups and to acid addition.salts of amino groups of the hGH
molecule or analogs thereof. Salts of a carboxyl group may be formed by means known in the art and include inorganic salts, for example, sodium, calcium, ammonium, ferric or zinc salts, and the like, and salts with organic bases as those formed, for example, with amines, such as triethanolamine, arginine or lysine, piperidine, procaine and the like. Acid addition salts include, for example, salts with mineral adds, such as, for example, hydrochloric acid or sulfuric acid, and salts with organic acids, 0 such as, for example, acetic acid or oxalic acid. Of course, any such salts must retain the biological activity of hGH relevant to the present invention, i.e., the ability to bind to the hGH
receptor and initiate receptor signalling.
A "fragment" of the growth hormone according to the 5 present invention refers to any subset of the molecule, that is, a shorter peptide which retains the desired biological activity.
Fragments may readily be prepared by removing amino acids from JaN-04-1999 16~35 FROM BROIJDY AND NEIMARK TO GOWLING&HENDERS P.22i45 either end of the hGH molecule and testing the resultant fox its properties as an hGH receptor agonist. Proteases for removing one amino acid at a time from either the N-terminal or the C-terminal of a polypeptide are known, and so determining fragments which retain the desired biological activity involves only routine experimentation.
Additionally, the polypeptide which has such hGH
receptor agonist activity, be it hGH, an analog or variant, salt, functional derivative or fragment thereof, can also contain 0 additional amino acid residues flanking the hGH polypeptide. As long as the resultant molecule retains the hGH receptor agonist ability of the core polypeptide, one can determine whether any such flanking residues affect the basic and novel characteristics of the core peptide, i.e., its receptor agonist characteristics, 5 by routine experimentation. The team "consisting essentially of", when referring to a specified sequence, means that additional flanking residues can be present which do not affect the basic and novel characteristic of the specified sequence. This term does not comprehend substitutions, deletions or additions within the 0 specified sequence.
A "variant" of the human growth hormone according to the present invention. refers to a molecule which is substantially similar to either the entire peptide or a fragment thereof.
Variant peptides may be conveniently prepared by direct chemical 5 synthesis of the variant peptide, using methods well known in the art. Of course, a variant human growth: hormone would have similar hGH receptor binding and signal initiating activity as hGH and JAN-04-1999 16=35 FROM BRO~ID'Y AND NEIMRRK TO GOWLING&HENDERS P.23i45 which would, therefore, be expected to have similar anti-HADDS
activity to hGH.
Amino acid sequence variants o~ the human growth hormone can be prepared by mutations in the DNAs which encode the synthesized human growth hormone derivatives. Such variants include, for example, deletions from, or insertions or substitutions of, residues within the amino acid sequence. Any combination of deletion, insertion, and substitution may also be made to arrive at the final construct, provided that the final 0 construct possesses the desired activity. Obviously, the mutations that will be made in the DNA encoding the variant peptide must not alter the reading frame and preferably will not create complementary regions that could produce secondary mRNA
structure (cf. European latent Publication No. EP 75,444, the S entire contents of which axe hereby incorporated by reference).
At the genetic level, these variants ordinarily axe prepared by site-directed mutageneis (as exemplified by Adelman et al, 1983) of nucleotides in the DNA encoding the peptide molecule, thereby producing DNA encoding the variant, and thereafter 0 expressing the DNA in recombinant cell culture. The variants typically exhibit the same qualitative biological activity as the non-variant peptide.
An "analog" of human growth hormone according to the present invention refers to a non-natural molecule which is substantially similar to either the entire molecule or to an active fragment thereof. An analog of human growth hormone useful in the present invention would exhibit anti-HADDS activity.
- az -_ _ CA 02257804 1999-O1-OS
JRN-04-1999 15:36 FROM BROI~)DY RND NEIMRRK TO GOWLING&HENDERS P.24/45 The types of substitutions which may be made in the human growth hormone according to the present invention may be based on analysis of the frequencies of amino acid changes between a homologous protein of different species. Based upon such analysis, conservative substitutions may be defined herein as exchanges within one of the following rive groups:
I. Small, aliphatic, nonpolar or slightly polar residues:
Ala, Ser, Thr, Pro, Gly II. Polar, negatively-charged residues and their amides:
Asp, Asn, Glu, Gln III. Polar, positively-charged residues:
His, Arg, Lys IV. Large, aliphatic non-polar residues:
Met, Leu, Ile, Val, Cys V_ Large aromatic residues:
Phe, Try, Trp Within the foregoing groups, the following substitutions are considered to be "highly conservative":
Asp/Glu His/Arg/Lys Phe/Tyr/Trp Met/Leu/Ile/Val Semi-conservative substitutions are defined to be exchanges between two of groups (I)-(IV) above which are limited to supergroup (A), comprising (I), (II), and (III) above, or to JAN-04-1999 16:36 FROM BROWDY AND NEIMRRK TO GOWLING&HENDERS P.25i45 supergroup (B), comprising (IV) and (V) above. Substitutions axe not limited to the genetically encoded or even the naturally-occurring amino acids. When the epitope is prepared by peptide synthesis, the desired amino acid may be used directly.
Alternatively, a genetically encoded amino acid may be modified by reacting it with an organic derivatizing agent that is capable of reacting with selected side chains or terminal residues.
Cysteinyl residues most commonly are reacted with alpha haloacetates (and corresponding amines), such as chloroacetic acid 0 or chloroacetamide, to give carboxylmethyl or carboxyamidomethyl derivatives. Cysteinyl residues also axe derivatized by reaction with bromotrifluoroacetone, alpha-bromo-beta-(5-imidazoyl)propionic acid, chloroacetyl phosphate, N-alkylmaleimides, 3-nitro-2-pyridyl disulfide, methyl-2-pyridyl .5 disulfide, p-chloromercuribenzoate, 2-chloromercuri-4-nitrophenol, or chloro-7-nitrobenao-2-oxa-1,3-diazole.
Histidyl residues are derivatized by reaction with diethylprocarbonate at pH 5.5-7.0 because this agent is relatively specific fox the histidyl side chain. Parabromophenacyl bromide ;0 is also useful; the reaction is preferably performed in 0.1 M
sodium cacodylate at pH 6Ø
Lysinyl and amino terminal residues are reacted with succinic or other carboxylic acid anhydrides. Derivatization with these agents has the effect of reversing the charge of the lysinyl :5 residues. Other suitable reagents for derivatizing alpha-amino acid-containing residues include imidoesters such as methyl picolinimidate; pyridoxal phosphate; pyridoxal; chloroborohydride;

JAN-04-1999 16:37 FROM BROWDY AND NEfMARK TO GOWLING&HENDERS P.26i45 trinitrobenzenesulfonic acid; O-methyliosurea; 2,4-pentanedione;
and transaminase-catalyzed reaction with glyoxylate.
Arginyl residues are modified by reaction with one or several conventional reagents, among them phenylglyoxal; 2,3-butanedione; and ninhydrin. Derivati~ation of arginine residues requires that the reaction be performed in alkaline conditions because of the high pKa of the guanidine functional group.
Furthermore, these reagents may react with the groups of lysine, as well as the arginine epsilon-amino group.
p The specific modification of tyrosyl residues per se has been studied extensively, with particular.interest in introducing spectral labels into tyrosyl residues by reaction with aromatic diazonium compounds or tetranitromethane. Most commonly,.
N-acetylimidazole and tetranitromethane are used to form O-acetyl 5 tyfosyl species and e-nitro derivatives, respectively.
Carboxyl side groups (aspartyl or glutamyl) are selectively modified by reaction with carbodiimides (R'N-C-N-R') such as 1-cyclohexyl-3-[2-morpholinyl-(4-ethyl)]carbodiimide or 1-ethyl-3-(4-azonia-9:,4-dimethylpentyl)carbodiimide. Furthermore, 0 aspartyl and glutamyl residues axe converted to asparaginyl and glutaminyl residues by reaction with ammonium ions.
Glutaminyl and asparaginyl residues are frequently deamidated to the corresponding glutamyl anal aspartyl residues.
Alternatively, these residues are deamidated under mildly acidic 5 conditions. Either form of these residues falls within the scope of this invention.

JAN-04-1999 16:37 FROM BROIJDY AND NEIMARK TO GOIJLING&HENDERS P.27i45 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. patents RE 33,653; 4,959,314; 4,588,585 and 4,737,462, to Mark et al; 5,116,943 to Koths et al; 4,965,195 to Namen et al; and 5,017,691 to Lee, et al, and lysine substituted proteins presented in US patent 4,904,584 (Shaw et al).
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. patents 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; 5,533,352; 5,597,709; and 5,534,617.
Preferably, the hG~-i variant or analog will have a core sequence, which is the same as that of the native sequence or biologically active fragment thereof, which has an amino acid sequence having at least 70~ identity to the native amino acid sequence and retains the biological activity thereof. More 0 preferably, such a sequence has at least 80% identity, at least 90% identity, or most preferably at least 95% identity to the native sequence.
The term "sequence identity" as used herein means that the sequences axe compared as follows. The sequences are aligned using Version 9 of the Genetic Computing Group's GAP (global alignment program), using the default (BLOSUM62) matrix. (values -4 to +11) with a gap open penalty of -12 (for the first null of a JAN-04-1999 16:38 FROM BROIJDY RND NEIMARK TO GOIJLING&HENDERS P.28i45 gap) and a gap extension penalty of -4 (per each additional consecutive null in the gap>. lifter alignment, percentage identity is calculated by expressing the number of matches as a percentage of the number of amino acids in the claimed sequence.
Analogs or variants in accordance with the present invention may also be determined in accordance with the following procedure- The DNA of the native sequence is known to the prior art and is found in the literature (Martial et al, 1979).
Polypeptides encoded by any nucleic acid, such as DNA or RNA, p which hybridizes to the complement of the native DNA or RNA under highly stringent or moderately stringent conditions, as long as that polypeptide maintains the biological activity of the native sequence, are also considered to be within the scope of the present invention.
Stringency conditions are a function of the temperature used in the hybridization experiment, the molarity o~ the monovalent cations and the percentage of formamide in the hybridization solution. To determine the degree of stringency involved with any given set of conditions, one first uses the 0 equation of Meinkoth et al. (1984) for determining the stability of hybrids of 100% identity expressed as melting temperature Tm of the DNA-DNA hybrid:
Tcn = 81.5°C + 16.6 (LogM) ~ 0.41 (mGC) - 0.61 (% ~orm) - 500/I~
where M is the molarity of monovalent cations, °sGC is the S percentage of G and C nucleotides in the DNA, % form is the percentage of formamide in the hybridization solution, and L is the length of the hybrid in base pairs. For each 2°C that the Tm JRN-04-1999 16:38 FROM BRO~1DY AND NEIMARK TO GOIJLING&HENDERS P.29i45 is reduced from that calculated for a 100% identity hybrid, the amount of mismatch permitted is increased by about lo. Thus, if the Tm used for any given hybridization experiment at the specified salt and formamide concentrations is 10°C below the Tm calculated for a 100% hybrid according to equation of Meinkoth, hybridization will occur even if there is up to about l0%
mismatch.
As used herein, highly stringent conditions are those which are tolerant of up to about 15~ sequence divergence, while moderately stringent conditions are those which axe tolerant of up to about 20% sequence divergence. Without limitation, examples of highly stringent (7.2-15°C below the calculated Tm of the hybrid) and moderately (15-20°C below the calculated Tm of the hybrid) conditions use a wash solution of 2 X SSC (standard saline citrate) and 0.5% SDS at the appropriate temperature below the calculated Tm of the hybrid. The ultimate stringency of the conditions is primarily due to the washing conditions, particularly if the hybridization conditions used are those which allow less stable hybrids to form along with stable hybrids. The 0 wash conditions at higher stringency then remove the less stable hybrids. A common hybridization condition that can be used with the highly stringent to moderately stringent wash conditions described above is hybridization in a solution of 6 X SSC (or 6 X
SSPE), S X Denhardt's reagent, 0.5a~SDS, 100 ~Cg/ml denatured,.
fragmented salmon sperm DNA at a temperature approximatEly 20° to 25°C below the Tm. If mixed probes are used, it is preferable to . JAN-04-1999 16=38 FROM BRO~.JDY RND NEIMARK TO GOLJLING&HENDERS P.30i45 use tetramethyl ammonium chloride (TMAC) instead of SSC (Ausubel, 1987-1998).
while the present invention provides recombinant methods for making the human growth hormone derivatives, these derivatives may also be made by conventional protein synthesis methods which are well known to those skilled in the art.
The growth hormone treatment in accordance w~.th the present invention may be accomplished either by administration of.
exogenous growth hormone or by administration of a substance which stimulates production of endogenous growth hormone either directly or indirectly by supressing endogenous somatostatin secretion. It is known that human growth hormone releasing hormone (hGHRH) stimulates the release of hGH. Thus, the biological activity of hGH can be indirectly obtained by administering GHRH or a functional derivative, salt, variant, analog or fragment thereof which retains the biological activity of GHRH, i.e., the ability to stimulate the release of growth hormone. Thus, fox example, besides GHRH there may be used functional derivatives thereof in accordance with the above definition, analogs or variants thereof, 0 which have at least 70% sequence identity, more preferably 80% or 90% or, most preferably, 95% sequence identity therewith, yet retains the biological activity o~ GHRH, or a variant or analog which is a polypeptide encoded by a DNA which hybridises to the native DNA encoding GHRH under moderately stringent conditions, or 5 preferably under highly stringent conditions, all in accordance with the definitions given hereinabove. L~ny of the GHRH or GHRH
analogs or agonists known in the literature and disclosed as _ ~8 _ JAN-84-1999 16:39 FROM BROI~IDY RND NEIMARK TO GOL.ILING&HENDERS P.31i45 simulating the release of growth hormone can be used in the present invention, such as those disclosed in U.S. patents 5,792,747; 5,776,901; 5,696,089; 5,137,872; 5,767,085; 5,612,470;
5,846,936; and 5,847,066. See also Thorner et al (1997), Felix et al (1995), Alba-Roth et al (1988), Friend et al (1997).
Other substances capable of promoting the release of growth hormone in vivo which can be used in accordance with the present invention include those disclosed in U.S. patents 5,807,985; 5,804,578; 5,795,957; 5,777,112; 5,767,118; 5,731,317;
0 5,726,319; 5,726,307; 5,721,251; 5,721,250, etc.
There can also be used in accordance With the present invention any other molecule which binds to the hGH receptor and initiates signalling of that receptor. It is known, fox example, that small. molecules, sometimes called secretagogues, have been 5 developed which bind hGH receptors and cause them to aggregate and initiate signalling, which signal initiation is the same as one obtains with natural hGH binding to the receptor. Such molecules axe known, for example, from U.S. patents 5,773,441; 5,798,337;
5,830,433; 5,767,124; and 5,723,616. See also Bowers et al 0 (1991), Thorner et al (1997), Camanni et al (1998), Ankersen et al (1998), Smith et al (1993) and Ghigo et al (1998). Thus, the present invention is intended to include any substance which binds to hGH receptor and initiates signalling thereof so as to obtain the same ultimate qualitative effect as the administration of 5 natural hGH, insofar as the treatment of HADDS is concerned.
Pharmaceutical. compositions for administration according to the present invention can comprise at least one human growth JRN-04-1999 16:39 FROM BROL.1DY AND NEIMARK TO GOLJLING&HENDERS P.32i45 hormone according to the present invention in a pharmaceutically acceptable form, optionally combined with a pharmaceutically acceptable carrier. These compositions can be administered by any means that achieve their intended purposes. Amounts and regimens for the administration of a composition according to the present invention can be determined readily by those with ordinary skill in the art for treating HADDS.
Fox example, administration can be by parenteral, such as subcutaneous, intravenous, intramuscular, intraperitoneal, 0 aerosol, or transdermal routes. The dosage administered depends upon the age, health and weight of the recipient, type of previous or concurrent treatment, if any, frequency of the treatment and the nature of the effect desired.
Compositions within the scope o~ this invention include all, composition comprising at least one human growth hormone or derivative, analog, or variant thereof according to the present invention in an amount effective to achieve its intended purpose.
while individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art. Typical dosages comprise about 0.01 to about 0.1 mg/kg body weight per day, which will usually amount to about 1-6 mg/day, subcutaneously for 5-30 weeks. When administered to AIDS
patients, the hGH anti-HADDS therapy may be administered concomitantly with other AIDS therapies.
It should also be understood that, to be useful, the treatment provided need not be absolute, provided that it is sufficient to carry clinical value. An agent which provides JAN-04-1999 16:40 FROM BROLJDY RND NEIMRRK TO GOIJLING&HENDERS P.33i45 treatment to a lesser degree than do competitive agents may still be of value if the other agents are ineffective for a particular individual, if it can be used in combination with other agents to enhance the overall level of protection, or if it is safer than competitive agents.
It is understood that the suitable dose of a composition according to the present invention will depend upon the age, health and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired. However, the most preferred dosage can be tailored to the individual subject, as is understood and determinable by one of skill in the art, Without undue experimentation. This typically involves adjustment of a standard dose, e.g., reduction of the dose if the patient has a low body weight.
The total dose required fox each treatment may be administered in multiple doses or in a single dose. The compositions may be administered alone or in conjunction with other therapeutics directed to the disease or directed to other symptoms thereof.
p In addition to the compounds of the invention, a pharmaceutical composition may contain suitable pharmaceutically acceptable carriers, such as excipients, carriers and/or auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
Experimez~tal Eight AIDS patients, six male and two female, with a history of long-term use (an average of 12 months) of highly - 3J. -JAN-04-1999 16:40 FROM BROWDY AND NEIMARK TO GOlJLING&HENDERS P.34i45 active antiretroviral therapy (HAART), including protease inhibitors (6 indinavir, 2 ritonavir/saquinavir) developed HADDS, including buffalo humps, central adiposity and peripheral muscle wasting associated with fatigue, along with elevated levels of plasma triglycerides +/- cholesterol.
Therapy with rhGH (SEROSTIM.) was initiated in all patients at a dose of 5 mg/day subcutaneously. Four patients completed three months of rhGH and had notable improvements in fat maldistr~.bution, with 25-75% reduction in buffalo hump syndrome and abdominal girth, but no change in peripheral hipodystrophy.
weights were stable, and there were no consistent changes in total body fat and blood lipids, despite 5-10% gain in fat-free mass.
One patient discontinued rhGH due to carpal tunnel syndrome and had recurrence of HADDS. Three patients have had over six months of therapy. One patient was lost to follow-up after six weeks of therapy, and one patient has received fewer than eight weeks of therapy. Yet, at last observation, all had notable reductions in the size of and firmness of the buffalo hump and truncal adiposity. These experiments establish that rhGH is effective in treating H.ADDS, including reduction of buffalo humps and truncal adiposity_ Having now fully described this invention, it will be appreciated by those skilled in the art that the same can be performed within a wide range of equivalent parameters, concentrations and conditions without departing from the spirit and scope of the invention and without undue experimentation.

.T~aN-04-1999 16:41 FROM BROUIDY AND NEIMRRK TO GOWLING&HENDERS P.35i45 While this invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications. This application is intended to cover any variations, uses or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth as follows in the scope of the appended 0 claims.
All references cited herein, including journal articles or abstracts, published or unpublished U.S. or foreign patent application, issued U.S. or foreign patents or any other references, are entirely incorporated by reference herein, 5 including all data, tables, figures and text presented in the cited references. Additionally, the entire contents of the references cited within the references cited herein are also entirely incorporated by reference.
Reference to known method steps, conventional methods 0 steps, known methods or conventional methods is not any way an admission that any aspect, description or embodiment of the present invention is disclosed, taught or suggested in the relevant art_ The foregoing description of the specific embodiments 5 will so fully reveal the general nature of the invention that others can, by applying knowledge within the skill of the art (including the contents of the references cited herein), readily SAN-04-1999 16:41 FROM BRO~IDY AND NEIMRRK TO GOSLING&HENDERS P.36i45 modify and/or adapt for various application such specific embodiments, without undue experimentation, without departing from the general concept of the present invention. Therefore, such adaptations and modifications are intended to be within the meaning an range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology herein is for the purpose of description and not of limitation, such that the terminology or phraseology of the present specification is to be 0 interpreted by the skilled artisan in light of the teachings and guidance presented herein, in combination with the knowledge of one of ordinary skill in the art.

JAN-04-1999 16:41 FROM BROLJDY AND NEIMARK TO GO~ILING&HENDERS P.3'7i45 REFE$ENCES
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Claims (10)

1. A method for treating HADDS comprising administering to a patient in need thereof an effective amount of a substance which binds to and initiates signalling of the human growth hormone (hGH) receptor or a substance which stimulates release or potentiates the activity of endogenous hGH.

2. A method in accordance with claim 1, wherein said substance is:
a) a naturally-occurring human growth hormone;
b) a fragment of a) which has agonistic activity on the hGH receptor;
c) a variant of a) or b) which has at least 70%
sequence identity with a) or b) and which has agonistic activity on the hGH receptor;
d) a variant of a) or b) which is encoded by a DNA
sequence which hybridizes to the complement of the native DNA
sequence encoding a) or b) under moderately stringent conditions and which has agonistic activity on the hGH receptor; or e) a salt or functional derivative of a), b), c) ox d) which has agonistic activity on the hGH receptor.

3. A method in accordance with claim 1, wherein said substance is a naturally-occurring human growth hormone.

4. The method according to claim 2, wherein said substance is recombinant human growth hormone.

5. A method in accordance with claim 1, wherein said substance is:

a) a naturally-occurring human growth hormone releasing hormone (hGHRH);
b) a fragment of a) which has agonistic activity on the hGHRH receptor;
c) a variant of a) or b) which has at least 70%
sequence identity with a) or b) and which has agonistic activity on the hGHRH receptor;
d) a variant of a) or b) which is encoded by a DNA
sequence which hybridizes to the complement of the native DNA
sequence encoding a) or b) under moderately stringent conditions and which has agonistic activity on the hGHRH receptor; or e) a salt or functional derivative of a), b), c) or d) which has agonistic activity on the hGHRH receptor.

6. A method in accordance with claim 1, wherein said substance is a small molecule which binds to and initiates signalling of the hGH receptor.

7. The method according to claim 1, wherein said substance is administered subcutaneously.

8. The method according to claim 1, wherein said substance is administered intramuscularly.

9. The method according to claim 1, wherein said HADDS includes dorsocervical fat pads and said patient is an AIDS
patient presenting dorsocervical fat pads.

10. The method according to claim 1, wherein said HADDS
includes truncal obesity and said patient is an AIDS patient presenting truncal obesity.