New Data Indicate Growth Hormone Benefits Wasting, Lipodystrophy and Immunodeficiency

By Graeme Moyle, MD

A symposium focusing on the therapeutic potential of growth hormone reported new data at the World AIDS Conference in Barcelona. Issues discussed in the symposium included the treatment of weight loss and wasting, the presence of growth hormone deficiency and the benefits of growth hormone therapy in lipodystrophy and the potential for growth hormone to contribute to immune recovery in people with HIV infection.

Weight Loss and Wasting

Wasting associated with progression of HIV disease was a well-recognised phenomenon in the pre-HAART era. Wasting was generally defined as 10 percent or greater in voluntary weight loss and was often accompanied by chronic diarrhea or persistent fever. Changes in body composition included loss of body cell mass, reduction in lean body mass and loss of fat.

In many individuals the weight loss was most predominantly lean body mass and this is associated with poor prognosis and increased risk of disease progression. Whilst poor in take of food was established as the main contributor to wasting, patients were also noted to have elevated resting energy expenditure malabsorption secondary to enteropathy and often hypogonadism. Additionally, several cytokines such as interferon Alpha and tumour necrosis factor Alpha were associated with wasting.

In the HAART era wasting and involuntary weight loss are still well recognised. Weight loss in HAART treated patients is often most evidently lipoatrophic with reductions in subcutaneous fat being more evident than reductions in lean body mass. Additionally these changes may be accompanied by the metabolic syndrome, dyslipidaemia, insulin resistance and visceral fat accumulation.

There continues to be evidence of a role for cytokine mediation, hypogonadism and elevated resting energy expenditure as well as evidence of reduced levels of growth hormone. In contrast to patients in the pre-HAART era the loss of fat and lean body mass in HAART treated patients is often observed despite good CD 4 cell counts and virological responses to therapy. In both circumstances weight loss and wasting our associated with diminished quality of life, particularly loss of physical functional capacity, fatigue and stigmatising physical changes. Importantly, it is also associated with an increased risk of morbidity and mortality suggesting the need for early intervention.

Treatment Approaches

Several approaches for the management of in voluntary weight loss are used in clinical practice. In the first instance dietary advice to improve food intake may be all that is necessary, although evidence in cachectic patients who have lost a significant amount of lean body mass suggest that re-feeding may lead to recovery of weight but not necessarily normal body composition. Exercise has also demonstrated benefit in the recovery of lean body mass.

Appetite stimulants may be useful in individuals who have lost weight but not necessarily substantial amounts of lean body mass and who remain capable of regular exercise. The most widely used appetite stimulants include megestrol acetate and dronabinol. Dronabinol has the advantage of also being an anti nausea agent and unlike megestrol does not suppress gonadal or adrenal axes.

Testosterone supplementation, most physiologically done with topical gel or patches, is appropriate individuals who presented with persistent hypogonadism and may help to preserve or restore a lost lean body mass in hypogonadal individuals. Supraphysiological exposures of testosterone or synthetic androgens may lead to gains in weight and lean body mass particularly when combined with exercise.

However this approach risks elevation of liver function tests, worsening of dyslipidaemia, triggering of hypogonadism and the potential for misuse. Additionally, synthetic androgens tend to lead to reductions in subcutaneous fat and therefore may make the appearance of peripheral lipoatrophy worse. Studies evaluating tumour necrosis factor antagonists are limited to date and drugs such as pentoxyphylline and thalidomide have significant tolerability issues that have limited their investigation and use.

Two studies in the pre-HAART era indicated that doses of growth hormone of approximately 6mg/day were superior over 12 weeks treatment to placebo at increasing body weight lean body mass and improving physical function as measured by work output on a treadmill. In general patients in the studies gained around 2 kg of weight and around 3 kg of lean body mass.

Benefits of Growth Hormone in the HAART Era

New information regarding the benefits of growth hormone in HAART treated patients with involuntary weight loss were reported at the symposium and as a late breaker in the main conference program. The study represents the largest evaluation of growth hormone in HIV infection reported to date.

The study randomised 757 patients to receive either 6 mg daily or alternate daily growth hormone all placebo over 12 weeks after which all patients received a further 12 weeks of open-label growth hormone. Entry criteria included either > 10 percent involuntary weight loss, a body mass index < 20 or a weight < 90 percent of ideal body weight. 570 patients completed 12 weeks treatment. Their baseline characteristics included a mean age of 41yrs with 91% of individuals being male, 92% on at least three antiretroviral agents, a mean weight of 65.6 kg and a means CD4 of 444/mm³.

In general growth hormone therapy was well tolerated with only 2% of patients in the two growth hormone arms discontinuing therapy. However a greater proportion of individuals in the daily dose growth hormone group were required to have dose reductions or data interruptions during the 12 week treatment period relative to placebo patients. Of noted differences in the proportion of individuals requiring dose reductions or interruptions differed significantly across study sites, suggesting patients support and physician experience may enable patients to treat through adverse experiences.

The most common adverse events observed with growth, and relative to placebo were related to peripheral fluid retention and include arthralgia, myalgia and peripheral oedema. The events are generally promptly reversible upon discontinuation of growth hormone that may also respond to diuretics or anti-inflammatory agents. Regarding lab abnormalities a dose-dependent rise in fasting glucose was observed in the growth hormone arms which was most evident at week 4 and had partially resolved by weeks 12. These changes really lead individuals to have fasting glucose values in the diabetic range. Falls in cholesterol were also noted in the daily dose group, where the total cholesterol fell 15% and triglycerides fell approximately 4%.

Use of growth hormone was noted to lead to a range of improvements in physical function in and body composition. Work output as assessed by cycle ergometry improved in both growth hormone groups to a similar degree with this benefit being superior to placebo. In the small number of individuals receiving less than three antiretroviral agents benefits on work output were limited to the daily dose group. No differential effects were seen by choice of antiretroviral. Benefits on lean body mass by both bioelectric impedance and DEXA scan were seen in a dose-dependent manner, with a 10.6% increase observed over 12 weeks in the daily dose group.

Growth hormone therapy also lead to a fall in the mass as measured by DEXA scan which was almost entirely accounted for the reductions in truncal fat. This reduction in truncal fat lead to relative normalisation of the trunk to lean fat ratio in growth hormone treated individuals. Over 12 weeks therapy, those doses of growth hormone lead to significantly more patients experiencing an increasing body weight and more individuals with low body mass index at study entry restoring to values considered normal. Despite adverse effects related to peripheral fluid retention patients reported an overall quality of life benefit with daily dosing being significantly superior to both alternate daily dose in and placebo in this regard. The study authors concluded that growth hormone appears beneficial in HAART treated patients who have experienced in voluntary weight loss or who have low body mass indices.

Growth Hormone and Lipodystrophy

Previous studies have indicated that individuals who have truncal fat accumulation have reduced growth hormone secretion relative to non-obese individuals. Individuals with wasting in the setting of HIV infection, generally have elevated growth hormone secretion in association with growth hormone resistance. Recent data assessing 21 individuals with clinical lipodystrophy including a waste hip ratio greater than 0.95 have indicated relative to HIV positive age and body mass index matched controls and HIV negative age and body mass index matched controls that growth hormone amplitude is reduced although the frequency of growth hormone pulses is not reduced. Univariate regression modelling suggests that growth hormone levels are lower in individuals with greater amounts of intra abdominal fat as measured by CT scanning. Differences in growth hormone levels not appear to be influenced by antiretroviral choice.

The data have led investigators to study the potential of growth hormone treatment in the management of lipodystrophy. New data presented at the symposium provided 12 week outcome information on a randomised placebo controlled trial of 239 patients given either 4 mg daily, 4 mg alternate daily growth, and all placebo for 12 weeks. Patients entering the study were required to be on antiretroviral therapy and have excess abdominal adiposity as assessed by an increased waist circumference or a waist-hip ratio. Prior to entry patients were assessed by a glucose tolerance test and diabetic individuals excluded. Baseline characteristics included a mean CD4 count of 458/mm³ mean viral load < 5000 with 56 percent of patients on protease inhibitor based therapy.

As with previous studies the most common adverse events associated with growth hormone therapy included arthralgia, myalgia and peripheral oedema. Significantly more patients at week 12 had an elevated 2-hour glucose on glucose tolerance testing in the two growth hormone treated groups relative to placebo, however no significant differences were observed between growth, and doses. Visceral adiposity as measured by CT scan declined significantly in the daily dose growth hormone group with the change approaching statistical significance in the alternate daily dose group. Trunk to limb fat ratio fell significantly in both growth hormone treatment groups towards more normal values.

As observed in the wasting study with growth hormone daily dose growth hormone therapy lead to significant declines in total cholesterol and to non-HDL cholesterol. Quality of life was reported to improve in both the growth hormone treated groups with benefits being observed in terms of general perceived health, psychological distress and psychological well-being. Patients were also able to provide self-report of benefit with significant improvements being reported in distress levels regarding breast, leg, buttock, arm, belly, buffalo hump and overall body appearance. Only modest benefits, which did not reach statistical significance, were observed with regards to distress about facial appearance.

The studies suggest that individuals with lipodystrophy growth hormone may provide benefits in terms of reducing areas of fat accumulation but also lead to patient perceived benefits at peripheral sites.

Growth Hormone and Immunity

Growth hormone deficiency is known to be associated with thymic hypoplasia in rodents, and treatment with growth hormone leads to reversion of thymic atrophy and augments T cell production. Additionally growth hormone therapy has been noted in animal studies to accelerate immune reconstitution in immunodeficient animals.

Several recent studies discussed at this symposium suggest that these benefits of growth hormone may also be observed in persons with immunodeficiency secondary to HIV infection.

Presented data focused on a five patient cohort of individuals receiving growth hormone for the treatment of lipodystrophy. The patients were receiving a range of antiretroviral agents and had low viral load and a mean CD 4 count of 419. Four of the five patients received growth hormone for 12 months. The study assessed the thymic atrophy by CT scan. Scans at six months in all patients indicated apparent increase in thymic mass at sites where the thymic tissue had not been evident on baseline scans.

Additionally, an increase in CD4 positive naive cells was observed during growth hormone therapy but not in a matched controlled population of treated individuals who did not received growth hormone. Effects on CD8 were not observed. Other small studies have suggested that levels of TRECs (recent thymic emigrants) are increased in individuals receiving growth hormone and that growth hormone therapy leads to improvements in function of both CD4 and CD8 cells. These improvements in function include responses to both recall and HIV specific antigens.

The study of implantation of human thymic tissue into an immunodeficient SCID mouse followed by treatment with growth hormone indicated that growth hormone led to an expansion or hyperplasia of the thymic tissue. These data therefore suggest that growth hormone has a range of immune benefits in individuals with HIV infection that warrants further investigation.

Editor’s Note: Serostim [somatropin (rDNA origin) for injection] is the only growth hormone approved by the US Food and Drug Administration (FDA) for the treatment of AIDS wasting or cachexia. Serostim received FDA accelerated approval in 1996 based upon the analysis of changes in body weight and lean body mass in surrogate endpoints in clinical studies up to 12 weeks in duration. Full prescribing information for Serostim is available at www.aidswasting.com

07/10/02

References

1. E Daar and others. Recombinant Human Growth Hormone (r-hGH) is effective to treat HIV/AIDS associated wasting in the era of Highly Active Anti-Retroviral Therapy (HAART). Abstract LbPeb9012. .

2. DP Kotler and others. Growth Hormone (Serostim) effectively reduces visceral adipose tissue (VAT) accumulation and non-HDL cholesterol. Abstract LbOr18.