by Suman Srinivasa, M.D.
NEPTCC Newsletter Volume 23, Issue 1, Winter 2016/2017 [PDF version]
Perturbations in the growth hormone (GH) axis are common among the well-treated human immunodeficiency virus (HIV)-infected population . Acquired GH deficiency (GHD) secondary to HIV is a clinical diagnosis in the absence of known pituitary or hypothalamic pathology and should be differentiated from idiopathic adult GHD. Studies have determined that a GH peak cutoff of 7.5 ng/mL during the GHRH-arginine test can adequately discriminate GHD in HIV-infected individuals compared to healthy individuals with good specificity. As much as a third of HIV-infected individuals are estimated to have an inappropriate response to GHRH-arginine stimulation testing .
A spectrum of disease from true GHD to GH insufficiency exists among the HIV population. Recent studies have reported that the severity of GHD is far greater in the setting of pituitary disease compared to HIV infection , as measured by peak GH and area under the curve GH during GHRH-arginine testing. When an abnormally low IGF-1 is detected, it may be prudent to formally rule out pituitary insufficiencies and determine whether pituitary imaging is warranted; however, in most scenarios, the GHD may likely be ascribed to a known history of HIV.
Normal GH levels play an important role in the maintenance of body composition. In this regard, GHD is associated with accumulation of visceral fat and loss of lean body mass. The visceral fat depot is associated with increased cardiometabolic mortality . Studies demonstrate that HIV-infected individuals have increased visceral adipose tissue (VAT) accumulation when compared to non-HIV individuals  and are at risk for acquired lipodystophy . Several mediators have been implicated in VAT accumulation, including non-contemporary antiretroviral therapies, the HIV virus itself, chronic inflammation and immune activation, or perturbations in hormone systems, particularly the GH axis. Moreover, HIV-infected individuals are at risk for age-related disease, not limited to cardiovascular disease, and some have hypothesized that impairment in the GH axis could be related to a phenotype consistent with premature aging . Indeed, studies in the non-HIV population have determined that GH replacement can play a significant role in improving metabolic outcomes, related to improvements in body composition, dyslipidemia, inflammation, cardiovascular and bone health [7-13], which could serve as an important treatment paradigm in HIV lipodystrophy.
Detailed physiology studies have been performed to characterize GH dynamics in HIV. Overnight frequent sampling among HIV-infected individuals with and without lipodystrophy and healthy individuals demonstrated that the HIV group with lipodystrophy had reduced basal and mean GH concentration, as well as GH pulse amplitude, while GH pulse frequency and IGF-1 levels were normal when compared to the HIV non-lipodystrophy and healthy control groups . Visceral adipose tissue (VAT) accumulation was predictive of reduced GH in the HIV population.
The directionality and interrelationship between GHD and VAT accumulation in HIV remain largely unclear. That is, VAT accumulation, as seen in lipodystrophy, could attenuate GH secretion. Alternatively, GHD could lead to VAT accumulation, as is demonstrated in pituitary conditions resulting in GHD. Aside from VAT accumulation, other proposed mechanisms responsible for perturbations in GH dynamics in HIV include: altered ghrelin release, increased somatostatin tone, and suppressive effects of fatty free acids on GH .
Further studies have determined an effect of sex on GHD among the HIV population. Under formal GH stimulation testing, HIV-infected men have reduced peak GH in response to the GHRH-arginine stimulation test when compared to HIV-infected women matched for age, BMI, and race . A sex-specific mechanism remains unclear. The differences in GH physiology could be attributed to endogenous estrogen, which is recognized to decrease IGF-1 and therefore reduce inhibitory feedback on GH. Other studies have proposed that fat redistribution is a key driver, such that an increased VAT to SAT ratio among HIV-infected men vs. HIV-infected women accounts for the observed differences in GH physiology .
Restoration of GH physiology could have the potential to decrease the risk of morbidity and mortality in HIV if there is visceral fat reduction and reduced cardiometabolic risk. Overall, few treatment strategies exist to decrease cardiometabolic risk in HIV. Leveraging unique GH physiology in HIV, several studies have investigated the benefit of GH and growth hormone releasing hormone (GHRH) analogues to restore GH function among HIV-infected individuals.
A randomized controlled trial was conducted to assess the effects of low dose GH (average dose 0.33 mg/day) vs. placebo over 18 months on body composition and metabolic indices in a group of HIV-infected individuals with abdominal fat accumulation and reduced GH secretion (peak GH <7.5 ng/mL during the GHRH-arginine test). Results demonstrated a significant treatment effect of GH to reduce VAT area by -19cm2 with preservation of the subcutaneous adipose tissue (SAT) area. However, the benefits to improved body composition might be outweighed by a significant worsening of 2 hour glucose levels on glucose tolerance (treatment effect of GH on glucose +22 mg/dL) . Withdrawal of low dose GH among HIV-infected individuals was associated with reaccumulation of VAT . There is relatively more VAT reduction with higher dose GH (2-4 mg/day), but this is accompanied by SAT reduction as well [20-22]. SAT reduction could be detrimental if there is clinical evidence of lipoatrophy, as SAT is a vital storage depot for triglycerides. Moreover, continued loss of fat in the limbs or face in HIV-associated lipodystrophy is not typically desired and can have negative effects on quality of life. GH treatment is currently not approved for use in HIV-associated lipodystrophy.
Newer studies have evaluated the use of a growth hormone releasing hormone (GHRH) analogue, tesamorelin, in HIV. Use of a GHRH analogue takes advantage of the fact that that adequate endogenous pituitary reserve may be present among HIV-infected individuals, which can be augmented with an exogenous hypothalamic peptide. In addition, stimulating pulsatile GH secretion maintains the negative feedback system from IGF-1 signaling. Compared to GH, tesamorelin is thought to have neutral effects on glucose and therefore may avoid worsening insulin sensitivity.
The majority of studies evaluating tesamorelin have enrolled HIV-infected individuals regardless of their baseline GH status. Nonetheless, use of a GHRH analogue demonstrates good efficacy in reducing VAT. Data from a randomized controlled trial of over 400 HIV-infected individuals demonstrate a significant VAT reduction by 15.2% after 26 weeks treatment with tesamorelin, while those individuals on placebo had a 5% increase in VAT . HIV-infected individuals identified to be responders to tesamorelin based on VAT reduction of at least 8% demonstrated a more favorable metabolic profile over 52 weeks, such as improved triglycerides and adiponectin levels and maintenance of glucose homeostasis . In addition to targeting VAT accumulation, a 6 month study demonstrated modest effects on liver fat reduction in those HIV-infected individuals randomized to tesamorelin vs. placebo independent of weight changes . Liver fat reduction is mechanistically plausible, as treatment with a GHRH analog may have direct effects on liver fat through reducing hepatic de novo lipogenesis or indirect effects through oxidation of the visceral fat depot. Evidence also suggests there could be modest benefit on inflammation in HIV , which needs to be elucidated further and may be related to VAT reduction. Similar to GH treatment, withdrawal of GHRH may result in VAT reaccumulation .
Based upon these published data, tesamorelin is currently the only FDA approved medication for use in HIV-associated lipodystrophy, particularly for those with evidence of lipohypertrophy. The medication is a once daily subcutaneous injection usually prescribed by an endocrinologist. Use of tesamorelin requires careful safety monitoring of IGF-1 and HbA1c levels. While the medication is generally tolerated, rare side effects include injection site reactions, arthalgias, myalgias, and peripheral edema. Observational studies are currently ongoing to determine the long term benefits and safety profile of tesamorelin.
Further detailed studies are needed to understand the effects of GHRH analogues on other indices of cardiometabolic disease as well as cardiovascular mortality in HIV. Moreover, future investigations should determine whether similar cardiometabolic benefits may be achieved in other disease populations in which there may be relative GHD without evidence of pituitary disease and an increased risk of cardiometabolic disease, such as generalized obesity.