Growth Hormone RH Therapy for HIV Lipodystrophy

1
Growth Hormone RH Therapy for HIV Lipodystrophy

• Shrin Hebsur
• GIM Dec 2007

2
Definition of Lipodystrphy

• Lipoatrophy in limbs (lt10 tricep skin fold).
• Can also see atrophy of fat in face.
• Fat accumulation in abdomen and back of neck
  (gt95 waist to hip ratio for men, gt85 for women)

3
Prevalence

• Different studies have shown the incidence is
  anywhere from 10 to 80
• The large range is due to multiple factors, most
  importantly HAART and methadology
• Important because
• Increased risk of CAD with patient inc VAT
• Body dysmorphia can affect patients standard of
  living and compliance to ART regimens

4
Lipoatrophy

• Atrophy of buccal pads gives appearance of facial
  wasting.
• NRTI inhibit mitochondrial DNA polymerase gamma.
  Zidovudine, stavudine, didanosine, lamivudine,
  abacavir, and tenofovir

5
Fat Accumulation

• Prevalence Estimates are that 35-50 have
  abnormal fat accumulation.
• A study of pts w/wo HIV have shown that the rate
  of abdominal girth increase is the same.
• Pinchable fat may be more indicative.
• Protease inhibitors may not be the culprit

6
Lipid Abnormalities

• NHANES-Overall prevalence of metabolic syndrome
  was same between HIV/non HIV
• HIV individuals DID have lower HDL, higher TG,
  higher LDL
• Protease inhibitors have been the most implicated
  of the classes of ART drugs
• Multiple studies have shown an increase in
  cardiovascular risk amongst HIV individuals.

7
Insulin Resistance

• Either IGT, IFG, diabetes is uncommon.
• Prevalence Several studies have shown that ART
  leads to IGT, IFG
• Protease inhibitors in vitro may block GLUT4
• NRTI have also been implicated, Stavudine being
  the top culprit.
• In HIV men, study looked at waist to hip ratio
  and there was an association of insulin
  resistance.

8
Treatment options

• Change ART
• Thiazolindiones
• Uridine
• Leptin
• Surgical Approach Temporary fillers,
  CaHydroxyappetite
• Growth Hormone

9
Growth Hormone

• Shown to be lipolytic
• Side effects include Arthralgias, headaches,
  fluid retention, carpal tunnel, diabetes mellitus
• Recombinant human growth hormone to treat
  HIV-associated adipose redistribution syndrome
  12 week induction and 24-week maintenance
  therapy. AU Grunfeld C Thompson M Brown SJ
  Richmond G Lee D Muurahainen N Kotler DP SO J
  Acquir Immune Defic Syndr. 2007 Jul
  145(3)286-97.
• 325 HIV randomized to either 4 mg HGH or placebo
  for 12 weeks
• Study arm-visceral abdominal fat was reduced by
  20 ,
• Study arm had reduction in LDL and TG as well
• This study largely excluded patients with a
  impaired glucose tolerance or diabetes

10
Metabolic Effects of a Growth Hormone Releasing
Hormone in Patients with HIV

• Recent studies have shown that GH replacement CAN
  decrease VAT and decrease dyslipidemia. But, can
  affect insulin tolerance, and have statistically
  significant high rates of HA/arthralgias
• Purpose Prove that GHRH can decrease VAT,
  improve lipid profile, and self assessed body
  image
• Julian Falutz M.D. et al.
• From Primary Researcher from Montreal Gen
  Hospital, McGill U.
• Funded and designed by Theratechnologies

11
Methods

• Recruitment 43 sites between 6/05-4/06
• ART for 8wks waist circumference of 95 cm, wh
  of 0.94 wh of .88 in females
• Pts on lipid lowering therapy within 3
  mo/testosterone within 6 mo
• Exclusion pts receiving estrogen GH or related
  products within 6 mo

12
Study Design
Pts Randomized to drugplacebo 21 of 2mg
tesamorelin daily between 6am-12pm Assesments
were made at baseline, 13wks, 26wks Extension
Pts who received drug were randomized to get drug
in 31 ratio, and patients receiving placebo got
the drug
13
Assessment

• Adipose tissue CT from a 5mm slice between L4-L5
• Total body dual energy XR absorptiometry used to
  assess fat in trunk and limbs
• Body image survey by Phase V Technology
• Lipid, inflammatory cytokine, IGF-1 also done

14
Patients

• 412 patients randomized
• 275 received Tesamorelin, 137 placebo (21)
• Discontinuation rt (22.7 drug vs 16.1 placebo,
  P0.12)

15
Statistical Analysis

• Primary endpoint change in VAT from baseline to
  26wks.
• Secondary endpoint Total CholHDL TG IGF-1,
  body image perception
• Least-square means from covariance
• Use of NNRTI was included in supportive models
  for VAT and lipid end points.

16
Results

• Body Composition Drug group -27.8cm vs 5.1 cm
  Plt0.0001, adjusted for testosterone, impaired
  glucose/dm sex, nnrti
• Change was more drastic when there was a larger
  baseline VAT
• Sub Q fat increased 0.4 is drug vs 1.7 placebo
• Changes in fat in limbs was 0.6 vs 3.8 placebo

17
Secondary Endpoints
18
Adverse Events
19
Discussion

• Previous studies HAVE shown GH decreases visceral
  abdominal fat but at the expense of worsening
  insulin resistance
• Tesamorelin is a GHRH peptide-which was
  postulated to not affect insulin resistance

20
Study Positives

• Primary endpoint and secondary endpoints DID show
  that there was a significant change with GHRH
  peptide
• At end of 26 week, there was no statistically
  significant worsening of glucose tolerance

21
Study Negatives

• The Body Image Survey was not published
• Did not comment on lipoatrophy, especially in the
  face
• Did not enroll enough people with impaired
  glucose or DM individuals, eventhough GHRH was
  not supposed to chance insulin tolerance.
• Initial study demographics did not comment on
  drug vs placebo wrto ratio of subQ fatVAT
• The protocol was designed by drug company
• There was a statistically significant difference
  in number of d/c patients on the treatment arm
• There were more pts in drug arm that received
  NNRTI vs placebo (but was controlled)

22
Further Investigations

• Does GHRH improve overall lifestyle?
• What is the actual effect on CAD?
• Is there a difference between different age
  groups?
• What is the long term effects of GHRH (cancer,
  pituitary overstimulation, SE)
• What is the effect of GHRH in DM2 pts?
• What would happen if pts discontinued?
• What will the overall cost to healthcare
  system/pts be to use GHRH/GH

23
References

• Kotler, DP, Muurahainen, N, Grunfeld, C, et al.
  Effects of growth hormone on abnormal visceral
  adipose tissue accumulation and dyslipidemia in
  HIV-infected patients. J Acquir Immune Defic
  Syndr 2004 35239.
• Wanke, Christine. Epidemiology, Clinical
  Investigation, and Diagnosis of HIV associated
  Lipodystrophy. www.uptodate.com. 2007.
• Metabolic Effects of a Growth Hormone Releasing
  Factor in Patients with HIV. Falutz, Julian et
  al. New England Journal of Medicine 2007.