testosterone replacement in men who are...
TRANSCRIPT
Testosterone Replacement in Men who
are HIV-Positive
Adrian S. Dobs, MD, MHSProfessor of Medicine and Oncology
The Johns Hopkins University School of Medicine
Division of Endocrinology, Diabetes and Metabolism
This man should be treated with
testosterone therapy because:
• He is symptomatic for conditions often seen
men with low circulating testosterone
concentrations
• Hypogonadism is common in HIV-infected men
and the pathophysiology is often known
• The benefit out ways the risk
• He can be monitored for any potential
risk/benefit
• GU conditions are a non-issue10/14/2016 2
Outline
• Pathophysiology and epidemiology of
male hypogonadism in general and in
HIV disease
• Common metabolic problems in HIV
infection and its relationship to TTh
• Risks of TRT
10/14/2016 3
Production and
Regulation of
Testosterone
T = testosterone
Only 2% is free testosterone;
98% is bound
Free T
2%SHBG-bound T
40%-50%
Albumin-bound T
48%
Adapted from Bagatell CJ, Bremner WJ. N Engl J Med.
1996;334:707-714.
GnRH
LH FSHTestosterone
Testosterone
Sperm
Hypothalamus
Pituitary
Testis
Adapted from Braunstein GD. In: Basic & Clinical Endocrinology.
5th ed. Stamford, Conn: Appleton & Lange; 1997:403-433.
Prevalence of hypogonadism
in HIV - infection
• Pre-HAART:16-65%;
• Post- HAART: 3-54%
• Recent MACS: Hypogonadism seen in
24% (104/434) of HIV-infected vs.
7.8% (13/167) of HIV-uninfected men
(p < 0.0001).
10/14/2016 Monroe, AIDS Research and Therapy 2014, 11:6 5
Slama, JAIDS I71(1): 2016, p 57–64
SHBG is higher in HIV – infected men
β HIV status: -0.20, p<0.001; β age: -0.01, p<.0001Monroe, Endo Soc, 2010
Get a Free Testosterone! Many men had
Normal Total, but Low Free testosterone
10/14/2016 Monroe, AIDS Research and Therapy 2014, 11:6 8
More Specific
• Reduced or diminished
• Sexual development
• Libido
• Spontaneous erections
• Fertility
• Secondary sexual
characteristics
• Increased
• Reduced BMD, fragility
fractures
• Hot flushes, sweats
Signs and Symptoms of
Hypogonadism
Less Specific
• Reduced or diminished
• Energy and vitality
• Mood
• Concentration and
memory
• Physical performance
• Muscle bulk / strength
• Increased
• Body fat
Bhasin S, et al. J Clin Endocrinol Metab. 2010;95(6):2536-2559.
Endocrine Society
Recommendations
• Morning samples of total or free
testosterone
• Laboratory diagnosis, as well as
signs/symptoms of hypogonadism
• Attempt to define the etiology
• Trials of testosterone is a reasonable
option
10/14/2016 10
Relatively Clear etiology:
Suggest Evaluation
• Infiltrative infections of
pituitary or testes
• Medications
(Glucocorticoids, Opioids)
• Cancer therapies –
chemotherapy, radiation
• HIV/cancer-associated
weight loss
Pathophysiology of Hypogonadism in
HIV infection is Often Known
Unclear mechanism: Suggest
evaluation in presence of
signs/symptoms
• End stage renal disease and
maintenance hemodialysis
• Type 2 diabetes mellitus
• Moderate to severe COPD
• Co-infection with
• HCVOsteoporosis/low trauma
fracture (young men)
Low testosterone is associated with poor
health status in men with HIV infection
Rochira,, Andrology 3 (2), pages 298-308, 2015
Low testosterone is associated with
poor health status in men with HIV
Rochira,, Andrology 3 (2), pages 298-308, 2015
Utilization Data Show Increased Use
with PCPs Largest Group of Prescribers
0
2.000.000
4.000.000
6.000.000
8.000.000
00 01 02 03 04 05 06 07 08 09 10 11 12 13
TRT
Prescriptions
Year
TotalEndocrinologyUrologyPCPAll Other
SHA Integrated Database, nonprojected claims counts
10/14/2016 Haberlen 2016 15
Testosterone Use Prevalence,
by HIV Serostatus and Age Category.
5,6%
17,2%
25,5%
17,0%
1,9%
7,3%
6,2%5,4%
0,0%
5,0%
10,0%
15,0%
20,0%
25,0%
30,0%
<50 50-59 >=60 Total
HIV+ HIV-
Interim conclusion
• Low testosterone is common in HIV
• Symptoms, however non-specific are
common
• The mechanism is often clear
• Testosterone therapy is commonly used
in HIV infected men
10/14/2016 16
Outline
• Pathophysiology and epidemiology of
male hypogonadism in general and in
HIV disease
• Common metabolic problems in HIV
infection and its relationship to TTh
• Risks of TRT
10/14/2016 17
Common Problems in HIV that are
Associated with Hypogonadism
• Decreased bone density
• Diabetes
• Obesity
• Increased abdomenal girth
• Accelerated heart disease
• Sexual dysfunction
10/14/2016 18
3
Prevalence of osteopenia and osteoporosis:(a) HIV+ vs. HIV-; (b) Tx vs. unTx; (c) PI vs. no PI
Brown, AIDS. 20(17):2165-2174, November 14, 2006.
Finkelstein; JCEM 2001, 86, 2020-2026.
Increase in lumbar spine BMD with T Th
vs. placebo in HIV infection with wasting
Risk of Incident Diabetes Mellitus in the
Multicenter AIDS Cohort Study (1999-2003)
p= 0.001
* Adjusted for age and BMI at study entry Brown, Arch Int Med, 2005
4 fold increased risk of DM in HAART-treated men
90
92
94
96
98
100
102
104
Wais
t C
ircu
mfe
ren
ce,
cm
86
88
90
92
94
96
Bo
dy
We
igh
t, k
g
aP<.05 vs baseline.
Saad F et al. Arch Androl. 2007;53(6):353-357.
Testosterone Therapy: Effect on
Metabolic Syndrome Parameters
a
±7.3
a
±11
a
±7
±7.9
±8.1 ±7.5
±8.2
±11 a
±11
±13
0 3 6 9 12
Testosterone Undecanoate Therapy, mo
0 3 6 9 12
Improved Body Composition with
Testosterone Treatment in HIV-infected Men
Knapp, Am J Physiol Endocrinol Metab 2008;294:E1135-E1143
10/14/2016 Bhasin, JCEM 2000 24
Increased Leg Press Strength with
Exercise and/or Testosterone in HIV+ Men
Increased Atherosclerosis in HIV: 61% greater
risk of Carotid Artery Plaque in 7 yrs
10/14/2016 Hanna, Clin Infect Dis 2015;61(4):640–50 25
Outline
• Pathophysiology and epidemiology of
male hypogonadism in general and in
HIV disease
• Common metabolic problems in HIV
infection and its relationship to TTh
• Risks of TRT
10/14/2016 26
Biological Plausibility: Consistent
Evidence
Potential CV Risks:
• Hematocrit
• HDL cholesterol
• Platelet aggregation
• Sodium retention
• Smooth muscle
proliferation
• VCAM expression
Potential CV Benefits:
• Vasodilator effect
– Increased coronary
and penile blood
flow
• Whole body fat
–SC and visceral
• Vascular reactivity
• Shortens QTc interval
Cebellos 1999; McCredie 1998; Hayward 2000; Chou 1996; Yue 1995 Ong 2000
Testosterone use associated with all-
cause mortality, MI, and ischemic stroke
Vigen, JAMA 2013
Limitations of Studies Suggesting
CVD Risk from testosterone
• No randomization,
• Only 60% had documentation of low T
prior to Tx,
• Insufficient treatment (175 to 335 ng/dl) -
may be a reflection of having low T
previously.
• Poor pre and post documentation of T
10/14/2016 29
Diabetes 1.28 (1.19, 1.38)
Incident CHD 1.19 (1.10, 1.28)
Myocardial Infarction 1.28 (1.08, 1.52)
Stroke 1.21 (1.05, 1.40)
Sudden Cardiac Death 1.35 (1.18, 1.54)
Observational study of 37,443 men with
prostate cancer in the VA
Androgen Deprivation Therapy and Risk
of Diabetes, CAD, MI, Stroke, and Death
Keating et al. J Natl Cancer Inst. 2010;102:39-46.
0,5 1.0 2.0
Adjusted HR (95% CI)
Adjusted HR (95% CI)
Araujo, 2007 1.04 (0.83-1.31)
Haring, 2010 3.62 (1.64-7.98)
Khaw, 2007 1.58 (1.20-2.11)
Laughlin, 2008 1.37 (1.10-1.69)
Lehtonen, 2008 2.52 (1.00-5.45)
Menke, 2010 1.08 (0.82-1.42)
Shores, 2006 2.09 (1.41-3.09)
Smith, 2005 1.05 (0.86-1.29)
Szulc, 2009 1.00 (0.72-1.41)
Tivesten, 2009 1.72 (1.46-1.99)
Vikan, 2009 1.02 (0.80-1.29)
Random-effects Model 1.35 (1.13-1.62)
0,1 1 10
Lower Testosterone Levels Associated
with Higher All-Cause Mortality
Araujo et al. J Clin Endocrinol Metab. 2011;96(10):3007-19.
Relative Risk (95% CI)
1st Tertile vs. 3rd Tertile
Relative Risk (95% CI)
ARIC: Testosterone is not Helpful or
Harmful to the Development of CHD
10/14/2016 Srinatha, JCEM 2014. 32
Free T is lower in HIV-infected Men,
but unrelated to CAC
• Adjusted mean log FT was lower in HIV-
infected men than in HIV-uninfected men,
(P = 0.0004), equivalent to the FT in an
HIV-uninfected man 13 years older
(P < 0.0001)
• No relationship though of FT to coronary
artery calcium or carotid intimal medial
thickness
10/14/2016 Monroe, HIV Medicine (2012),13,358-366
U-shaped Mortality Curves in Men and
Women with Low or High Hematocrits
in a Large Prospective
Boffetta P et al. Int. J. Epidemiol. 2013;42:601-615n=50K, 5 yr F/U
Yes- He should be treated
• Men with HIV are more likely to have low
testosterone, especially a low free level
• Testosterone deficiency is associated with
DM, obesity and chronic disease
• Treat if the levels are low and there are
symptoms
• Testosterone therapy may or may not help
any underlying conditions, but there is no
data to say that HIV-infected men are at
greater risk from testosterone Tx