Testosterone Replacement in Men who are...

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