Daniel S. Berger MD
There are many hormones that one considers to have important
utility within the field of HIV therapeutics. This article
will discuss specifically two of them; testosteone, the oldest
therapeutic intervention first used to combat wasting now
administered more often and in more healthy individuals. Egrifta
is the latest hormone recently approved for the treatment
of HIV associated abdominal fat accumulation.
To date, there has been much information about testosterone,
difficult to cover its’ full particulars and finer points
in an article. However, a recent book , “Testosterone, A Man’s
Guide” written by Nelson Virgil has excellent detailed information.
In contrast, Egrifta, which is growth hormone-releasing factor
(GHRH), is the latest hormone making its’ way into the HIV
armamentarium; it has only recently been approved as of November
2010. The information we know is very much based on two large
phase III trials, for which am proud to have participated
in as a lead principle investigator. Its’ development is historic.
As the first and only agent to have gained approval to combat
a component of lipodystrophy it has shown to reduce fat accumulation,
also known as visceral hypertrophy, or increased belly fat.
To open this dialogue on these hormones as treatment, it’s
important to put it into clinical context. This article will
begin with 4 real cases that I’ve recently seen in the exam
room at Northstar and will pose as a useful vehicle for this
article’s discussion to illustrate salient points. The names
have been changed to protect the innocent.
CASE 1 Dustin is a 31 year old attractive healthy guy
who is devout in his practice of gay religion: going regularly
to the gym (Gay church) and healthy eating, – overall he’s maintaining
himself in the best and great shape. He’s not seen a doctor
in years but came into my office because particular issues have
been bothering him. He stated that ever since he can remember,
he seems to have less of a libido than his friends; when he
does meet an attractive “hot” man and finds himself in the “position”
he has a difficult time maintaining an erection, despite feeling
sexually aroused. He also has difficulty gaining weight, though
he does all the right things…diet, exercise, protein supplements.
He does not have fatigue or depression symptoms.
CASE
2
Mark is a 54 year old college professor, not married, has
a girl friend with benefits. Throughout his life he was an
ardent athlete staying in shape but now finds himself with
less of a desire to go to the gym. He’s noticed that his libido
is down, as well. When discussing these issues with his then
primary care physician, the doctor who checked on his testosterone
(T) levels, told him that it was “normal” for his age. He
came to my office looking for a second opinion and stating
that he didn’t want a testosterone level that was normal for
his age, but rather a more normal testosterone level for any
age. He wanted to regain that zest for enjoying all that life
has to offer, for which has been dropping off, as of recent.
CASE 3
Doug is a 37 year old HIV-positive man who has been well-controlled
on his antiretroviral cocktail, undetectable and with good
CD4 counts. He has no other significant problems but noticed
that he has become more tired, even early in the day and upon
first getting out of bed in the morning. He also notices that
he’s been putting on the wrong kind of weight, more fat and
less muscle, despite trying his best to exercise. He mentions
that he’s not had much desire for sex, and doesn’t consider
this too important, but “wouldn’t mind if things were different".
Case 4
Mike is HIV-positive and had complaints of low libido, feeling
depressed and fatigued. His doctor told him his T levels were
“normal”. When he pressed his doctor to tell him what his
levels were, his previous doctor said that normals are between
280 and 900 and that he was within the normal, at 330. Mike
nearly freaked, but his doctor continued to reassure him.
The other important fact is that Mike has noticed that his
waist size has been growing, despite the fact that he’s not
changed his diet. His doctor reassured him and explains that
he is doing well. Mike confides in me saying all he could
think of was the fact that the only thing normal about himself
was that he didn’t have a soprano voice, nor have developed
breast tissue, yet. He finally got a second opinion.
Egrifta, Much Anticipated, Newly Approved
It has long been understood that HIV-positive individuals
are prone to develop unusual increases of fat in specific
parts of their bodies. Until only recently, there was no product
approved for its’ treatment, nor was it clear about what could
be done about it.
Egrifta, developed by the Canadian firm Theratechnologies
Inc, is also known as tesamorelin or growth hormone-releasing
factor. It works by stimulating the body’s own production
of growth hormone and leads to oxidation or burning of body
fat, specifically visceral or abdominal fat associated with
HIV disease, a component that makes up the syndrome of lipodystophy.
Certain medications including the older protease inhibitors
such as Crixivan [indinavir], Kaletra (lopinavir/ritonavir)
as well as the non-nuke, Sustiva (also a component of Atripla)
has been shown in studies to be associated with developing abnormal
body fat increases. Some older nucleosides, such as d4t and
AZT and also shown to be associated with abnormal body fat changes
as well, most often fat loss or lipoatrophy. These agents reduce
mitochondrial functioning. Fat tissue is rich mitochondria,
which are cellular organs known as metabolic power houses. It
is also believed that HIV infection itself can cause the fat
and body habitus changes of lipodystrophy. Egrifta, no doubt
will become a very important product used for this purpose.
It will be marketed by EMD Serono.
What we can expect of treatment with Egrifta is a resultant
decrease in 17% to 18% of visceral fat. This effect is indeed
significant and easily noticeable by patients who I was seeing
as they participated in the clinical trials. I think that
when exercise and diet is combined with Egrifta use, the loss
of abdominal fat will only be heightened. Additionally, from
what I personally observed in the exam room during both trials,
patients who had low self esteem from their perceived unsightly
appearance and body image became less depressed with treatment.
Patients will need to self administer Egrifta daily by subcutaneous
injection.
Patients often notice their body habitus changes long before
their physicians. Case 4 illustrates how a patient brings
it up in the exam room. One doesn’t need to wait till the
lipohypertrophy is severe. If the problem is beginning to
manifest itself, I believe one can be proactive and consider
treatment early to avert worsening of the condition.
Among side effects, Egrifta was generally well tolerated but
because it is associated with increased levels of insulin-like
growth factor they include mild stiffness of joints, mild swelling
of hands or feet, injection site reactions, redness or tenderness
at the injection site and there is a slight possibility of reduced
or impaired glucose tolerance. However patients with mild diet
controlled diabetes did not have worsening glucose levels during
the clinical trials. Nevertheless, physicians should monitor
their patients on treatment, as appropriate.
Testosterone:
Many Important Functions
Testosterone, known as the male sex hormone is important
for many physiologic and metabolic functions other than simply
improving performance in the bedroom. Low and deficient levels
may be associated with fatigue, depression, irritability,
bone thinning and in older age individuals, reduced cognitive
functions . These are in addition to the more well known problems
of low libido and erectile dysfunction. The cases above illustrate
various scenarios and Case 3 illustrates a patient complaining
of constitutional symptoms that is a typical presentation
of low testosterone levels ( in addition to complaints of
low libido). When low testosterone levels persist, a syndrome
of hypogonadism can develop and includes symptoms of low libido,
fatigue, depression, very common in HIV disease. In HIV-positive
individuals, serious loss of lean body mass results is defined
as Wasting Syndrome. Also, low testosterone levels are also
associated with increased abdominal fat. When wasting occurs
in persons with HIV-infection, it is associated with more
infections, many constitutional symptoms and increased risk
of death. Some years ago, we published a study which showed
that 25% of individuals with wasting in the era of HAART (the
cocktail) may be due to low testosterone levels.
Originally, it was several community-involved HIV specialists
that began recognizing the importance of testosterone replacement.
Back in the early 90’s, we began offering our patients “physiologic
replacement” by injection. In other words, we administered
dosages of testosterone that are consistent with what the
body should normally have to maintain its’ normal levels and
function. This led to much improved sense-of-well-being among
our patients and the reduced potential for weight loss and
other HIV complications. Eventually, several companies developed
testosterone products in the form of gels and studying its’
use in normal (non-HIV infected) men. Low and behold, there
is a large prevalence of men who have low levels and whom
derive benefits from replacement treatment. I occasionally
see young men in their 20’s and 30’s who have a deficiency,
never mind that they are HIV-negative. The patient of case
1 is not an uncommon phenomenon.
Although blood levels of testosterone are checked by physicians,
many do not understand that these numeric values are relative,
because there is a large range of normal quoted by each lab.
An individual who may have a value in the normal range, may
not be normal for him, since first, he’s developed symptoms.
Second, previous levels are not always available to compare.
The individuals in Cases 2 and 3 demonstrate that levels may
not correlate with symptomatology.
There are two ways that testosterone can be administered:
intramuscular injection and topical administration in either
gel or cream form. By either route the replacement of testosterone
from my experience can show dramatic effects. These include
a marked improvement in energy levels, reduced anxiety and
depression symptoms, improved libido and self confidence,
improved stamina and in the gym, individuals note their improvement
in body mass and reduction in fat. Overall there’s a greatly
improved sense of well -being.
A common side effect includes increased red blood cell production
(hematopoesis) which we treat at Northstar with therapeutic
phlebotomy and sometimes need to modify dosing. Other side
effects, increased blood pressure, elevated hepatic transaminases
or increased liver enzymes, gynecomastia, acne or skin outbreaks,
increased appetite and mood swings can also occur. Thus monitoring
of side effects is important and includes blood testing for
vigilance liver enzymes, blood count, blood pressures, testosterone
levels and prostate specific antigen levels. Side effects
get detected early and can be easily managed.
There has been concern that testosterone replacement may
have a causal relationship to prostate cancer. This has long
been myth that is unfounded. Several clinical studies have
now been consistent in showing in persons who do develop prostate
cancer, lower testosterone levels are associated with a more
aggressive cancer; another study demonstrated that testosterone
levels did not result in increased levels of prostate specific
antigen (PSA), a marker used for the early detection of prostate
cancer. It is believed however, that only if there is prostate
cancer already present, untreated, testosterone administration
may stimulate tumor growth, or worsening of the cancer. Therefore,
for patients without prostate cancer, there is no evidence
or data that shows testosterone to cause cancer. Several urologists
agree that there is no danger of administering testosterone
in whom patients were treated for prostate cancer by prostatectomy.
Patients receiving injections are often on testosterone cypionate
(Depo-tesosterone) and are on various intervals of treatment
and at varying doses. In the injectable form, the intervals
and dosing are often chosen based the perceived durability
of effect by the patient. In other words, patient will often
tell me that at a certain point in time after their injection,
they begin to feel its’ effects wearing off. With each administered
injection there is a surge of testosterone in the blood that
occurs promptly. This surge is associated with individuals
feeling great relief from their symptoms of deficiency. However
sometimes, testosterone levels in the blood may begin to drop
off rapidly after a few weeks and sometimes within only a
few days of the injection, and can remain low until the next
injection. Additionally, the surge in testosterone levels
can stimulate the brain’s biofeedback mechanism, and sensing
the high testosterone levels sends a message to the adrenals
and testes to shut down its’ own endogenous production, sometimes
making it difficult to maintain normal levels. Nevertheless,
patients receiving intramuscular injections of testosterone
derive very quick relief of symptoms and often prefer this
mode of replacement.
Another mode of administration is by transdermal or topical
gel or cream. Individuals usually apply the gel to an area
of skin every morning and thus, testosterone is absorbed gradually
over several hours. This daily therapy often leads to more
consistent blood levels that avoids up and down symptoms that
are associated with injectable replacement. Two such products
are available: Androgel and Testim. Both products are applied
similarly. What differentiates them is that the Testim formulation
contains a delivery system that allows for higher levels of
testosterone absorption and has made it a more efficient replacement
overall. The delivery system is a compound that gives Testim
a musky aroma, not unlike a musky cologne such as Brut, but
dissipates over the course of a few hours. It is my experience
that patients often achieve higher levels with Testim. Additionally,
individuals who don’t achieve normal testosterone levels with
Androgel often respond better with Testim
Conclusion
The development of Egrifta is an important milestone in HIV
therapeutics. It provides patients an option to combat visceral
adiposity and body image issues. Facial wasting is a different
manifestation of lipodystrophy that had already been overcome
by effective treatment with Sculptra and Radiesse and is widely
administered at Northstar in Chicago and other clinics nationally.
Thus together, we have a more rounded line of therapy for
various manifestations of lipodysrophy and the psychological
ramifications of altered body image. However, dietary measures
and exercise should not be overlooked.
In contrast, testosterone deficiency is common among HIV
infected individuals and is associated with many daily symptoms.
Replacement treatment improves quality of life through improving
daily energy levels, reducing depression and helps build body
mass, strength and improved cognitive function, in addition
to its’ effect on libido. Testosterone treatment has been
used by physicians for many years. With mounting evidence
for its’ benefits, it is hoped that other physicians who have
been reluctant to provide hormonal replacement easily, may
feel more comfortable with its’ management and safety. As
patients are increasingly living longer healthier lives, they
can be empowered with the knowledge of the various treatment
modalities, realize their therapeutic options and help themselves
achieve an improved quality of life.
Dr. Daniel S. Berger is a leading HIV physician in the U.S.
and is Clinical Associate Professor of Medicine at the University
of Illinois at Chicago. He is founder and medical director
of Northstar Healthcare, the largest private HIV treatment
and research center in the Greater Chicago area. Dr. Berger
has published extensively in such prestigious journals as
The Lancet and The New England Journal of Medicine and serves
on the Medical Issues Committee for the Illinois AIDS Drug
Assistance Program and the AIDS Foundation of Chicago. Dr.
Berger has been honored by Test Positive Aware Network with
the Charles E. Clifton Leadership Award. Dr. Berger can be
reached at DSBergerMD@aol.com and www. Nstarmedical.com
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