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Lisa Capaldini, M.D., practices medicine in San
Francisco and sees many patients with HIV; we
interviewed her last August on protease inhibitor side
effects. Recently she spoke in San Francisco on
HIV-related fatigue. We conducted the following
interview after attending that talk and seeing the
public interest in the subject.
AIDS Treatment News: What should patients know about
different kinds of fatigue -- for example, whether you are
generally tired in the morning, or after physical
exertion?
Dr. Capaldini: Fatigue is one of those important and
tricky body symptoms that can be caused by just one
specific disorder, or by several problems working
together. Because it is a feeling we all experience once
in a while, there is a tendency to view it as a normal
part of daily life. And because in HIV disease it tends
to come on slowly, fatigue is easy to miss; unlike a
high fever which was not there and then is one day,
fatigue tends to come on subtly and become worse over
time. So it is important for patients with HIV and their
doctors to do a fatigue inventory every six months or
so, since the problem could be overlooked. And in a
large majority of patients, the causes of fatigue can be
identified and treated.
One kind of fatigue -- physical fatigue -- shows up after
specific activities -- for example, getting unusually
short of breath after climbing a hill, or having your
legs give out while walking three blocks to the grocery
store, or having your arms be too weak to stack soup
cans on your kitchen shelf. Abnormal physical fatigue is
often due to a specific system of the body
malfunctioning -- for example, lung problems, heart
problems, nerve problems, or muscle problems.
Psychological fatigue -- which might be called
motivational fatigue -- means not having the get-up-and-go
to do things because they do not matter as much, they
are not worth doing. This has a specific name in Western
medicine; we call it anhedonia, meaning that activities
do not give pleasure as they used to, so you do not put
the energy into doing them. A way to distinguish
physical from psychological (or motivational, or
spiritual) fatigue, is to notice if you are not doing
something because you do not have the physical resources
to undertake it, because it is not worth what the
activity will take out of you -- vs. not wanting to do it
because it is not enjoyable for you any more.
Another way to look at fatigue is when does it bother
you. If you regularly wake up tired, and that tiredness
persists through the day, that is a strong clue that you
may be depressed -- as opposed to waking up feeling pretty
good and then getting tired as the day goes on, during
specific activities, which is more characteristic of
physical fatigue.
Morning fatigue may be a symptom of biochemical
depression which is primarily a brain hormone problem,
characterized by low levels of serotonin and/or
norepinephrine. Sometimes depression symptoms are due to
low levels of sex hormones, a condition called
hypogonadism. The same symptom can have quite distinct
causes.
ATN: In your recent talk you mentioned lack of
restorative sleep. Where does that fit in?
Dr. Capaldini: Good sleep is not just an issue of how
long are you in bed with your eyes closed and not
conscious, but also whether you go through several
appropriate cycles during your sleep. In certain serious
illnesses, for example cardiac or lung diseases, it has
been found that people often do not go into the deepest
parts of sleep; so even though they have been in bed for
eight hours, they do not wake up having slept normally.
A different example is when people are jet lagged; they
may be able to sleep, but not feel rested afterwards
because their sleep and circadian rhythm cycles are not
in synch.
With HIV disease, there are many reasons why people may
not have uninterrupted sleep -- for example, getting up to
take medicines, diarrhea, having to urinate because of
taking lots of fluids with Crixivan, etc. Even if a
person is able to fall asleep and stay asleep as far as
they can tell, their actual sleep architecture may not
be normal. Some investigators have identified a pattern
of non-normal sleep in persons with HIV who have no
known reason not to sleep normally. That suggests
something involving HIV, and/or its treatment, may
affect the brain.
Another common cause of not sleeping at all, or poor
sleep, is pain. One of the challenges in finding
appropriate pain treatment is to find a drug that
controls the pain enough to permit good sleep, without
causing the person to be so sedated in the morning that
it is hard for them to get up and get going.
ATN: What are the most common causes of physical fatigue
in persons with HIV?
Dr. Capaldini: Some of the common causes are anemia,
chronic diarrhea, chronic pain, chronic respiratory
insufficiency from prior pneumonias or new pneumonias, a
general lack of energy from malaise due to certain drugs
(for example, Norvir, Crixivan, or AZT), and pain due to
neuropathy.
But the two causes of fatigue in HIV which I believe are
most easy to miss are depression and hypogonadism.
Also remember that fatigue is contextual. If you have a
given level of energy and you are trying to commute
three hours a day, put in a 40-hour work week, and get
your kids to school, etc., that is quite different from
being able to wake up and get up when you want to, you
do tasks when they are convenient or easy for you. One
reason people need to think about disability is not so
much that they cannot work, but that given their limited
energy, they are putting all their energy into their
work tasks and not having any left for day to day
activities.
It is very important for people who are
either trying to get on disability, or are on disability
and may need to maintain that, to make sure their
doctors are documenting their limited energy reserves,
in case down the line the disability needs to be renewed
or is challenged. It is easy to see someone with HIV who
looks tanned and fit and think they are doing great; but
the reality may be that you are seeing them in their
three good hours a day, and then they are going home to
have a nap which the average person would not need.
ATN: What about problems in concentration?
Dr. Capaldini: You can divide psychological fatigue into
two categories, one being more motivational or spiritual
issues of meaning -- it's not worth it, I don't enjoy this
any more -- vs. more simple mental fatigue, as if the
brain were an organ that just tires more quickly. So
tasks of attention, concentration, or calculation which
were previously taken for granted are now difficult or
unreliable.
The earliest sign of this is usually what I call benign
forgetfulness, which basically means that unless you
make a point of paying attention to things you may more
easily forget them. Often patients are concerned that
this may represent early HIV dementia, but I find that
more often than not, this is not a symptom of dementia
but of fatigue. When a person is challenged in their
energy level, one of the ways it will show up is that
their attention does not function as well as it normally
does. But this is not dementia.
ATN: What are some questions people might ask themselves
before they see their doctor?
Dr. Capaldini: One of the ways fatigue is best picked up
is to check in with yourself every six months or so, and
compare your energy level to six months ago -- and equally
importantly, two years ago, and five years ago. If there
is a dramatic difference, it would be an indication of
fatigue that may have been accommodated to but not
recognized.
Are there activities that require physical effort that
you used to do routinely that you do not or cannot
do -- like carrying the laundry to the laundromat,
carrying more than one bag of groceries up the steps,
being able to ride a motorcycle, walking your dog? Are
you no longer doing the things that you used to make
time to do because they were fun for you -- gardening,
making dinner for your friends, going out to movies,
going to the gym? Are there specific activities that
used to be fun that are not fun any more -- the best
example for many people being sex? Is your libido gone?
Are there specific problems with your body when it comes
to physical activities? Do you get short of breath more
easily? Do your muscles tire more easily? Do you get
dizzy more easily? And if you notice these things, it is
very helpful when you go to your clinician, to say I
think I am having problems with my energy, and this is
what I'm noticing; that helps the doctor beam in to what
area is most appropriate to start evaluating.
Unfortunately many of us in medicine tend to assume that
fatigue is (a) a normal part of HIV disease, and (b) a
normal part of aging. And while it is clear that fatigue
is more common in people with HIV disease, and in people
as they get older, that does not mean it is normal; it
just means you have to look to find the cause. There are
some patients who have fatigue for whom no specific
cause will be found, but in my experience that is very
much the exception rather than the rule.
ATN: What medical tests are usually run when diagnosing
fatigue?
Dr. Capaldini: To some extent this is guided by your HIV
status; the more advanced your HIV disease is, the more
likely certain problems will occur. But a general list
would be:
- A test called the CBC, primarily to look at your red
blood cell count to see if you are anemic;
- A testosterone level to see if you are hypogonadal.
This test is much harder to interpret in women than in
men. We do not have a very good way to assess androgen
status in women, although I think getting a DHEA level
and a testosterone level is a reasonable place to start
in a woman.
- A chemistry panel to look for electrolyte
abnormalities, and to check liver and kidney function.
- Consideration of a chest X-ray and/or pulmonary
function test, if breathing seems to be the main
problem.
- Patients who are receiving dapsone therapy should also
get a methemoglobin level.
- There are some other tests worth considering, if the
evaluation suggests a specific problem -- for example, a
Cortrosyn test for adrenal insufficiency, or if it seems
there may be a cardiac problem, a test called an
echocardiogram.
Hypogonadism in Men
Dr. Capaldini: Hypogonadism -- low levels of androgens
and/or other sex hormones -- can cause a syndrome that is
very difficult to distinguish from depression: low sex
drive, listlessness, trouble concentrating, depressed
mood, etc. So I always check testosterone level in men
with HIV disease if I am considering a diagnosis of
depression. If it is hypogonadism, you replace the
testosterone, with either shots or patches, to see if
the symptoms clear up. If so, you know they were due to
the low testosterone; if not, then the patient may have
biochemical depression.
ATN: What are the different tests for testosterone?
Dr. Capaldini: There is a regular testosterone level,
which is your total testosterone; that can be broken
down into free and bound testosterone. Free testosterone
is what is physiologically active; bound testosterone is
available to be used, but not biologically active. Most
people with hypogonadism in HIV disease have low-normal
total testosterone levels; if you break that down into
free and bound, their free testosterone is also
low-normal.
The tricky part diagnositically is to recognize that
while the testosterone may be technically in the
normal range, it may be lower than normal for that
individual. For example, the normal range in most labs
is 300 to 1100, and is not adjusted for age; but most
men in their 30s, for example, have a level around 750.
If I test them and their level is 350, that is in the
"normal range" but not normal for them. This has been a
barrier dealing with managed care, when they ask how can
you justify replacing this hormone since it is in the
normal range. But all hormone test results have to be
interpreted contextually. And if a person who is having
trouble with their libido and energy has a "low-normal"
level of testosterone, that is not normal for them.
Usually it is straightforward to replace testosterone
and to determine if it reverses fatigue. The real choice
for patients is deciding which drug delivery system to
use, whether patches, pills, or shots. Also note that
with testosterone or other androgen replacement, therapy
may not work optimally without exercise.
There is also an oral anabolic called oxandrolone, and
it is an excellent drug for treatment of weight loss and
appetite problems due to hypogonadism. But it typically
does not correct the sex drive, mood, and energy
problems associated with this condition. So if a person
takes oxandrolone, they may also need to take a
testosterone-type treatment.
ATN: What are the options for delivering testosterone?
Dr. Capaldini: Testosterone is available different ways.
One is by an intramuscular shot; you get a very
unphysiologic pattern of rapid peak and fall of blood
levels, but it seems to work fine clinically. Some
people like the shots because getting one every two
weeks fits easily into their routine. But for others the
injections are uncomfortable or inconvenient.
A common dose is 400 mg. of testosterone cypionate
intramuscularly every two weeks. An alternative
injection drug is nandrolone (also known as
Deca-Durabolin) 200 mg every two weeks. Some patients
and doctors have found that combining them in certain
ways can give better results than either drug alone. We
need better data on these treatments. If you survey
doctors in the San Francisco area who use androgen
replacement therapy, you find that we use rather
different approaches.
There are two different patch delivery systems for
testosterone. One, called Testoderm, is placed on the
scrotal skin -- not to be adjacent to the testes, but
because that skin is very thin. An advantage of that is
that you cannot see the patch, for example if you are
wearing a bathing suit. But some men, particularly those
who live in humid environments, find it does not stay on
very well.
An alternative is Androderm, which is placed on
non-hairy regular skin. Both the problem and virtue of
this patch is that it sticks very well. Some people find
removing the patch to be difficult, and/or they get
inflammation at the site. (This is an irritant reaction,
not an allergic reaction, and can be treated with
topical steroids.)
What about testosterone gel?
Because of the cosmetic or logistical problems with the
patches or shots, many people have tried using
testosterone through gel or cream formulations, which
are designed to deliver a fixed amount of testosterone
in a given volume of cream or gel which is applied to
the wrist area, or to the skin between the thighs, both
of which are relatively thin skin areas. I have found
that for some people this works great. But others do not
seem to absorb the drug very well; when you measure
their testosterone level, they are not able to get
levels they had with either injection or patches. I
think this is worth a try for people who do not like
shots or patches. But you need to find a pharmacy which
does what is called "compounding"; there is at least one
in San Francisco, and others elsewhere (that can fill
prescriptions by mail). But some prescription plans do
not pay for compounded drugs (drugs that the pharmacist
must prepare, rather than pre-packaged drugs). And
these compounded forms of testosterone generally run
about $50 to $60 a month.
ATN: What is the expense of testosterone shots, or of
patches?
Dr. Capaldini: Testosterone shots are quite inexpensive
for the actual drug. The cost is mainly with the doctor
visit fee in giving the shot. Sometimes the patient can
save money by finding a friend who can give the
injection.
The patches cost about $60 a month, and generally are
covered by insurance; occasionally the doctor has to
provide a letter that says that this is treatment for
wasting syndrome or HIV-associated fatigue. Because
none of these drugs have been used in trials to look
specifically at HIV-associated hypogonadism or
HIV-associated fatigue, technically they are not
FDA-approved for that specific indication (oxandrolone,
like growth hormone, is FDA approved for HIV-associated
wasting). That is where you get into hassles with
managed care, because by the book they may only have to
cover FDA-approved interventions. I have been surprised
at how difficult it has been to get certain payers to
cover testosterone treatment; Medicare and Medi-Cal are
not a problem, but some of the PPOs (preferred provider
organizations) are.
But if you are hypogonadal, it is worth the money to
treat it. After a month or so of treatment, if you
dramatically feel better, it is worth the cost to
continue.
The down side of hormone replacement therapy is that
many men who take testosterone supplements will get
acne, usually on the back or on the face, and some will
notice that their testes shrink; if they are interested
in having children, there might be fertility concerns in
the long run.
It is important to distinguish between physiologic
replacement doses of testosterone, and much higher doses
used in gyms, that are not replacing what is missing but
instead giving the body far above what is normally
present. There are serious side effects associated with
these large doses -- for example, behavioral problems,
liver problems, and cardiovascular disease -- that as best
we know are not associated with physiologic replacement
doses. Some men will notice feeling a little edgy when
they take testosterone replacement; they may be
unusually sensitive to the drug, and the dose may need
to be reduced. Some patients have worried that they
might "go postal" from replacement doses, but that does
not happen.
Hypogonadism in Women
Dr. Capaldini: In women with hypogonadism, treatment is
quite a bit more difficult than with men, because in
replacing androgen drugs in women, you have to be
careful not to cause a problem called virilization, a
syndrome characterized by facial hair, deepening voice,
enlarged clitoral size; these cosmetic-like
abnormalities may not fully reverse with stopping the
drug. There is a pilot study using nandrolone 100 mg.
intramuscularly every two weeks, and preliminarily these
investigators have not seen any virilization in women.
We need data on women and wasting, and are trying to get
women to enroll in wasting studies so that we can learn
the best way to replace these hormones in women with
HIV. We have extensive background in replacing
testosterone in hypogonadal men even before the HIV era,
because hypogonadism has been a common disease of
younger and particularly older men. But we have very
little experience in women. Most of the time when a
woman is hypogonadal, that is picked up because she is
not menstruating or is unable to get pregnant. We have
less experience evaluating hypogonadism in the setting
of fatigue.
In women androgen replacement is more complicated,
because the predominant hormone in women is
estrogen -- yet androgen (testosterone, etc.) levels in
women, while they are lower than in men, still have
important roles. How to best replace these hormones when
they are abnormally low in women, without causing
menstrual bleeding or other side effects, is more
complex, and we have much less anecdotal experience or
information from studies to guide us.
ATN: When women are depressed, when that is a major
presenting problem, do you commonly find hypogonadism?
Dr. Capaldini: In my experience, no, unless there is a
large or prominent component of decreased libido. Even
if there is some hypogonadism, it is not clear how
effective drugs like DHEA are in women with HIV. So in
treating women who have depressive symptoms, including
low libido, I will try to
- see if there is a role for
antidepressant therapy, and
- look at hormone
replacement therapy -- with estrogen, perhaps with a
little testosterone added.
A formulation called
Estratest, consisting of estrogen with a small amount of
testosterone, is designed for women; it is unlikely to
cause virilization.
You have to be careful giving women estrogen, because if
they are still having periods, it may give them abnormal
periods; and if they are not having periods, it may lead
to abnormal bleeding. Someone familiar with hormone
replacement therapy needs to either be the primary
physician, or be involved in designing hormone
replacement. It is trickier in women than in men.
DHEA
ATN: In men or women, what do you think about DHEA?
Dr. Capaldini: This is an interesting and inadequately
studied area. Because of the lack of definitive trials,
there is little evidence yet to back up the claims that
some have reported for this treatment.
There is also no data yet to suggest it is harmful. But
I have concerns about replacing hormones in an
open-ended or careless fashion. When you give the body a
hormone, you may be turning off the body's normal
production of it or related hormones. So the idea that
because it is a hormone already in the body, and
therefore I can safely take as much as I want because
the body makes it, is not true.
DHEA therapy should be studied. Meanwhile I generally do
not have a problem with patients taking lower doses of
it, say 50 mg per day. When patients start taking 200,
500, or 1,000 mg per day I start to worry that it might
have an adverse effect in suppressing normal hormone
synthesis.
[Part II of this interview will look at depression,
anemia, and several other causes of fatigue in persons
with HIV.]
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