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[Part I of this interview, published in issue /content/art31526.html/content/art31526.html#291,
looked at different kinds of HIV-related fatigue,
diagnosis issues, and treatment of hypogonadism in men
and in women. Part II focuses on depression, anemia, and
other causes of fatigue in persons with HIV.]
Depression
Dr. Capaldini: One of the most easily missed conditions
that can cause fatigue is depression. It is easy to
overlook because (1) there is no test that can be done
to rule it in or out, it is a clinical diagnosis, and
(2) most of the physical symptoms of depression are also
common with HIV disease in the absence of depression:
sleep disorders, pain, libido problems, fatigue, etc.
There is also a large overlap between the mood symptoms
of depression and the day to day difficulties many
people with HIV have, such as feeling hopeless,
irritable, angry, guilty, etc. And many clinicians can
miss depression, because in our attempt to be empathic
with our patients' struggles with their HIV disease, we
may incorrectly assume that some coping difficulties are
a normal part of that person's illness, rather than due
to a treatable biochemical abnormality called
depression. Biochemical depression is caused by
abnormally low levels of serotonin, norepinephrine, or
both, in the brain, which in turn cause the physical and
mood symptoms of depression.
Clues that depression may be the cause of fatigue are
that the patient has had (1) an episode of depression
pre-dating their HIV disease, or (2) a history of
recreational drug abuse (people with drug abuse
histories tend to also have depressive disorders), or
(3) a family history of mood disorders -- bipolar disease,
depression, or panic disorder -- which suggests that the
person is genetically prone to depression. If depression
is diagnosed, the next decision is whether to treat with
psychotherapy, antidepressants, or both.
AIDS Treatment News: What is your experience with the
medications in persons with HIV?
Dr. Capaldini: My experience is that antidepressants are
as effective in treating biological depression in people
with HIV disease as in HIV-negative people. Two major
issues in using antidepressant therapy in people with
HIV are (1) to make sure you are not missing
hypogonadism (characterized by fatigue, decreased
libido, concentration/mood problems) [see Part I of this
interview, in AIDS Treatment News #291], and (2) to
choose an antidepressant with full knowledge of its side
effect profile. There are certain side effects that may
be helpful; for example, the tricyclic antidepressants
[for example, amitriptyline] may help chronic pain and
help people sleep. There are certain side effects that
can be specifically detrimental to a person because of
the problems they already have; for example, tricyclic
antidepressants can cause dry mouth, dizziness, or
constipation, and if these are already problems for the
patient, then those drugs should be avoided.
By class, probably the most frequently prescribed
antidepressants today are in the SSRI category
(selective serotonin reuptake inhibitors). These are
drugs that affect the level of serotonin in the
brain--Prozac, Zoloft, Paxil, and Luvox. The main
disadvantage of this class of drugs is that they tend to
cause sexual dysfunction (decreased libido, trouble
getting physically aroused, or most commonly trouble
"getting stuck," as it were, before climax). These
problems often get better over time, and if they do not,
the patient can be switched to a different
antidepressant.
Bupropion, or Wellbutrin, is the least likely of the
newer antidepressants to cause sexual dysfunction, and
is taken twice a day.
Effexor is midway between Wellbutrin and SSRIs with
regard to sexual dysfunction.
Serzone (nefazodone) is not as likely to cause sexual
dysfunction as the SSRIs, but tends to cause sleepiness
during the day in a fair number of people. It does tend
to help people gain weight, which is a good thing if
they are having trouble with appetite or weight loss.
Remeron is like Serzone in that it tends to cause
sleepiness and weight gain, although the published data
suggests that these side effects tend to be more
short-lived with Remeron.
Patients starting an antidepressant should know that for
the first two weeks they are most likely to have the
side effects, but the antidepressant effects typically
do not begin for two to four weeks. Patients need to
understand that they will not get instant results. If
after four weeks there is no effect and also no side
effects, then the doctor may increase the dose and check
again in another three weeks or so.
The only way to tell ahead of time whether a given
antidepressant is likely to be more effective for you
than for the average person is to know if anyone in your
family has had a good response to it. Depression is such
a genetically determined disease that this is often the
best way to predict what will work best for you.
Also, unlike many other drugs that act in the brain,
antidepressants are not addictive or mind-altering in a
recreational sense. Patients in recovery are often
concerned about this. But in fact these drugs do not
sell on the street; there is no market because they do
not make people euphoric. Antidepressants make
biologically depressed people less depressed; if a
person is not depressed and they take an antidepressant,
they do not become euphoric.
For many patients, psychotherapy works as well as or
better than medications. For some patients, face to face
contact with another human being feels like a better way
to work through depression problems. The obstacles are
financial and logistical; therapy may run $100 a week,
and most managed care plans cover it incompletely. In
choosing a therapist, it is important for a person who
has a depressive disorder associated with HIV disease to
work with someone who is familiar with the ups and
downs, the pragmatics of this disease, so they are
familiar with what the person is going through.
Also, many recreational drugs are depressogenic, that
is, they can cause depression. For example, large
amounts of alcohol can cause depression, as can most
other street drugs. So if a person has a drug-use
problem, the first step is to get into a treatment
program and be evaluated by a mental health specialist.
This clinician will try to determine whether the patient
was using recreational drugs partly to "treat" or mask
pre-existing depression symptoms; in this case it would
be appropriate to consider antidepressant medications as
part of the drug-recovery treatment.
Making this distinction -- is an alcoholic, for example,
looking and feeling depressed because the alcohol made
him depressed, or did he start drinking because he was
depressed already and the alcohol made him not feel
sadness as deeply -- is tricky. The area of "dual
diagnosis" in the mental-health field is fascinating,
and in flux. There are studies to show that people in
acute alcohol recovery have a better response rate with
antidepressants than without, but these are short- term
studies. I think that in this area, a mental-health
specialist working with your primary care doctor is in
the best position to help decide what is the best
initial program for each specific patient. There is
nothing wrong with taking antidepressants during
recovery; but if you have a drug or alcohol problem, it
needs to be dealt with thoroughly through support
groups, individual therapy, or both.
A newer issue with antidepressants is drug interactions
between these drugs and combination-therapy
antiretrovirals. While all protease inhibitors and
NNRTIs [non-nucleoside reverse transcriptase inhibitors,
for example nevirapine or delavirdine] have potential
drug interactions with many antidepressants, the major
drug interaction problems with antiretrovirals are with
ritonavir and delavirdine. These two antivirals are
powerful inhibitors of the P450 enzyme system, which
metabolizes many antidepressants. If you are on one of
those two drugs, your doctor needs to either avoid
certain antidepressants, or to prescribe them in lower
than typical doses, taking care to check drug levels for
those drugs which have tests available, like the
tricyclics. My rule of thumb is that if a patient is on
either ritonavir or delavirdine, I would not prescribe
Wellbutrin (because when that drug's levels get very
high there is a possibility of a seizure), or tricyclics
(as these can cause serious cardiac rhythm disturbances
when their levels are high). The tricyclics can be
safely used with antiretrovirals other than ritonavir or
delavirdine, but their blood levels should be monitored
closely, and initial dosing should be low and adjusted
upward based on drug levels.
For other antivirals and HIV therapies, I do not
routinely adjust or modify antidepressant dosing.
Patients and doctors should not be inappropriately
spooked by some of the warnings about drug interactions;
some companies have speculated that their drug may
increase the levels of other drugs, based on
theoretical, non-clinical data, and have translated
these speculations into specific warnings. I am all for
being cautious, but think that in some cases the caution
has been overstated.
Anemia
ATN: What about anemia as a cause of fatigue in persons
with HIV?
Dr. Capaldini: Anemia means that your number of oxygen-
carrying cells has decreased. On your lab work that can
be reflected by one of three measurements: your red
blood cell count, your hemoglobin, or your hematocrit,
which are all interchangable ways of expressing how many
red cells you have. If you look at the hematocrit, a
normal hematocrit in a man is between 40 and 48; in a
women it is between 36 and 40. (The difference is
because women have menstrual blood loss.)
When a patient has anemia, she or he may experience
fatigue. But also there are people who are anemic who do
not have fatigue. So being anemic does not always mean
you will be fatigued; and you can have a mild anemia and
that may not be why you are fatigued.
Anemia-associated fatigue tends to show up primarily
with physical activity: trouble climbing up hills, with
physically challenging tasks like carrying groceries, or
with endurance activities like walking, running,
cycling, or swimming. But it can also spill over into
more psychological fatigue.
How much anemia causes symptoms depends not only on how
severe the anemia is, but on how quickly the person went
from the normal range of red blood cells to an abnormal
range. For example, if my normal hematocrit is 36, and I
develop anemia due to AZT therapy over two weeks and go
to 27, I am very likely to have noticeable shortness of
breath or dizziness. But if on the same treatment my
hematocrit fell over six months, I may slowly
accommodate and not notice any clear symptoms.
Anemia can be due to blood loss -- for example
gastrointestinal bleeding, or trauma. In HIV disease, it
is usually due to inadequate production of red blood
cells from the bone marrow. We do not know what happens
in the bone marrow to make it less efficient in
producing blood cells. But in the great majority of
cases, either stopping a medicine that is causing the
problem (such as AZT or certain forms of chemotherapy),
or stimulating the bone marrow (with a hormone called
erythropoietin, or EPO), can reverse the anemia. So if
you are anemic, the first questions are (a) are you
anemic because of a drug, and (b) do you have to stay on
that drug or can you stop it? If the anemia is not from
a drug, the erythropoietin level should be tested; if it
is low normal or low, then erythropoietin replacement
therapy is begun with shots which are given three times
a week subcutaneously. That is continued until the
anemia is corrected.
When people become anemic very rapidly, and are short of
breath and dizzy, sometimes they will require a
transfusion for their initial treatment. But then it
becomes important to find out why they became anemic,
and if it is a chronic problem, to consider
erythropoietin therapy.
ATN: This drug is very expensive. What has been your
experience in getting it paid for?
Dr. Capaldini: Usually erythropoietin is not a problem
with reimbursement, because Ortho Biotech has an
FDA-approved indication for treating people with HIV
disease. In my experience, with reasonable documentation
it is easy to get it covered.
ATN: Can people give themselves the shots?
Dr. Capaldini: Yes, easily. Unlike testosterone shots,
which have to be given in the buttock area and require
some strength in the hands because the material is
viscous, erythropoietin injections are subcutaneous
shots, like taking insulin.
ATN: What about nutritional causes of anemia?
Dr. Capaldini: In the general population the most common
causes of anemia are nutritional, due to inadequate
intake of iron, or folate or B-12. While these disorders
are occasionally seen in people with HIV, they are less
often the cause of anemia in these patients. So it is
very important to find out why you are anemic, because
it is unlikely to be due only to a vitamin deficiency.
ATN: Should we include some warning about taking too
much iron?
Dr. Capaldini: Most people can take iron safely. But if
you have a tendency toward a genetic illness called
hemochromatosis, you could get into trouble. (This
disease is diagnosed by a high serum iron level,
accompanied by a high iron binding saturation.)
Vitamin B-12, which is given by shot, is harmless in
extra doses. So it is unlikely that people will hurt
themselves by using vitamins in an attempt to correct
their anemia. The larger concern is that they may be
going down the wrong road; if it is a significant
anemia, they need to find out why they are anemic. It
is possible but unlikely to be due to a nutritional
deficiency.
Other Causes of Fatigue
Adrenal Insufficiency
Dr. Capaldini: Adrenal insufficiency -- when the adrenal
glands are not making the proper level of
glucocorticoids -- is relatively rare but easy to treat.
The symptom complex includes fevers, postural dizziness,
and unremitting fatigue; some patients have the fatigue
as the predominant symptom. The way to screen for this
condition is a two-part blood test called a Cortrosyn
stimulation test. The treatment of adrenal insufficiency
is quite easy; it involves taking a couple pills a day.
While this disease is rare, its impact is so great that
if I am seeing someone with unexplained fatigue,
particularly if their T-cells are in the lower range, I
will screen for it even if the fatigue is the only
symptom of the disease. I have, however, seen a couple
people whose T-cells were higher, in the 300 to 400
range, and with no known opportunistic infections, who
had this condition, so it is not an HIV endocrine
complication that is limited to advanced disease.
Methemoglobinemia
Dr. Capaldini: Another relatively rare condition is
called methemoglobinemia [pronounced
met-hemoglobinemia]. This is an oxygen transport
disorder that, in people with HIV, can occur with
dapsone therapy. Dapsone can cause a change in how
oxygen binds to hemoglobin. Functionally it is like
being anemic, because your red blood cells cannot carry
oxygen properly. The condition is diagnosed by a blood
test called a methemoglobin level, and the treatment
essentially is to stop the dapsone (rarely, other
treatment may be needed if the condition is unusually
severe and acute). So if people taking dapsone are
finding that they have unexplained breathlessness, it is
a good thing to check for this. In my practice I have
seen four cases in 12 years. But since this disorder is
serious and easy to treat, it is worth thinking about.
(Note: G-6-PD deficiency, another disorder exacerbated
by dapsone, is an entirely separate condition. It is
seen largely in African-Americans, and is screened for
by a G-6-PD test.)
HIV Itself
Dr. Capaldini: It is clear that for many people HIV-associated fatigue is due to or connected to high levels
of HIV viremia. We know this because when patients with
high viremia go on potent antiretroviral therapy and
their viral load rapidly falls, the majority of them
will feel better in their day-to-day energy. Many will
recognize after the fact that they were quite tired,
because they feel so much better energy-wise when their
viral load has cleared.
But about 10% to 15% of my patients who have an
excellent virological response to combination therapy,
an excellent T- cell response, and control of previously
refractory opportunistic infections, still remain
fatigued. So simply controlling the virus does not
necessarily fix fatigue. I have a couple patients whose
T-cells are in the 600 to 800 range, with undetectable
viral load, who are tired. They notice it in relatively
subtle ways, such as when they are reading complex
materials and their attention tends to fade after a
while. These are people who used to be doctors, or do
desk work where their attention over hours was routine,
who find that they can no longer do these previously
"routine" tasks. This suggests that something is going
on in the hormonal or central nervous system milieu
besides HIV per se, changes that can mediate fatigue in
people with HIV disease -- that it is not simply the
level of the virus in the blood that determines how
fatigued HIV-infected people are.
Hepatitis
Dr. Capaldini: Many people with HIV disease, either as a
result of HIV or their medications, may have low-grade,
chronic, often trivial elevations of their liver
enzymes; that usually has nothing to do with fatigue.
But if a patient has chronic hepatitis B or C, when
those illnesses flare, or with disease progression over
time, a patient can have fatigue as a result. It may be
hard to tell when the hepatitis is causing the fatigue,
instead of HIV. As a rule of thumb, if your T-cells are
high and your HIV viral load is undetectable or very
low, and you are very tired, it is more likely to be due
to the chronic viral hepatitis than to HIV. Levels of
hepatitis B and hepatitis C are measurable, like HIV,
and may help determine whether symptoms are attributable
to viral hepatitis.
Malnutrition
Dr. Capaldini: Fatigue can result from malnutrition -- not
getting enough proteins, calories, and vitamins in your
diet. Often I am asked whether foods like pastries,
cakes, and cookies are harmful. In general these
so-called junk foods are only harmful if they cause you
to not eat more nourishing foods. If you are eating a
healthy diet and supplement it with junk food, for
most people there is no harm, and junk food may be a
pleasant way to obtain enough calories. But if you are
not getting adequate proteins and fresh fruits and
vegetables, if junk food replaces healthy foods, this
can cause protein and vitamin deficiencies.
Food should be a source of pleasure in your life, and
the main thing is to make sure your protein, calorie,
mineral, and vitamin requirements are met. To the extent
that you can get your fruits and vegetables from fresh
sources, these are probably more nutritious than
pre-cooked fruits and vegetables.
Lack of Exercise
Dr. Capaldini: When people notice they are tired, they
may reduce their exercise, either because they do not
feel up to it, or because they fear it may make their
fatigue worse. But in most cases, continuing a regular
exercise program helps keep the fatigue from getting
worse.
If someone is dizzy or feverish, they should skip
exercise that day. But if it is one of those days where
you wake up and are tired, you will probably feel better
taking a good walk on the beach, or going to the gym,
rather than skipping it. Only rarely does exercise make
fatigue worse; and, if you do notice that, you should
tell your doctor, as it suggests you may have something
that requires specific treatment, such as anemia.
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