Fatigue and HIV: Interview with Lisa Capaldini, M.D.
Part II

By John S. James

[Part I of this interview, published in issue #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 al 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 anoxygen transport disorder that, in people with HIV, can occu 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 thi 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.

Nevirapine: One-Year Combination Results Published

By John S. James

Some triple-drug combinations not including a protease inhibitor have been proposed as "protease sparing" regimens, for certain patients who might want to start with a somewhat easier combination treatment and/or save the protease inhibitors for later. Last week, results of the one-year INCAS study (named for the countries where it was run--Italy, the Netherlands, Canada, and Australia) were formally published.(1) One arm of this study, which treated 51 volunteers with AZT plus ddI plus nevirapine, found that viral load was undetectable for one year in about half of those treated. The patients in this study were among the easiest to treat, however--as they were antiretroviral naive, and also had not had any AIDS-defining diagnosis.

An accompanying editorial,(2) also in the same issue of the JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, concluded, "Currently, for patients with advanced HIV disease or AIDS, effective antiretroviral therapy requires starting treatment with a regimen that includes a protease inhibitor. For patients with earlier stages of HIV disease, the choice among currently available regimens should be carefully considered, with easier-to-take regimens kept in mind. The philosophy of 'treat early, treat hard' in early HIV infection must now yield to a philosophy of 'treat smart' for all stages of HIV infection."

The article and editorial are currently available on the Web, http://www.ama- assn.org/special/hiv/library/readroom/jama98/joc71782.htm

and

http://www.ama- assn.org/special/hiv/library/readroom/jama98/ed80016x.htm

References

1. Montaner JSG, Reiss P, Cooper D and others. A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients. JAMA; March 25, 1998; volume 279, pages 930-937.

2. Gulick, RM. HIV Treatment Strategies. JAMA; March 25, 1998; volume 279, pages 957-958.

Notice on Efavirenz and Pregnancy

DuPont Merck has informed researchers, physicians, and patients using the experimental drug efavirenz (Sustiva(TM), also known as DMP-266) that malformations were found in three of 13 monkey fetuses after their mothers were given the drug throughout their pregnancy, at doses which approximate human blood levels of the drug. All the malformations are believed to have occurred very early in pregnancy.

The trials of efavirenz have always required volunteers to use effective contraception, and have required pregnancy tests for women at each study visit; this was done as a general precaution because the drug is experimental. The new information emphasizes the importance of not becoming pregnant while taking efavirenz.

Earlier studies in rats and rabbits had not found any such problems. According to DuPont Merck, this is the first time a pharmaceutical company has tested an antiretroviral in monkeys for safety during pregnancy.

Because there is no indication of harm in late pregnancy, the drug has not been ruled out for use in preventing maternal/infant transmission of HIV.

More than 4,000 patients have received efavirenz in trials so far, and these trials are continuing as planned.

AIDSWatch May 3-5 in Washington

Each year hundreds of people with AIDS and their supporters come to Washington to advocate for funding and commitment to HIV prevention, care, treatment, research, and housing. This year's program, the 7th annual, will start Sunday May 3 with a half-day briefing and training, followed by two days on Capitol Hill meeting with representatives and senators and their staff members.

[Northern California note: a half-day briefing for Northern California participants will be offered April 25 in San Francisco. For more information, contact Lisa at the HIV Advocacy Network, 415-487-3034.]

For more information about AIDSWatch '98, including briefings before the event, contact Mr. Jean-Michel Brevelle, National Association of People with AIDS, 202-898-0414, ext. 103.

Medical Marijuana: Time to Contact Your U.S. Representative

By John S. James

Now is a particularly good time to educate your U.S. representative on medical marijuana, and the importance of this issue to his or her constituents.

"The U.S. House of Representatives has delayed its vote on House Resolution 372, the anti-medicinal-marijuana resolution, until Tuesday April 21 at the earliest. This would be the first-ever congressional vote on medicinal marijuana. If you are a patient, doctor, or otherwise have a personal story to tell about medicinal marijuana, please call the office of your U.S. representative to schedule a meeting while he or she is visiting his or her office near your home town during the April 4-20 congressional recess." [from March 27 press release of Marijuana Policy Project, Washington, D.C.]

House Resolution 372 (abbreviated H.Res. 372, *not* H.R. 372) states in part, "The U.S. House of Representatives is opposed to legalizing marijuana ... a dangerous and addictive drug ... for medicinal use, and urges the defeat of state initiatives which would seek to legalize marijuana for medicinal use."

Opposition to H.Res. 372 has been growing rapidly. For example, when the House Judiciary Committee issued a 15-page report on the resolution on March 18, nine Democrats on the committee strongly dissented: "If a state, by referendum or legislative enactment, adopts a policy that marijuana can provide some relief to those of its citizens who are suffering from AIDS or cancer, it is the height of Washington-centered arrogance for the Congress to override that state's position."

The Marijuana Policy Project suggests the following language for writing or calling your representative: "I am writing/calling to urge you/Representative ____________ to vote against House Resolution 372, the anti-medicinal marijuana resolution. I believe patients should be allowed to use medicinal marijuana if their doctors approve of such use. At the very least, Congress should not take any action on this issue until the Institute of Medicine completes its review of medicinal marijuana this coming December."

You can call your representative through the Congressional Switchboard, 202-225-3121. If you do not know who your representative is, the switchboard can use your ZIP code to connect you. Or you could contact their local office; the phone number is probably listed in the U.S. Government section of your phone book.

For more information, contact:

Marijuana Policy Project
Phone: 202-462-5747
Fax: 202-232-0442
Mail: P.O. Box 77492, Capitol Hill, Washington, D.C. 20013,
Email: mpp@mpp.org
Web: http://www.mpp.org.

California AIDS Lobby Day, April 20 in Sacramento

The Eighth Annual California AIDS Lobby Day will take place Monday April 20th from 10:00 a.m. to 5:00 p.m. in Sacramento. Persons are asked to register by April 14 so that the organizers can set up appointments with their legislators. Some travel and hotel arrangements are being made for persons who need them; from Los Angeles, for example, a bus and hotel package is available for about $38.

Local briefings on California AIDS issues and on advocacy skills will be held on various dates in Santa Rosa, San Francisco, Oakland, San Jose, Sacramento, Fresno, San Diego, Palm Springs, and Los Angeles.

AIDS Lobby Day is sponsored by the AIDS Budget Coalition: AIDS Project Los Angeles, AIDS Services Foundation Orange County, ARIS in San Jose, Los Angeles Gay and Lesbian Center, LIFE Lobby, Planned Parenthood Affiliates of California, Project Inform, San Francisco AIDS Foundation, and San Mateo County AIDS Programs.

For more information:

Northern California: call the HIV Advocacy Network, 415-487-3034;

Southern California: call AIDS Project Los Angeles, 213-993-1622.

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AIDS TREATMENT NEWS reports on experimental and standard treatments, especially those available now. We interview physicians, scientists, other health professionals, and persons with AIDS or HIV; we also collect information from meetings and conferences, medical journals, and computer databases. Long-term survivors have usually tried many different treatments, and found combinations which work for them. AIDS Treatment News does not recommend particular therapies, but seeks to increase the options available.

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