AIDS TREATMENT NEWS Issue #184, October 1, 1993
Denny Smith

Opportunistic Infection Prophylaxis

DS: Everyone knows to prophylax against Pneumocystis pneumonia, but beyond that, there isn't a solid consensus. When do you initiate the different prophylaxes, and what do you use?

LC: I try to have a structured routine with my HIV patients; those with very low CD4 [T-helper cell] counts (less than 50- 100) get regular eye checks, MAC prophylaxis and of course, PCP prophylaxis. I think AZT can actually be used as a prophylactic measure, in that it seems to help prevent dementia. [AZT, unlike many drugs, is known to cross the blood/brain barrier.] AZT also seems to reduce the incidence of HIV enteropathy, which can cause serious diarrhea and weight loss.

For MAC prophylaxis, you can make a good argument for single- drug therapy, with either rifabutin, clarithromycin, or azithromycin when CD4 counts fall below 100. I have been using clarithromycin, 1000 mg a day for people who can tolerate it. It's important not to combine this with Seldane, which can lead to a cardiac rhythm complication called prolonged QT syndrome. A good thing about clarithromycin is that it may also prevent some of the respiratory infections that people with HIV are prone to, like pneumococcus, and haemophilus, and staphylococcus. The cousin of clarithromycin, azithromycin, is probably just as good. If rifabutin is used, it's important to explain to patients that their body fluids, especially urine, will turn orange. But none of these drugs can be expected to control MAC indefinitely.

I think that detecting early, even asymptomatic, CMV disease is really important. By the time CMV causes an identifiable retinitis, it is already a disseminated infection, capable of causing fevers and wasting. People with CD4 cells less than 200 should have their eyes checked every three months, and if the CD4s drop below 100, then every two months. If you catch CMV disease early, you may prevent some of the constitutional symptoms associated with a disseminated infection; if you notice visual symptoms but wait to treat them, you may compromise someone's vision, as anti-CMV therapy does not fully reverse visual symptoms.

DS: Are you recommending anything for prophylaxis of fungal infections?

LC: Yes, I'm suggesting that people with less than 200 CD4s take ketoconazole, fluconazole, or itraconazole, daily. We're seeing much less cryptococcal meningitis than we used to, probably because so many people have already been taking one of these drugs for Candida infections. Even though ketoconazole does not cross the blood-brain barrier, I believe it can prevent CNS fungal disease by decreasing extra-CNS fungal burden. Fluconazole does cross the blood- brain barrier, but is much more expensive. In my experience, it is rare for someone taking daily ketoconazole prophylaxis to develop cryptococcal meningitis.

With ketoconazole, it's important to take the drug on an acidic stomach, so I tell people to take it with an acidic beverage, like orange juice, coffee or a cola. This is especially important if they are also on an acid-lowering drug like cimetidine or ranitidine. Another precaution about ketoconazole is that, rarely, it can interfere with androgen binding and androgen receptors, which can cause a situation that's clinically indistinguishable from androgen or adrenal hormone deficiency.

On the other hand, there is a danger in overdoing preventive medicine in not individualizing recommendations, and scaring people. I try to streamline my prophylaxis recommendations for my patients, so they don't feel like they're a carton of eggs and one little misstep will mean disaster. Psychologically that can wear people out. I am seeing more and more people with lower and lower CD4 cells who do not have any opportunistic infections and whose overall health is quite good.

Cervical and Anal Cancer

DS: The incidence of cervical and anal cancer has been reported at the last two International Conferences on AIDS to be increased in people with HIV. Has this been true in your patients?

LC: The more mucosal infections someone's had -- whether it's warts, herpes, chlamydia, syphilis -- the more prone that individual will be to have dysplasia [precancerous cells] on that mucosal surface. If I'm caring for an HIV-positive woman who has never had a sexually transmitted disease [STD], her risk for cervical or anal dysplasia is probably no greater than for a comparable HIV-negative woman. But a woman who's had multiple sexual partners, and multiple STDs, should be having regular pelvic exams and colposcopic exams. Analogously, for men or women, anal dysplasia will be seen more in individuals who have a history of chronic rectal infections, with HIV added as a cofactor that reduces immune surveillance and allows the dysplasia to emerge and perhaps develop into cancer.

I have some concerns about the emphasis on gynecological care for women with HIV. There are some women who very much need thorough, regular gynecological examinations, and there other women for whom that emphasis could be unnecessary and somewhat misfocused. In other words, some women may get their negative Pap smears and normal gynecological checks every six months and think they're OK overall, when really they may need to be more concerned about the standard problems for which everyone with HIV, men and women, are at risk (vaccinations, PCP prophylaxis, diet education, etc.). HIV can get misconstrued as a gynecological condition in women because in some women, that may be how the disease first shows up. But women who are HIV infected need to have a primary practitioner with HIV expertise, someone other than solely a gynecologist, directing their care. Women in this country are accustomed to getting their primary care from a gynecologist, but gynecologists cannot be expected to be completely familiar with HIV care in women any more than a proctologist would be for HIV-infected men. So we need to stretch the model -- HIV-primary care practitioners (internists, family practitioners) are already familiar with working closely with oncologists, but it may take some getting used to these clinicians working collaboratively with the gynecologist.

DS: There was some commotion in the activist community around the phenomenon of false-negative Pap smears. Because of the incidence of misleading smears, shouldn't women with HIV just be given a regular colposcopy [a more aggressive technique than the Pap smear]?

LC: I think again you have to consider the individual's history. A reasonable approach is that women should have a baseline colposcopy; in HIV-positive women without risk factors for cervical dysplasia beyond HIV, six-month Pap smears should be sufficient. But if a woman has had multiple STDs, she should have an annual colposcopy, and Pap smears every six months. If at any point either test finds something abnormal, then the screening can be intensified according to what the gynecologist recommends.

Fatigue: Hormone Replacement, Other Treatments

DS: One of the most common problems for some people with AIDS is unremitting exhaustion. I understand you have used androgenic steroids (male hormones like testosterone) for some of your male patients who are chronically fatigued.

LC: Some fatigue, I believe, is attributable to adrenal insufficiencies, either of glucocorticoids (like prednisone) or androgens/anabolic steroids (like testosterone). If someone becomes suddenly tired by just standing up, or walking a few steps, they probably have orthostatic hypotension, or low blood pressure. This can be caused by adrenal insufficiency, which in turn is treatable. (Incidentally, prednisone can be extremely useful for helping people cope with end-stage respiratory distress, such as that caused by pulmonary KS.)

But fatigue accompanied by muscle wasting and low libido probably results from androgen insufficiency. Borderline low testosterone levels are often seen in men with ARC or AIDS, and replacing that testosterone can help reverse weight-loss and appetite as well as problems with erections and fatigue. Testosterone cypionate, 200 mg every two to four weeks, has helped some of my debilitated patients, and has not caused any serious side-effects. It has also, I feel, reversed anemia and low platelets in some of my patients. Because of its potential masculinizing effects, I prefer to offer women Megace or Marinol rather than androgens, to treat refractory weight loss and fatigue. In men, Megace or Marinol can supplement testosterone therapy. Of note, the dose of testosterone I use is far below the amounts of anabolic steroids used by body builders.

Another possible treatment for either women or men who are emotionally as well as physically fatigued is dextroamphetamine. This can help people through difficult days, make them brighter and more interactive.

Survival Trends

DS: The statistics on AIDS say that people are living longer. Have you seen that empirically in your practice?

LC: Yes, certainly, although in my practice there is a definite bias, because I think my patients tend to have more resources than the average patient with AIDS in this country. I don't just mean money -- I also mean having friends, family or neighbors who will be supportive and will look out for my patients' welfare. As far as statistical survival goes, I see two trends. Many people are living longer, learning how to live with CMV and MAC or other illnesses, but some people are deciding when to stop treatments, which may silently alter the statistics. The issue isn't always how long did someone live after an AIDS diagnosis but how long did they choose to live.

Depression and Its Treatment

DS: What particular measures would you say might enhance someone's life such that they would choose to live?

LC: I have never seen enough emphasis on treating reversible affective disorders, like depression and panic attacks. I have been amazed at how many people with AIDS, people who are dealing with multiple infections and really difficult times, function better day to day with antidepressants. Absolutely. Some clinicians may be hesitant to "cross over" into practicing psychiatric medicine, but we who treat HIV already treat a number of clinical situations that we once would have referred to a specialist. Who doesn't prescribe amphotericin, or erythropoietin, when indicated, rather than referring every symptom to an infectious-disease specialist, or a hematologist? There is an aura around antidepressants that misleadingly implies they are in a completely different realm.

I think if primary-care providers only feel comfortable referring psychiatric symptoms to a psychiatrist, they should at least become familiar with recognizing depression and anxiety in their patients. It would be great if those providers also became comfortable treating the patient directly. For logistic and reimbursement reasons alone, it's helpful for patients to not have to go to a number of providers for their care. More importantly, the primary-care physician is often in the best position to pick the right medication. The main concern with antidepressants is not their efficacy, but their side-effect profile. Sometimes you may actually want to exploit side effects, like drowsiness for insomiac patients, or stimulant effects for lethargic patients.

You may not always know for sure if the depression or anxiety will respond to medication, but you can't know if you don't try it. If the stigma around using antidepressants comes out of the provider's unfamiliarity with the drugs, then they should familiarize themselves.

Perhaps their discomfort stems from talking to their patients about personal, emotional issues; a lot of health-care providers may be dealing with their own depression, since many of them have lost loved ones to this disease. But it's good for the provider to open up so that the patient can open up. And the benefit of doing that is being able to offer the patient a positive healing message: I am looking at you as a whole individual, with dreams and struggles and worries and hopes, and not just a collection of opportunistic infections. In medicine it's actually good to have double vision: to be able to see the ordinary as well as the extraordinary.

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