Treatment Strategies: Interview With Larry Bruni, M. D.

To help support strategic, individualized programs for controlling HIV disease, we interviewed Larry Bruni, M. D., a Washington, D. C., physician who has maintained a large HIV practice for several years. Dr. Bruni is known as an innovator in the care of his patients; a Cable News Network (CNN) interview with him should air later this month.


DS: For people who are still above 500 T-helper cells, what do you look for to make decisions about intervention in the progression of HIV?

LB: The various blood markers aren't very useful at that point, so I look carefully at the clinical picture. I've come to regard anything except a broken bone as possibly related to HIV. That may be a fallacious assumption, but better to be too vigilant, rather than trivialize something like a rash or headaches that could be tied into disease progression. I don't dismiss anything. When people worry that they are being hypochondriacal, I tell them that they're not. By just recording patients' complaints in their charts, I can sometimes discern a pattern of symptoms. Small things that would ordinarily go unnoticed may be significant. For example, when I examine the ears, I look for small bubbles behind the eardrums. These can be caused by infections of mycoplasma, which sometimes colonize the middle ear. I'm more willing to try doxycycline than to tell the patient "don't worry about it."

DS: When do blood markers become noteworthy?

LB: Well, the T-4 helper cell counts and percentages are important because, of course, progressive depletion of helper cells is the hallmark of HIV infection. But you can't rely on this alone, partly because the methods of counting the cells are not absolutely precise; there are many calculations involved in deriving the final "count."

DS: That's a good point, because I think a lot of people, including myself, don't understand all the calculations involved in lab results. We often assume that the total blood cell population is ordinarily stable, so any variation in one component is alarming.

LB: No one should be alarmed by small variations. Also, the percentage of T-helper cells is more revealing than the absolute count.

DS: When someone who is on AZT experiences a drop in T- helper cells, is that ever attributable to a drop in the overall white count, which can in turn be attributed to AZT?

LB: Yes. So I don't routinely put people on nucleoside analogs [AZT, ddI, ddC] for T-helper cell counts above 500. But there are circumstances that may warrant the use of AZT in that range, particularly clinical symptoms that indicate disease activity. For example, if someone is having repeated bouts of genital warts.

DS: In other words, a relatively minor problem which is resistant to normally successful treatment may be a signal of HIV activity.

LB: Not only that, but I think HIV would be a rather indolent [slow to change] infection if it weren't for all the other infections our bodies have to process at the same time. I don't really make a distinction between opportunistic infections and the idea of cofactors. I teach my patients that HIV disease is a slow process if not for other things that push it, such as other infections, exposure to sunlight, etc. And infections can transactivate each other. While the warts are allowed to recur by HIV, HIV is stimulated by the wart virus. So for both practical and theoretical reasons, we need to control this cycle by controlling any problem that is potentially chronic, like bronchitis or adenovirus colitis.

DS: In light of that, what are some of the things you look for in patients who would ordinarily think of themselves as asymptomatic?

LB: Sinus infections, skin rashes, fungal infections of the toenails, athlete's foot that is persistent, prostate infections, and of course, headaches and fatigue. Headaches, especially, are too often chalked up to "tension," but since stress can contribute to immune dysfunction, and to emotional dysphoria, I think even a tension headache may deserve intervention.

DS: You mentioned sunlight as a cofactor.

LB: Yes, even before studies were published about its effect on HIV, sunlight was known to provoke herpes outbreaks. Strong sunlight, probably the ultraviolet rays, can impair immune response. You don't have to worry about the regular exposure during daily activities. I'm talking about laying out in the sun, or playing volleyball in your swimsuit for hours at a time. T-helper cell counts drop almost invariably after someone spends a long weekend at the beach.

DS: I understand that you favor the empirical use of antibiotics, when a set of symptoms is eluding any particular diagnosis or treatment. Is there a concern that antibiotic drugs could suppress the immune system further?

LB: I haven't really seen any systemic damage from antibiotics. Indeed, my own experience is that a course of antibiotics frequently perks up the immune picture. The first antibiotic I tried on an empirical basis was doxycycline, in 1988, based on Stephen Caiazza's ideas.

DS: Since HIV isn't affected directly by antibiotics, this must be a way of dealing with cofactors in hiding.

LB: It often seems that something else is driving the infection. The notion that latent syphilis may be treated this way is interesting. I can't think of any topic in medical school that professors were more smug about than syphilis treatment. "We know everything there is to know about this disease," they'd say. Reminds me of the character in Voltaire's Candide.

DS: Dr. Pangloss!

LB: Yes, as though we live in the best of all possible worlds, and we know everything we need to know. But meanwhile, one treatment they were using to treat syphilis failed to cross the blood/brain barrier, and those people may be chronically infected with syphilis, including many people with HIV.

DS: So the cerebrospinal fluid could be "reseeding" the body, and doxycycline may be dealing with it?

LB: I've had some excellent results with doxycycline; tetracycline, as well, will cross the blood/brain barrier. I try it in people who have a residual indicator of syphilis in their blood. And now we know that we could be treating mycoplasma infections empirically, too. I have actually seen rises in T- helper cells in some patients during treatment with doxycycline.

DS: How do patients and physicians make judgment decisions together?

LB: Physicians need to be willing to make some intuitive judgments, because we won't find advice in the medical journals, whose reports invariably end with something like "not statistically conclusive, more investigations needed." Patients can be limited by their preconceptions. I still get patients who say to me, "I'll try anything except AZT. " "Why won't you try AZT? " "Because it's poison." Yet studies clearly show that when we use AZT correctly, we can improve the quality and the length of life.

DS: So you're trapped between patients who do not like the primary option available, and a medical establishment which cannot seem to improve the options.

LB: Well, I'm really happy now that we have ddC, even if people have to use the "gray market" version. I think ddC works, without horrible side effects. Now routinely, when I start people on AZT, after three months I tell them it's time to switch to ddC. Another three months, we return to AZT, and I continue alternating like that.

DS: What's the rationale for rotating instead of using them together?

LB: Well, it takes about three months for AZT side effects to appear, at the current low doses. This dosing may avoid indefinitely those predictable drops in white cells and hemoglobin. By using them separately, you can also see how each drug affects each patient.

DS: You've mentioned AZT and ddC, but not ddI.

LB: For a year and a half, our office has been overwhelmed by the paperwork associated with ddI. And the manufacturer's criteria for ddC eligibility are ridiculous. I'm ready to forego all that if patients can reliably obtain ddC through the buyers' clubs.

DS: Are there other important treatments that patients can get through the buyers' clubs?

LB: In addition to ddC, I'm glad to see the clubs carrying levamisole [a potential immunomodulator] and clarithromycin [a new antibiotic]. I started recommending levamisole to patients last November, before it was approved by FDA for use in colon cancer. When it became available by prescription, I started slowly, not being familiar with its use and wishing to avoid toxicities. Now I give it to people who do not improve on more standard therapies. I think it holds great promise as an immunomodulator.

DS: Is clarithromycin still looking promising for treating MAI, cryptosporidiosis, or toxoplasmosis?

LB: I've replaced all the old MAI drugs with clarithromycin and ciprofloxacin. The dose we're trying is eight pills [250 mg each] of clarithromycin daily, which unfortunately is expensive. I'm seeing some weight gain, and reduced fevers. These patients feel it's working. I'm trying the related drug azithromycin to treat toxoplasmosis in several patients who were obviously failing the pyrimethamine/sulfa combination. It's too early in follow-up to say for sure, but I think it will work. I'm also advocating some prophylaxis in people who have been exposed to Toxoplasma, and who have dropped below 200 T-helper cells. I believe azithromycin and clarithromycin probably will become the best drugs with which to treat toxo or prevent active infections. Anecdotally, two of my patients with cryptosporidiosis found complete relief from the diarrhea within five days on azithromycin, and after ten days of treatment they maintained normal bowel function and regained all their lost weight for months.

DS: Something we have been hearing a lot about lately is gall bladder inflammation and bile duct obstructions. Is this becoming a common HIV-associated trouble?

LB: Very common. This is usually a condition called acalculous cholecystitis, meaning an inflammation which is not caused by gallstones. The cause could be any of a number of pathogens, like CMV, cryptosporidiosis, or other parasites. But the drugs we give to treat those infections do not penetrate the gall bladder very well, making it sort of a reservoir of infection. The signs are abdominal pain, often connected with diarrhea. Since this tends to persist and not respond to antibiotics, the best treatment seems to be removal of the gall bladder. You can get along nicely without a gall bladder, and the surgery should improve both appetite and nutrient absorption.

DS: Getting back to the empirical use of treatments, you have found IVIG [intravenous immune globulin] useful, haven't you?

LB: It can be very helpful, also very expensive. It's valuable for treating the kind of recurring bacterial infections that a healthy immune system ordinarily handles, especially sinus infections. It is also a good complement to use with ganciclovir when treating CMV pneumonia or colitis. Adding it to therapy for retinitis does not help much, according to studies which have been completed.

DS: Can you make immune globulin specific, engineer it to be concentrated in certain antibodies?

LB: It's not engineered so much as graded for counts of particular antibodies. I use Gammagard, made by Baxter, because it has the highest concentration of anti-CMV antibodies.

DS: Do you have any advice about nutritional supplements?

LB: I have recommended a short list of supplements for several years, and have recently added NAC and coenzyme Q-10 to that list.

DS: Why has interest in coenzyme Q been revived recently? [Note: do not confuse coenzyme Q with compound Q.]

LB: It might be helpful for countering some of the heart muscle degeneration being reported now in connection with HIV infection.

DS: I saw one such report that alerted physicians to the possibility of HIV cardiac abnormalities, and that some symptoms casually attributed to lung involvement, like fatigue and shortness of breath, instead could be implicating the heart.

Research Politics

DS: What are some of the politics affecting the clinical care picture today?

LB: I see the Food and Drug Administration and the National Institutes of Health as having a symbiotic relationship with the pharmaceutical industry. They are in a codependent relationship. People on both sides have their complaints, but they do not seriously analyze themselves. Congress plays along with the game, too, funding and regulating the relationship. And as in codependency, something like a disaster has to happen for a real change to occur. No one is presently in charge of an overall plan for AIDS. But you watch -- five years from now, when straight teenagers are dropping like flies, then AIDS will become a national priority. Of course, we will probably have a new administration by then, too. Meanwhile, we need clinicians and researchers to talk to each other, to try to build solutions to the problems of HIV disease. Instead of obsessing on basic research, we must constructively analyze what the problems are, and start acting on priorities toward the solution. Plan the work and work the plan. No organization in the world is doing
that now.

DS: Perhaps we should aim for solutions that fit the problem, instead of problems that fit someone's solution.

LB: Exactly right. And we need innovators. More AZT studies are not innovative. The non-innovative answers are not solutions. They are solutions in search of problems, as you said. And all the while researchers around the world traipse around their own little garden path, doing their own personal research. By contrast, we could harness that creative thinking, and integrate this research chaos into a bigger picture. One model I've worked with is the National Community Research Initiative, in Washington, D. C. We began by developing computer software, called CRIS, to let physicians keep up with each other's experiences, to correlate all the raw data of our practices. We've developed a database that can work as a total clinical management system. We can directly download results of bloodwork from the laboratory by modem into the database. This technology could help to share statistics, to generate statistically valid correlations. In my office we will soon have a computer work station in each patient examination room, so we can have the
patient's history and treatment experiences and all lab work at our fingertips.

DS: It would seem that physicians in different countries, using different therapies, could use the database to learn from each other.

LB: Yes, this information is eminently exportable. Communication technology is an innovative, useful approach.