Treatment Strategies: Interview with Paula Sparti

For a practical look at AIDS treatment advances, we interviewed Paula Sparti, M. D., who has a large HIV and family practice in Miami, Florida. Dr. Sparti also participates in the recently reconvened immune-based therapies group at the National Institutes of Health (NIH).

Traditionally, most AIDS/HIV treatments have been divided into antivirals, treatment or prophylaxis for opportunistic infections, and immunomodulators. New developments in these areas include combinations of antivirals (for example AZT with ddC, or with interferon, or with compound Q), and multiple opportunistic infection prophylaxis (using drug combinations to prevent most or all of the common OIs, not only pneumocystis).

Immunomodulators (agents which might fight HIV by affecting the body's various natural immune mechanisms rather than by acting on the virus directly) may account for the most numerous and least understood approaches. Since immune responses involve elaborate "cascades" of precise, sequential events in the body, attempts to alter a certain immune activity can prove even more complicated than the prospect of developing treatments which act against HIV directly. We hope to cover specific immunomodulators in upcoming issues of AIDS TREATMENT NEWS.

DS: I want to pose some questions to you which we at AIDS TREATMENT NEWS are often asked to answer, such as when to start anti-HIV drugs; what combinations of drugs look feasible; when to start prophylactic measures; is there such a thing as planning for infections, or planning access to various drugs?

The notion of immunomodulation is gaining momentum now, but the spectrum of potential agents and rationales is overwhelming. Also, and perhaps most urgently, many people are facing the prospect of AZT resistance, with unanswered questions about the prospective antivirals -- ddI, ddC, and compound Q.

PS: In deciding when to begin antiretrovirals, I monitor bloodwork every three months, because I have seen a number of people who have had precipitous T-helper cell drops in a six month period of time. I have also been following some patients for nine or ten years who have had very stable counts. So I look for a sustained decline in helper cells and the T-cell ratio, more than just an absolute count that drops below 500 once or twice. I have two or three people who have had absolute T-helper cell counts below 500 since 1981, and who have been completely stable without an antiretroviral; without a doubt they would have been damaged a long time ago had I started them on nucleoside analogs.

I try much more to follow how stable people are, their percentage of T-helper cells, and their helper/suppressor ratio, rather than an absolute cell count. If you follow the absolute count over a long period of time, you can see that it goes up and down, and it is very dependant on an individual's total white count and lymphocyte count on a given day.

I haven't found that beta 2 microglobulin is very helpful. Sometimes I will see an increase in the beta 2 and the neopterin before a decline in immune competence. I'm finding that the p24 antibody [not to be confused with p24 antigen] is probably much more sensitive; I am just now getting fairly consistent results on quantitative p24 antibodies. You can follow them, and if they begin to fall, it may herald a fall in T-helper cells as well.

When I do start people on antiretrovirals, I start them on AZT alone. For years I have been starting people on 400 to 600 mg daily, for a typical 150 lb. person. There is community access to other drugs, and I know a number of my patients who are choosing to add ddC to their AZT.

I think there is a lot more myopathy [muscle disorder] associated with AZT than other people seem to be reporting. I have had some patients on AZT for up to four years, and they may not have obvious myositis [muscle discomfort]; they don't necessarily show significant increases in their CPKs, but they experience progressive wasting and muscle loss. There were a number of sessions at the last ACTG meeting elaborating the effect of AZT on mitochondria of muscle, and of ddI and ddC on nerve mitochondria. So although early intervention is very, very important, I think we still have to remember how toxic nucleoside analogs are.

DS: Would such myopathy be distinct from anything HIV alone might cause?

PS: It is distinct. HIV myopathy is inflammatory, for the most part. We can do a muscle biopsy here at the University of Miami and distinguish inflammatory myositis from a necrotic kind of cell death caused by AZT. And the difference is important to know, too, because if it is inflammatory and not due to AZT, you can treat it with non-steroidal anti-inflammatories, and if it's really bad you can treat it with short term steroids. You could stop the AZT to see if the myopathy or weight loss stops. But the problem is that it takes a long time to develop the myopathy and a long time to reverse it. It's not wise to have people off of an antiretroviral for the time it would take to decipher the problem, unless you have an effective substitute. A biopsy can help you know what you're dealing with.

DS: Is there any immediate way to mitigate the AZT- related myopathy?

PS: One of the things that comes to mind, considering the mitochondrial defect related to myopathy, is coenzyme Q- 10 [not to be confused with compound Q], which supposedly helps the function of the mitochondria. This isn't strictly scientific, but I know that in Japan, coenzyme Q-10 is given to decrease the cardiac damage resulting as a side effect of adriamycin. It's available here by prescription.

DS: You know it's also available without a prescription at local buyers' clubs.

PS: Yes, and at health food stores, but I was thinking that for people who have insurance, a prescription may help to pay for it. Another solution to myopathy, and side effects generally, will be combinations of low-dose AZT with low-dose ddI or ddC, which are less likely to cause myopathy, or the neuropathy seen with higher doses of the single drugs.

DS: Regarding nucleoside combinations, do you think it's better to use them together in low doses, or to alternate them?

PS: I think that using them together is better; the likelihood of postponing resistance could be better in a simultaneous combination than in an alternating regimen. But that's the kind of thing we don't know for sure yet. I'll be happier when we have more to combine than two nucleoside analogs!

DS: Are there non-nucleoside candidates you feel strongly about?

PS: Well, I'm interested again in Ampligen, as an adjunct, as something used in combination with other drugs. It's now planned for phase I and phase II studies combining it with AZT. Ampligen may make AZT more active.

DS: Ampligen seems to have been hard to categorize as either an antiviral or an immunomodulator.

PS: Right, it may have activity of both. It's mismatched double-stranded RNA.

DS: Are you optimistic about compound Q?

PS: Well, I know Martin Delaney and Drs. Alan Levin and Larry Waites are very much behind it. I'm not negative about Q, I just haven't seen the same results they've reported. I also haven't had as much experience as they've had. I have followed maybe 30 or 40 people who have used Q, while they have seen hundreds. I would probably need more exposure to see the results they're seeing. I have noticed that a few people who were on AZT or ddI with slowly declining bloodwork seem to have been stabilized with the addition of compound Q. So, although I don't have a lot of experience, I think with some people I'm seeing a stabilization benefit from Q, and perhaps a modest increase in T-helper cells.

DS: Have you seen any serious toxicities from Q?

PS: Nothing life-threatening, but quite a few allergic reactions; fortunately the Q doesn't stay in the body very long, so we just stop the infusion and give IV Benadryl, and epinephrine if we need it. In subsequent treatments we premedicate those people with Hismanal, and Decadron too, if warranted, for several days before their infusion and also the day after. This way we've been able to reinfuse people who have had reactions.

DS: Other antivirals or experimental agents you're interested in?

PS: I am anxious to see what happens with the non- nucleoside RT inhibitors. Merck and Upjohn have several possibilities. The sooner we get results the sooner we get expanded options. I have also been eager to see trials of hyperimmune HIV globulin, or passive immunotherapy, get started. Medicorp has not had the funding to sponsor a major protocol, but Abbott Laboratories, which is much larger, may be able to back one.

DS: What about some popular community treatments, like oral interferon, NAC, and hypericin?

PS: NAC is more popular than hypericin, in which interest seems to have faded for lack of controlled clinical trial results. With NAC, a number of people report increased energy and appetite. I think there is a good rationale behind NAC, since it purportedly increases glutathione levels, which are deficient in virally infected cells. But the real benefits and dosage are uncertain, so again, we need clinical trials for quantitative results.

I have seen absolutely nothing with oral alpha interferon. I have heard of people who claimed increases in T-helper cell counts, but I have not been able to find anyone in my practice or our local community who has been able to show a sustained increase from oral interferon.

DS: That's pretty much what I have heard from other physicians. However, another antiviral I wanted to ask you about was the injectable alpha interferon, approved by the FDA to treat Kaposi's sarcoma. Anthony Fauci seems to talk a lot about it in terms of a potential HIV agent.

PS: I think the limitation there is that you have to use it early in HIV disease. If you use it later, you risk further compromise of the immune system. People with higher T- helper cells can tolerate interferon, and if you combine it with low- dose AZT you can obtain significant increases in T-helper cells as well as diminish their KS lesions. One of the factors is that late in HIV disease, endogenous [naturally occurring] levels of interferon are high, anyway. Simply adding more is not going to be helpful in that case.

I think interleukin [IL] is more interesting. The interleukins 2, 4, and 7 have a lot to do with T-cell proliferation and maturation. Of course IL-2 can be very toxic, but apparently you can use less of it if you combine it with IL- 4. I think this is the beginning of being innovative with immunomodulation. When you have been treating HIV for several years, you have a lot of patients with less than fifty T-helper cells, but who are not ill yet. We're desperately trying to find ways to increase the T-helper cells.

DS: I have spoken to a couple of people who have tried lithium as a way to boost their helper count, but I understand that it only produces a broad, non-specific increase in white cells.

PS: A few of my patients wanted to take lithium, but you're right -- if you're not increasing the number of mature T-helper cells, then it's not going to be really helpful. You may get a sort of artificial sense that T-cells have increased, because you've elevated the total white count, but not necessarily the percent of functioning, mature T-helper cells.

DS: Any thoughts on isoprinosine or Imuthiol (DTC)?

PS: Those two, and levamisole as well, have been receiving a lot of interest out here. Several recent reports show that levamisole increases cell-mediated immunity. Imuthiol has been studied much more in Europe than in the U. S., and it now is available in New Zealand. People here have tried an industrial grade DTC, or antabuse as a DTC substitute. We just need more results of controlled clinical trials to know for sure. Isoprinosine is something which more of my patients used back in 1984 and '85, not so much lately.

People should give more consideration to transfer factor. It may be a crude lymphocyte extract, with an indeterminate mixture of lymphokines, but I have definitely seen people whose energy and well-being improved on transfer factor. Perhaps it suppresses some of the herpesviruses. I had two patients in the past couple of years with CMV retinitis who chose not to go on ganciclovir, yet both of their infections were stabilized while on transfer factor. The people at the NIH are not prone to pursue transfer factor -- their position would be that this is just a concoction of various biological products, and it would be difficult to attribute a response to any one of its constituents. So verifying its worth may be a job for a community-based research group.

I have been trying quite a bit of intravenous immune globulin (IVIG) in some of my patients with very low T- helper cells. It's clear to me that their ability to produce antibodies to specific antigens is severely damaged. [IVIG supplies antibodies.] The results are anecdotal, but I have seen benefits in people with chronic sinusitis and chronic bronchitis after several months on IVIG.

DS: If you had a proven immunomodulator right now, when would you give it to patients? Would it be helpful to asymptomatics, including those with healthy blood markers?

PS: Well, we know so little about immunomodulation, it's difficult to say for sure. But agents that cause T-cell proliferation, the interleukins, for example, would probably work better when the T-cells are higher, when stem cells are in better shape. If your bone marrow is wiped out, there's not much for the interleukin to work with. If we had something that would help cell-mediated immunity, then using it early might avoid some of the down-spiraling which results from immune-complex disease and inflammation.

DS: It sounds like you're saying that immunomodulation should have specific targets.

PS: The more I learn, the more I realize how incredibly intricate the immune cascade is. You can't just throw an interleukin into somebody's body and obtain a known effect. You have to know how to use it and when to use it, in what dose and in what frequency. I'm excited that the immune-based therapy group is back together at the NIH.

DS: Regarding opportunistic infections, and prophylactic measures to thwart them, I spoke to Dr. Larry Bruni, who practices in Washington, DC, who suggests that not only does HIV infection allow other pathogens to cause infections, but those secondary infections might transactivate HIV, or enhance HIV progression, as well. So both things may be happening in tandem. What do you think about that, and the role of prophylaxis for the various AIDS-associated infections?

PS: I definitely believe that when people get sick, whatever that "sick" is, it affects viral replication and it affects their T-helper cell count. I have been using more and more multiple opportunistic infection prophylaxis. A lot depends on the toxicity of the drugs in question. Some of the studies being designed to address prophylaxis, other than for pneumocystis, are a little disturbing in that they use an inflexible, uniform T-helper cell cut-off of 200, even though infections do not appear uniformly at 200 helper cells. Most infections other than pneumocystis don't appear above 100, or even 50, T-helper cells.

Given that, I tell those patients that, although there is no proof that a certain drug will prevent an infection, my recommendation is for a prophylaxis. I offer fluconazole, 100 mg a day, to prevent cryptococcal meningitis in people who already need an antifungal for candidiasis. I see who can tolerate pyrimethamine, 25 mg a day, to try to prevent toxoplasmosis. In people with symptoms of herpesvirus infections, including leukoplakia, I use acyclovir liberally. And I think multiple prophylaxing works. I now have many more people who are three or four years past their first OI. That is different from what was happening a while ago, when people would die within the first year or two of an initial opportunistic infection.

DS: Is it useful first to check people for past exposure to a certain infections?

PS: Oh yes, we always do that. We always test for toxoplasmosis, which is common in Florida, as well as CMV, Epstein-Barr, herpes simplex. If people are negative, you can avoid the drugs and their possible side effects.

DS: Do you see many identifiable mycoplasma infections?

PS: I keep mycoplasma in mind, and if I see someone with interstitial pneumonitis, or pulmonary problems that I can't really explain, or they're just not getting better, I liberally use doxycycline. You can give it intravenously if necessary, or orally if they are not that ill.

DS: Have you seen results from doxycycline?

PS: You cannot always know what you're treating, and you see some strange things. I have seen thrombocytopenia resolve temporarily on doxycycline, for no apparent reason. Recently there was a relevant article in the Tropic, which is the Sunday magazine of the Miami Herald. It asked if the people at the NIH are missing the boat by having just one paradigm, the antiviral paradigm, and not looking at the importance of cofactors, and the autoimmune part of this disease.

But if you ask me whether Mycoplasma incognitus is more important than syphilis, or CMV, or HIV, I really doubt it. Of all the possible cofactors, so many are present, including some we may have not even identified yet. Mycoplasma is only the newest kid on the block.

DS: Do you see patients who use recreational drugs, and are some of those drugs a risk for aggravating HIV progression?

PS: Well, opiates are known to cause immune suppression. Interestingly, some of my patients are still using naltrexone, which is an opiate antagonist. One of them, anecdotally, has been using it for five years now, and he has had totally stable T-helper cells.

I think that the use of opiates is immunosuppressive, as are cocaine and alcohol. Narcotics are compromising also because they chip away some of the will to live, the will to fight. Some of my drug abusers want to feel better, but they don't want to do the work required to feel better. For them it's "too much trouble to eat, too much trouble to take a deep breath," or to get to appointments. The will to live is part of being a long- term survivor.

I think antidepressants are probably helpful. Depression itself can deplete T-helper cells. There is a fair amount of evidence that antidepressants used to treat chronic fatigue syndrome can achieve some beneficial immunomodulation -- increased natural killer cell activity, sometimes increased T- helper cells.

DS: Do you think there are particular AIDS diagnoses that frequently get overlooked?

PS: Nothing stands out, although I think sometimes people do not get treated at all because their complaints are simply chalked up to AIDS. I hope that's unusual.

I push to make a diagnosis if at all possible. If someone has got a fever, I don't wait for something horrible to happen; I begin a comprehensive workup. It is important to treat something before it gets out of hand. If someone has a fever, part of a fever workup should be sending them to an ophthalmologist to have them checked for CMV retinitis that may not yet be causing visual disturbance. You may have to check for cryptococcal antigen even though they might not have a headache. It requires a sixth sense. Some practitioners who do not have a daily familiarity with AIDS don't know to diagnose and treat aggressively, and when their patients are finally seen by AIDS experts, they are really sick, and more difficult to treat.

DS: What would you like to see added to the current treatment picture?

PS: I'm anxious to see a lot more things evaluated. I would like to see more results on photopheresis. There are some interesting discussions of low-dose total body irradiation as a method of decreasing suppressor cells, with a consequent increase in helper cells. There are so many potential therapies out there to be evaluated, and I'm frustrated because I want them all to be evaluated as soon as possible. Now that I am working within the NIH, I see that there's a handful of people who make most of the decisions.

Maybe we will be able to get them to really look at more substances, and new procedural ways of doing things, and not to be so immediately negative. You would think that under the circumstances they would give anything and everything the benefit of the doubt. It will be interesting to see what happens in the next year or so.