Paul Bellman, M.D., and his associate, Ricky Hsu, M.D., are
in private practice in Manhattan. We asked Dr. Bellman about
drug toxicity, treatment interruption, and other major issues
he is seeing today in HIV/AIDS clinical care.
AIDS Treatment News: Could you briefly describe your
Dr. Bellman: Dr. Hsu and I see many HIV-infected patients,
most of whom have long-standing infection or are highly treatment experienced -- and also some who are treatment naive or recently infected. Patients still come into our practice testing HIV-positive after many previous HIV-negative tests.
Our patients have access to all of the standard, FDA-approved treatments, as well as experimental drugs as they become available on expanded access, compassionate use, or experimental protocols for our office. We have also had experience with the HIV immunogen Remune, and other immune-based treatments including IL-2
, and gamma interferon, used
Many of our patients have sustained undetectable viral loads
and strong immune recoveries on combination therapies. A significant number have rebounded virologically, but maintained reasonably good immune responses and clinical health. And a small proportion of patients have been very difficult to treat -- with high viral loads and low CD4 counts, and recurrent opportunistic infections or malignancies despite many treatment efforts.
Our philosophy is to apply basic principles of antiretroviral therapy to each individual, depending on their medical condition and treatment history. These principles include considering the potency of the regimen, dosing (including blood levels and drug interactions), viral resistance, and adherence. Usually we can reasonably control HIV with the current drugs when these principles are used -- especially for patients who start treatment early. We are finding that much of the immune suppression which we had feared might be irreversible, is in fact reversible. Patients are clinically doing much better, and have a much lower incidence of any kind of opportunistic infection or malignancy. Many patients who were very sick are now doing extraordinarily well.
But at the same time, we also know that even if the patients are maximally suppressed for three or four years, the virus is not eradicated. So the period of time that patients need therapy may be indefinite. Long-term therapy raises even more concerns about drug toxicities, as they can accumulate over time, often in unexpected ways. So for many of our patients, we are trying to balance the efficacy of the treatments with the risks of the drugs -- and to develop strategies to limit the toxicity, which are becoming as important as strategies
to make the treatments more effective.
There is now a shift of concern from drug resistance to drug toxicity, as the major barrier to patients doing well. Especially since many of our patients are also infected with hepatitis B or hepatitis C -- and some common HIV drug toxicities can be confounded with exacerbation or progression of hepatitis. If we can treat hepatitis effectively -- and we are learning how to do a better job of it -- this would help in allowing optimal HIV treatments. And improving the immune
system by suppressing HIV probably improves the likelihood of treating hepatitis more effectively, although this has not been conclusively shown.
We try to do the best we can, learning as we go along to sense where the issues for a particular patient lie. And we are becoming more interested in including strategies which might allow people to interrupt their therapy, or lessen its intensity, in order to reduce drug exposure and toxicity. We are learning more about the immune system and the immune response to HIV. Structured treatment interruptions give us a
window to see this immune response in individual patients.
A key question has always been the variability in how HIV manifests itself -- why the great differences in time to illness, and in the problems that develop? As we better understand the immune responses to this virus, and the differences between patients, hopefully we will develop strategies to re-program some patients' immune systems to
help control HIV more effectively, in the same way that certain people fight it effectively without therapy. Some of the work on structured treatment interruption, and some of the work Dr. Kendall Smith of Rockefeller University is doing with IL-2, suggests that boosting HIV-specific CTL (cytotoxic T lymphocyte) responses at the time you interrupt therapy may enable a greater sustained HIV-specific response to mature, resulting in better control of virus [see "IL-2 Low Dose and Treatment Interruption: Interview with Kendall A. Smith, M.D.," AIDS Treatment News #329, October 15, 1999]. A more favorable set point may emerge, where the immune response is amplified by a cytokine like IL-2. Other immune approaches include vaccines like Remune, which may also amplify immune responses to HIV.
Lipodystrophy, and Other Toxicities
In drug toxicity, one of the important clinical
changes is the evolving understanding of lipodystrophy. At first it was thought to involve mainly fat deposition -- buffalo humps, abdominal fat, "Crix belly" [although it is not specific to Crixivan]. Then it became clear that fat wasting was also taking place. Fat wasting is the biggest problem clinically. A key point is that fat wasting is often
generalized, and results in a significant weight loss, as well as the visible cosmetic deformities. Fat accumulation can be addressed by fitness approaches, human growth hormone, or sometimes surgery, but fat wasting can be more difficult to treat.
There is more evidence now that the nucleoside analog drugs are involved with the fat wasting(1,2). d4T (stavudine, Zerit®) might be a main culprit in fat wasting. We have to reassess its use, especially when beginning HIV treatment, when many other options are available. My experience is that patients on triple-drug therapy with d4T are more likely to have fat wasting than if the d4T is replaced by AZT. Most of the patients who are having fat wasting have been on d4T for very significant lengths of time.
ATN: Do you take patients off d4T?
Dr. Bellman: I do, whenever I believe another antiviral can
safely and effectively be substituted.
ATN: What about heart or other toxicities?
Dr. Bellman: There is a whole range of concerns. The metabolic changes, which are primary, not only include fat redistribution and lipid abnormalities, but also osteoporosis, blood-sugar abnormalities, and others. We don't know the natural history on these drug-induced abnormalities, nor the impact of therapy to treat them -- although certainly if someone's cholesterol is very high, I think a cholesterol-
lowering drug is prudent, especially given how effective these drugs are.
I have seen pathological fractures in young men caused by osteoporosis, probably induced by protease inhibitors. We need to consider strategies such as screening for osteoporosis in protease-treated patients.
There is much we do not know. The protease inhibitors and efavirenz (Sustiva®), which seem to cause the lipid abnormalities, are of great concern over long periods of time.
Studies could answer whether two nucleosides and nevirapine
(Viramune®) or delavirdine (Rescriptor®), or two other nucleosides and abacavir (Ziagen®), are less toxic than two nucleosides and protease inhibitors or efavirenz. This is an important question, and my clinical experience would say that the former regimens are less toxic, especially if the two nucleosides are AZT and 3TC. Maybe even abacavir, 3TC and nevirapine may be a less toxic regimen. We need to define the least toxic combinations.
Another area where more research is needed is testosterone replacement therapy, and the use of anabolic steroids like deca-durabolin and oxandrone, which we use frequently in our practice.
Carnitine for Nucleoside Toxicities?
Dr. Bellman: There is some evidence that certain nucleoside
analog toxicities may be mediated by carnitine deficiency. Carnitine levels are often very low in patients on nucleoside therapy; we do not know the reason for that. We have noticed that by replacing carnitine, some of the toxicities, like neuropathy, start to improve -- just from putting someone on carnitine, or alpha lipoic acid. Carnitine deficiency might be an integral part of this problem.
It has been shown that patients with low carnitine levels are more vulnerable to neuropathy from nucleoside drugs.
There is a theory that mitochondrial toxicity to fat cells may be a mechanism for the fat loss. This theory suggests that different toxicities to the mitochondria by different nucleosides may be responsible for different adverse drug effects.
Being more aware of the toxicities of the different drugs, and monitoring patients more carefully for them -- and possibly even rotating drugs -- is becoming more important.
ATN: On carnitine, what dose do you use? And is the health-
food-store variety likely to be as good as Carnitor®, the
Dr. Bellman: I think it probably is as good. But we check the
blood levels before and after. We use the carnitine on prescription when it can be covered through the insurance, because it is a prescription drug; when it cannot be covered, patients use the health-food carnitine. If there are differences, I am not aware of them.
Carnitor comes in 330 mg pills; patients use one or two pills two to three times a day. The carnitine from the health-food store would be 500 or 1000 mg twice a day. We follow blood levels, and if patients respond clinically and their levels go up as they should, then we have found the dose.
ATN: You mentioned the possibility of rotating drugs to help
Dr. Bellman: There is a philosophical and scientific issue in
treatment approaches for patients. We [medical professionals] always want to know that studies support what we are doing. On the other hand, we may need to try approaches when there have not been well-controlled clinical studies, and will not be studies in the time frame needed to make decisions about an individual patient's therapy. So while we need to continue clinical trials, and design them well so that we get useful
information, we also need to use what we are learning in practice, and use basic principles of therapy, when there are not large studies to test specific treatment strategies.
On rotating therapies, for example, we know that many of the antiretrovirals are relatively equivalent in potency; we know some of the combinations that will maximally suppress the virus. And since we know that toxicities accumulate over time, we need to think about substituting treatments of equivalent potency, hoping to lower cumulative toxicities. When we are thinking about treatments that may continue for five, ten, or fifteen years, I think that drug substitution
or rotation needs to be considered.
It is tricky, because some patients can tolerate certain antiretroviral regimens for many years with very low toxicity. For example, a patient may be better off on AZT plus 3TC plus nevirapine (Viramune) for ten years, than if they were intermittently taking some of the other drugs. But when we put patients on regimens likely to have toxicities which accumulate over time, we need to consider changing or
rotating them. Many clinicians are doing so -- substituting a non-nucleoside for a protease inhibitor in some patients.
But even the newest non-nucleoside, efavirenz (Sustiva®), raises some concerns about systemic toxicities. It can increases lipid levels. I am not convinced it is such a benign drug as some have thought.
ATN: And we have certainly heard about the neurological side
Dr. Bellman: These can often be subtle with this drug, and
can be quite debilitating for some people.
Structured Treatment Interruption
ATN: What is your thinking of planned temporary discontinuation of antiretroviral drug treatment?
Dr. Bellman: It is an important area of research -- and one
where the anecdotal case can have much to teach us. A small percentage of patients control HIV without therapy very well. If we could shift a few patients toward controlling the virus better, by improved immune responses, that would be very important.
It is a misunderstanding of science to feel that if we do not completely understand something, it is not real. Most medical discoveries -- certainly before the biochemical/molecular-biological revolution -- were serendipitous. No one knew how the smallpox vaccine really worked, even when the disease was eradicated.
Just experimenting with stopping therapy, re-introducing it, giving immune modulators -- even if we do not have any map that tells us exactly how to do it -- may be appropriate, if we do it in a reasonable and relatively safe way. The studies suggest that it can be safe; we are not seeing patients developing high viral resistance, or having devastating illnesses as a result of breakthrough of the virus. Patients
who are highly treatment experienced and who have high baseline viral loads and low T-cell counts at the time they started therapy may have increased risk from structured treatment interruptions.
We are starting to learn that some of the way that HIV disrupts the immune system depends on how it gets presented to the immune system. If we can change that presentation -- perhaps by changing the amount of virus, or the number and kinds of immune cells responding to it -- then I think we may start to see patients shift from rapid to slower progressors, and slower progressors to non-progressors.
We also need to realize that we can be comfortable with patients who maintain low levels of viral replication. But one of the darker perspectives on treatment interruption is that even when patients have been completely suppressed, when they go off treatment it does not take long for their lymph nodes to be re-seeded with the virus and to become
hyperplastic [swollen due to abnormal growth] when off therapy -- which is obviously not a good thing.
A goal of therapy could be a reasonable control of HIV, to get people's loads below a threshold so that their lymph nodes are not re-seeded, highly infected, and dysfunctional. Some of the work of Franco Lori suggests that the patients who had low levels of viral load on treatment with ddI and hydroxyurea may over a long period of time develop an immune response that has allowed them to go off therapy. He has reported a three-month period with relatively low viral loads
in some patients. Followup on these patients is extremely important, to see the duration of time that this immune effect persists.
Treatment Registry for Strategic Treatment Interruptions?
ATN: How do we get a uniform database for keeping track of
treatment interruption in different physicians' practices? What are your thoughts on how to proceed?
Dr. Bellman: Unless we make a systematic effort to learn, we
may miss or delay very important discoveries. We need some kind of registry where physicians can log on, and used a case-report form to register patients who get treatment interruptions. I think clinicians would be interested in doing that -- because it's exciting when you have a patient who is doing very well. One could say that every patient who
interrupts therapy should be registered -- or there could be selected physicians who register all of their patients who do so.
Clinical trials of strategic treatment interruptions are starting -- but the best results might not come in a clinical trial, because so much is unknown. In many of the trials, when patients go off treatment, as soon as their viral load goes up to a certain level they have to resume the antiretrovirals -- and perhaps that might not allow certain maturation of an immune response. With a registry, we could catch those patients who do particularly well, and maybe start to understand what is different about them. I would certainly be interested and would participate in a registry, and could help design it.
When to Start Treatment
ATN: What do you think about starting antiretroviral treatment early vs. starting later?
Dr. Bellman: It is hard to know, because of the long time
frame; which gives better results over the next ten or 20 years? You can argue for delaying treatment and monitoring carefully, because at some point you can start patients on treatment. But if you wait too long, patients can develop opportunistic infections and malignancies; also, drug toxicity tends to be greater in more advanced patients. On the other hand, with drug toxicity being a primary concern, why expose someone who might be asymptomatic for ten years, to taking medications that will accumulate toxicity and may well not translate into greater lifespan and quality of life? However, it gets tricky; people are trying to come up with better guidelines.
But even within viral load and T-cell ranges, we do not know
enough about how to measure people's immune responses to HIV to tell more precisely who is going to progress, and who will remain relatively stable.
If someone is recently infected, there was a strong hope that with very early treatment, they could preserve HIV-specific immune responses. I think it is reasonable to try to treat these people very early; but no one knows for sure if this is the best thing to do. We need to explore whether less intensive therapy could be used some of the time, instead of having no option but taking three or four antiretrovirals indefinitely.
Treatment is still an individual decision between doctor and patient, trying to make use of the MACS database of risk of progression based on viral load and T-cell counts, in a three, six, and nine-year period -- as well as other aspects of the individual's situation.
Paying for Treatment: Where Are the Problems?
ATN: What are the major problems now in paying for treatment?
Dr. Bellman: There has not been much change. The major issues
on access to care in New York concern middle-class patients, whose insurance may not be adequate and may have problems with drug coverage -- while the patients make more money than ADAP (the AIDS Drug Assistance Program) allows. ADAP is generous in New York in giving those who qualify access to HIV medications.
In New York, patients who are indigent can get medications --
provided they have the social support they need to go through the process of getting into the system. This is the other major access issue; you can qualify for treatment under Medicaid but not get into a program that will allow you to be appropriately treated, although the benefits technically should be there. So the issues are poor patients actually receiving what is available to them, and middle-class
patients who may not have full access.
In my opinion, HIV patients have benefited enormously from accelerated access to medications for HIV, as well as off-label uses of medicines.
ATN: "AIDS dissidents," who say that HIV is harmless, or that
it does not exist, and that HIV treatments are useless poisons pushed by a corrupt AIDS industry, have been in the news recently. What are you seeing in your practice? Are many people going off treatment for such reasons?
Dr. Bellman: No. Clearly, questioning the establishment
canons is always important; these canons are often provisional, and often presented as if they were more true than they actually are. We are all trying to learn. But there are different levels of criticism and of benefit from criticism. And much of what we are hearing from "AIDS
dissidents" is old, recycled ideas that have been adequately refuted. This does not shed much light on the issues at present, which are whether or not patients should continue their therapy based on the risks and benefits of the regimens they are using.
Recently a patient brought a Celia Farber article from the
New York Post, suggesting that patients got sick more from the drugs than from HIV. Clearly that is not correct; very many patients were dying when there were no treatments, and today many who would have died are doing quite well, despite the many unknowns and questions, and serious problems with the drugs.
In my practice, patients are asking about whether to discontinue therapy more in the context of structured treatment interruption, than of AIDS dissidents. Patients are always interested in other alternatives and options. But they are careful in not just accepting at face value anything that comes along.
A Final Note
Dr. Bellman: Tremendous progress has been made, and yet
serious problems remain. We need to see these problems as challenges we can meet.
The drug toxicity, the fact that the virus is not eradicated, and other difficulties show that we need more progress. But patients and doctors should not feel hopeless, that these problems are insurmountable.
Our goals for patients are long-term survival, quality of life, and ultimately hope for a cure, or at least remission where people do not need to take drugs every day and deal with the drug toxicity, and where they do not transmit HIV. We do not know exactly how to get there, but clearly we are well on the way to the first two goals.
If you were taking a journey in ancient times, there probably were no maps; and even if there were, if you followed the map exactly, you could end up falling off a cliff. You have to pay attention along the way -- and then you have a good chance of reaching the destination. We need to pay attention and learn as much as we can about each patient's specific
situations, as well as learning more generally about HIV disease and how best to treat it.
- Saint-Marc T, Partisani M, Poizot-Martin I, and others. A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy. AIDS. September 10, 1999; volume 13, pages 1659-1667.
- AIDS. 2000; volume 14, pages 37-49.
ISSN # 1052-4207
Copyright 2000 by John S. James. Permission granted for noncommercial reproduction, provided that our address and phone number are included if more than short quotations are used.
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