How do you handle those borderline cases?
How do you handle those borderline cases?
Top experts review three cases
Nearly a year after the release of the first federal guidelines for combination therapy, clinicians are struggling with patients who fall outside the protocols set forth as the standard of care. During a recent teleconference, three of the nation's top AIDS experts gave their opinions on treating three such patients.
Below are the three cases and the opinions on them presented by Anthony Fauci, MD, MPH, director of the National Institute of Allergy and Infectious Diseases; John Bartlett, MD, chief of infectious diseases at Johns Hopkins University; and Eric Goosby, MD, director of the National Office of AIDS/HIV Policy in Washington, DC. (For their comments on other issues, see AIDS Guide for Health Care Workers supplement, inserted in this issue.)
· Case 1, presented by Fauci:
A 28-year-old man has been infected for at least 18 months and has had no prior therapy. From July 1996 to January 1998, his CD4 count and viral load have fallen outside the guideline cutoff points for when to start therapy (i.e., CD4 counts ranged between 510 and 690; viral load between 10,000 and 20,000).
Question: Should he be treated, and if so, with what regimen?
Fauci: This is not an open-and-shut case. When you get to that gray zone, you certainly have physicians who say, "there is virus present, the CD4 count might be within a range that isn't the so-called dangerous range, but as long as there is virus replication going on we should treat."
There are others who would say, "as a matter of fact, the virus level isn't that high, let's see where it goes. If it stays around 15,000-20,000, maybe we could watch the person and withhold therapy so that person can have a period of time where they have a large armamentarium of drugs available."
You could say to the patient, "given your CD4 count and viral load, you have an X percent chance of developing AIDS within three years and an X percent chance within 6 years." (Many experts are now using an arbitrary 10% in three years and 25% in six years as the point when a patient should seriously recommend therapy. This patient falls in that borderline.) So I would say it depends on understanding the toxicities of the drugs, the change in the lifestyle of the patient, and what it might mean about precluding in future decisions drugs that you might use right now.
If you decide to treat this individual, there is no question you should treat the individual with triple combinations of therapy starting off with a choice which was two nucleoside analogues, together with one of a number of protease inhibitors.
Bartlett: This is clearly a borderline case. There is no right answer to this. I looked on the [Mellor's] chart and he has a 7% probability of having an AIDS-defining diagnosis in three years and 25% within six years, and I think that is what the patient should know. He needs to be armed with that kind of information. The other thing patients need to know is if they decide to be treated, it is not a little bit of treatment. It is the full therapy and that means this person is going to be taking pills, multiple pills three times a day, and it may be that this patient chooses to withhold treatment until regimens get simpler or the need for therapy gets more demanding.
Goosby: I would echo that position. I think this is really a situation where the patients should be informed about their relative risks, weighing the potential for looking at future decisions that they may preclude by deciding to go on combination therapy at this point. With a dialogue with the patient over a relatively short time - two to three visits - I think a decision could be reached that both are comfortable with.
· Case 2, presented by Bartlett:
A 36-year-old woman has a medical history complicated by a splenectomy and pneumococcal meningitis before she had HIV infection. She had an acute retroviral syndrome in July 1991, but the first time she had a CD4 count was in 1992, at which time it was 200. She was put on ddI. Subsequently, therapy was changed to AZT and ddC for several years, during which her CD4 count dropped to a nadir of 49.
Her first viral load in April 1996 was 40,000, at which point her therapy was changed to a triple-drug regimen of 3TC, d4T, and indinavir. The patient, who weighed 96 pounds, developed a renal stone after four days and was hospitalized. Indinavir was replaced with ritonavir. She responded well, with her viral load dropping to 370. However, she could not tolerate ritonavir because of gastrointestinal side effects.
In December 1996, ritonavir was replaced with saquinavir. Her viral burden held at 400 and CD4 at 288. Currently, her CD4 count is over 500 and her viral burden is less than 90.
Question: Should she be changed over to fortovase? (Fortovase is a new formulation of saquinavir that achieves higher drug levels but increases the risk of side effects.)
Fauci: Yes. I think she should switch.
Goosby: I think you did have significant response with a good viral-load drop and a huge increase in the CD4 count. But what it also highlights to me is what clinicians and patients need to keep in mind about a decision to change a therapy because of a complication from the drug vs. a drug failure. You retained the 3TC and d4T therapies while changing the protease inhibitor in light of a sustained viral load depression without having to take into account a "drug failure" thought process that would make you want to change all three drugs.
Fauci: This patient is an excellent example of that, because in the same patient you have the need to change everything when you made the initial choice of going from AZT plus ddC to switching over to 3TC and d4T when you added indinavir. And then you went through several iterations because of the toxicities and you hung fast with your 3TC and d4T, which was obviously the appropriate thing to do. As Eric says, this is opposed to the thinking that every time you change you have to change everything, because you would have run out of drugs long ago if you did that.
Follow-up question by Bartlett: At this point should this patient receive PCP and MAC prophylaxis when she has had that in the past? Her CD4 nadir was 49, but she is over 500 now.
Goosby: It is a situation that we are confronted with regularly, where our response to therapy pushes the CD4 count up above the level at which prophylaxis is indicated, especially for PCP. There is a division in the thinking. Some would say you should prophylax. I believe you should take the nadir and believe it and take the prophylaxis on as the better part of valor.
Fauci: I believe we need to assume that even though the person has a reasonably good CD4 count, we should err on the side of caution because those CD4-positive cells may not be able to mount an adequate enough response against PCP or MAC. In our patients, when we have nadirs like in this case, you have to assume you are dealing with 49-type host defense, even though it may be shown as studies go on that these are quite functional CD4 cells. We don't know for sure whether they are.
Bartlett: This woman now wishes to get pregnant. This is the most important part of her life now. She got married two years ago and now wants a baby. She doesn't want to adopt. She wants her own.
Goosby: I think you have to support her through that decision and work with the realities of what the drug implications may have in the first trimester of pregnancy and the need for AZT, which we know is effective in decreasing vertical transmission. So the discussion would be around whether AZT should be part of the regimen, and whether in the first trimester you would try to continue combination therapy or wait until the second or third. My honest advice would be a very serious discussion around the risks of going ahead with the pregnancy, but if she decided she wanted to go ahead with it, I would support her.
Fauci: I agree. Sometimes, maybe too frequently, physicians get to be very puristic in their decision-making. We have all been faced with patients who feel genuinely that the most important thing in their life is to have a child. Now if you give the patient the information and she understands it and she still decides she wants a baby, then I would certainly support the individual. Then you are left with some interesting decisions - the question of the first trimester. Do you add AZT? Do you put AZT in and pull back the others because we don't know their teratogenic effects in the first trimester? This is information where we are wading in waters we have not been in before because we have no scientific information.
Bartlett: I sent her to an obstetrician who was an expert in this area. We decided we should support her. She is not pregnant yet. With regard to her therapeutic regimen, everyone would like her to take AZT but she is taking d4T and we can't combine those two. So the one caveat I would add is that if you are going to use AZT during pregnancy and you have d4T, one of the two drugs has to drop off. With regard to the prophylaxis, for her, she is a woman who feels very well except she is taking three antiretroviral drugs, PCP and MAC prophylaxis, and she has a big pill burden. So I stopped the MAC prophylaxis. She still takes the PCP prophylaxis.
· Case 3, presented by Goosby:
A 44-year-old patient is an injection drug user in a methadone treatment program. He has history of alcoholism. His infection was documented in 1992. Between June 1996 and December 1997, his CD4 count fluctuated from 401, to 551, to 492. The viral load was 29,000 initially, dropped to 2,460, and is now at 600. Therapy was initiated during this time with ddI and d4T, which was led to a sustained general trend downward in viral load and maintenance of CD4 count.
Comment by Goosby: This case raises a couple of issues. There is a lot of concern about adherence among injection drug users, and among homeless patients in particular. The guideline committee spent a lot of time discussing the ethics and appropriateness of withholding what could be a life-sustaining or life-saving therapy from an individual for fear of adherence problems. It was uniformly felt it was unethical to withhold a life-saving therapy from an individual for fear of lack of compliance. Individuals need to be taken as individuals and given an opportunity to understand the complexities and concerns that are raised by noncompliance.
Over time, I think a successful strategy can be instituted with very difficult social situations. Most of my practice is this population, and for the most part I would say I could not predict compliance differences as a function of being homeless or injecting drugs in any individuals. It is variable. We know from other compliance studies with hypertension, insulin therapy, and coronary artery disease that the predictive value of who will or will not be compliant is really a toss-up.
Follow-up question by Goosby: Is hydroxyurea a drug you would consider for this patient, and if not, would you change all three drugs in a non-failure setting or just add a protease inhibitor?
Goosby: This is a situation where hydroxyurea might be considered. This is a situation where one could intensify therapy, or one could be happy with a significant sustained response on two-drug nucleoside.
Bartlett: The methadone clinic and injection drug user don't bother me as much as alcohol. The experience in our clinic has been that alcoholism has been more of a problem with compliance than injection drug use, and that has to be addressed. With regard to his therapy, he is one of those patients who has had a nice response to two nucleoside analogues but he is not down to what we call successful therapy.
This is one of the paradoxes of our recommendations. Here is a patient who has had a nice viral response, who is likely to have a good prolongation of life and well-being as a result of his therapy. He is going to benefit, and yet from a virological point of view he is a failure. So we have a clinical success and a viral failure.
So you want to nudge him with hydroxyurea. This might get him down to the point where we want him. I feel reluctant to get into too many drugs in a patient who has CD4 count that is hovering around 500, so we don't run out of drug options too soon. I think this is a case that is a close call.
Fauci: Just so everyone understands what we mean by nudging: If you decided to give a protease inhibitor, you would want to start from scratch. Here you have someone who is doing well on two drugs. If your decision tree goes in the direction of [adding] a protease inhibitor, our recommendations then say you should stop two drugs, which this person is doing well on, and that makes us all a little uncomfortable, and then add two other nucleosides plus a protease inhibitor.
So what Eric is kicking around is that the mechanisms of action of the drugs and the cross-resistance are such that you can actually nudge with hydroxyurea. You wouldn't be able to nudge with a protease inhibitor because if you add the protease, you really want to start from scratch. It is a close call. New data on hydroxyurea is coming out each month. It looks promising, but we can't really say what the long-term effect is going to be.
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