Dr. Safai: Dr. Abrams, I am not convinced that the apparent drop in KS incidence is real. I see many referred patients who have developed KS, but whose KS has never been reported, since it was not the initial presentation of HIV infection. In many cases, the lesions are not even biopsied.
Dr. Abrams: That is true, Dr. Safai, but it is still my clinical impression that there were many more cases of KS earlier in the epidemic. Since people develop KS while their CD4 counts are still relatively high, I have always wondered whether that might have been an earlier manifestation of immune deficiency, plus the contribution of the KS cofactor. With safer sexual practices, transmission of that cofactor could have declined so that people do not develop KS until later in the progression of HIV. Clinically, I feel that we are seeing fewer patients with KS, that those patients have more advanced immune damage, and that their KS is more dangerous than the indolent cases we used to see.
Dr. Safai: I am not disputing that there is a trend toward decreasing incidence of KS. I just doubt that it is as steep as these numbers seem to suggest. In many cases I have seen, if the patient is relatively well and has only a few KS lesions, the KS is not reported. My next question is, if nitrites cause KS, why was there not more KS before the HIV epidemic?
Dr. Haverkos: Perhaps because the key element is some kind of interaction between HIV and one or more cofactors. This is a multifactorial tumor that probably requires both factors to trigger whatever cellular mechanism is involved.
Dr. Abrams: Dr. Safai, I am interested in the question of whether KS metastasizes. Early on, we realized that patients with minimal KS who presented with their first episode of Pneumocystis pneumonia would sometimes have increases in their KS lesions. What do you think is happening in such cases?
Dr. Safai: I think that it is either a flare or a proliferation of an existing tumor or the development of a new tumor at a different site. This is not true metastasis, which means that the cell of origin travels through the body, lodges in a new site, and begins to proliferate. This does not happen in KS, and therefore it does not metastasize in the same way that melanoma metastasizes.
Dr. Abrams: Perhaps an opportunistic infection adds further insult to the immune system or increases cytokine production.
Dr. Safai: We would like to investigate that, Dr. Abrams, but there are so many other infections in AIDS patients that sorting out the cytokine picture is very difficult. Frankly, I suspect that what is involved is not really immunosuppression, but immune dysregulation, which allows the overproduction of cytokines that cause the proliferation of the endothelial cell. Monocytes probably also play a role, since they are capable of secreting cytokines and are under the control of the immune system. Cytokine release may increase in response either to iatrogenic immune suppression or to amyl nitrite or some other factor. The ultimate question is, what is the cytokine that drives the KS cell, and does it go up or down when we block the immune system with prednisone(Drug information on prednisone) or cyclophosphamide(Drug information on cyclophosphamide)?
Dr. Abrams: We have all feared that steroids would cause the appearance or progression of KS in AIDS patients, but I cannot remember seeing KS flares in patients on steroids for idiopathic thrombocytopenia purpura or for respiratory compromise associated with Pneumocystis pneumonia. Dr. Safai, is this really an issue in our patients with HIV-related disease?
Dr. Safai: Probably not. In 20 years at Memorial Sloan-Kettering, I saw very few cases of KS arising in patients treated with immunosuppressive therapy. Furthermore, I have not seen or heard of any HIV-infected person who developed KS after steroid treatment.
Dr. Abrams: One final comment with regard to the edema you described. Our house staff has frequently worked up patients who have unilateral lower extremity edema, but few KS lesions, searching for deep-vein thrombosis or a pelvic mass, and these cases are invariably negative. Unilateral edema, particularly in the lower extremities, may appear much out of proportion to the extent of KS lesions on the extremity.
Dr. Abrams, after your initial approach, when the patient develops progressive KS lesions, what is your second-line therapy?
Dr. Abrams: Oral etoposide(Drug information on etoposide) is a useful salvage therapy, particularly since by the time the patient develops this kind of progression, there are often venous access problems that make an oral formulation desirable. There are problems with myelotoxicity, however.
Dr. Safai: Dr. Abrams, we have had similar problems to your's in developing a reproducible staging classification for KS. To some extent, this probably just reflects some of the special characteristics of this disease.
Dr. Abrams: It certainly hampers our ability to interpret and compare data, Dr. Safai. Moving on to research on DaunoXome, could you please explain, Dr. Chew, why, if the plasma area under the curve is so high with DaunoXome and the half-life is so long, there is so little toxicity?
Dr. Chew: Apparently because there is so little release of free drug into the circulation. The plasma drug levels reflect levels of the liposome-encapsulated drug. This translates into more drug delivered to tumor cells and less delivered to myocardium, hair follicles, bone marrow, gastrointestinal mucosa, and other tissues.
Dr. Safai: Why do you think there is more tumor concentration of this drug in the liposomal form than as free drug?
Dr. Chew: I believe there is probably active tumor endocytosis of the liposomal particles, which then breaks down and releases free daunorubicin(Drug information on daunorubicin) inside the tumor cell.
Dr. Abrams: Dr. Gallo, your comments about gamma interferon's role may explain some results we observed in an early trial. We concluded that interferon-g was contributing to a more rapid decline in our AIDS patients.
Dr. Gallo: In terms of KS, interferon-g appears to be the most important of the inflammatory cytokines released by activated T-cells. It is the most potent at inducing activated spindle cells, so I would predict that giving exogenous interferon-g would make matters worse for an HIV-infected patient.
Dr. Haverkos: I am interested in your suggestions about inflammatory cyto-kine levels possibly being higher in homosexual men than in intravenous drug users. However, we have been following cohorts of homosexual men and, of injection drug users in several cities, and we find very few differences in immunologic measures of disease progression between these two groups.
Dr. Gallo: Intuitively, I am amazed at that, but it does point out the need for more studies. As you know, assaying cytokines is extremely difficult. The available assays are often less than ideal, and turnover rates are very high. In addition, local production of cytokines may be most important, which could be even more difficult to measure. However, if this urine neopterin assay holds up, we should start measuring it in the urine of homosexual men vs IVDUs.
Dr. Abrams: Dr. Gallo, what is your general feeling about where AIDS research is going?
Dr. Gallo: I have the same "down" feeling many researchers have with regard to progress in vaccine research and to responding to the AIDS crisis in the developing world. I think we are in desperate need of inspiration right now-not just AIDS patients, but also AIDS researchers. However, I have just the opposite feeling about the status of KS research. We are beginning to really understand the underlying processes, and if researchers and clinicians work closely together over the next year or two, I think we will solve the problem of how to manage HIV-related KS.