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Being Alive
The Latest News on Kaposi's Sarcoma
presented by Steve Miles M.D. and reported by Jim Stoecker
May 5, 1995
Being Alive 1995 May 5: 1

The incidence of all types of cancer among people with AIDS is increasing. In the ACTG019 study, 27% of the study participants developed some form of cancer during the three years of study followup. The Concorde study reported a rate of 26% of participants developing cancer as an end point. And in the MAC prophylaxis study, ACTG196, 23% of the study subjects died from a cancer.

The reason that cancer is becoming a bigger problem for PWAs is not because of the chemicals people are taking or the AZT they are using. Rather, this phenomenon is part and parcel of what happens when you no longer have an intact immune system. All types of cancer are exacerbated by HIV and require a functioning immune system to be fought off. We are seeing more cancer today because people with AIDS are living longer and are thus more vulnerable at late stage disease for possible malignancies.

Kaposi's sarcoma (KS) remains the most common malignancy for people infected with HIV. And it is perhaps a bigger problem today than in the past because people are living longer, as we have said, and developing malignancies. However, we need to keep in mind that people with KS are living longer with this cancer than those who contracted the disease just ten years ago. In fact, we calculate that there is a 62% reduction in dying from KS compared to the early 1980s. Survival for people with KS has improved steadily since 1985.

There really is no reason for pessimism regarding the treatment of KS. As I will try to show here, there is a new and better understanding of the cause and development of KS. And this new understanding has led to many new treatment options. And we may even be approaching the day when we will have prophylaxis for those with HIV who are at risk for KS.

How KS Develops At UCLA, we have developed a working model of how AIDS-related KS develops and spreads in the cells. We postulate that the initial step is that the cells are transformed in some way. This transformation changes the way these cells respond to cytokines, proteins produced by the immune system, and to tat, one of the proteins of HIV itself. These cytokines and tat then act as growth agents for the KS cells. For all this to happen, there has to be some degree of immune suppression.

This notion of an initial transformation of the cells is controversial. Barbara Ensoli, working out of Robert Gallo's laboratory, postulates a model that rejects this initial transforming step. Rather, she would argue that normal cells are exposed to cytokines, and as a result of that exposure are changed. This change in the cells make them responsive to tat. Once tat has bound to the cell, it acts as the growth agent for the KS cells.

In both models, it should be noted, both the body's cytokines and the virus's tat protein are essential for the development of KS. Unlike other cancers, KS cells cannot grow on their own. This is important when considering treatment approaches.

The Role of IL-6 IL-6 is a protein made in the cells and has been identified as one of the growth factors for KS. We have shown in the test tube that if you can inhibit IL-6, you can inhibit the growth of KS cells.

Researchers have looked at the level of IL-6 in the blood of the men involved in the MACS (Multicenter AIDS Cohort Study). They have found that HIV-infected men have more IL-6 in their blood than do those who are not infected. Further, HIV+ men who do not have KS have less IL-6 detected in their blood than do the HIV+ men with KS.

The researcher also did a retrospective look at the blood samples stored at the MACS centers. They found that samples taken from men just before they went on to develop KS revealed elevated levels of IL-6. This may be important in possibly detecting which PWAs are at risk for KS.

Identifying the KS Herpes Virus For a long time, epidemiological data have suggested that some form of herpes virus is involved in the development of KS. Researchers have shown that there is a strong association between exposure to CMV, a type of herpes virus, and the development of KS. And data from the San Francisco Men's cohort have shown that as the incidence of CMV has declined so has the incidence of KS. We also know that kidney and heart transplant patients, who are not HIV-infected but have been exposed to CMV, are more likely to develop KS when their immune systems are suppressed after surgery. This is not to say that CMV causes KS; rather, there appears to be some association.

Now, researchers have found the KS Herpes virus (KSHV), soon to be named HHV8 or Human Herpes Virus-8. We know that this virus is similar to the monkey gamma herpes virus, called H. saimiri. To date, however, no one has isolated KSHV itself, although the TK gene has been located. This is the gene that activates acyclovir and other drugs like it, and this holds out the promise for future drug therapies specifically for this virus. Recently, a team of researchers at Columbia University used a new molecular technique called Representational Difference Analysis (RDA) to find the genetic sequences of KSHV. They then biopsied KS lesions to detect the presence of these sequences. They were able to find the sequences in 27 of the 30 biopsied lesions; sequences were found in the lesions of HIV-infected as well as non-infected KS patients.

It should be noted that these genetic sequences were detected in the KS cells, but not in the blood. This would suggest why KS is not found in those infected with HIV through blood-to-blood transmission, but is found in seronegative, high-risk men with KS. KSHV is a sexually transmitted agent.

In sum, this identification of KSHV is a major breakthrough in KS research. It puts us on the path to a better understanding of what causes KS and thus how best to treat it. Further, it can even lead to possible prophylaxis for those at risk for KS. In the months ahead, we should be hearing more and more about this new virus.

Treatment Options for KS One thing I tell people with KS to keep in mind is that observation is not treatment. If you go to your physician with early KS and your physician tells you "let's just keep an eye on it," I suggest you tell your doctor to keep an eye on his/her own lesions. You want yours treated. With all the treatment options emerging, there is no reason to settle for simple observation.

There are several approaches to treatment. One is to modulate the cytokines that cause KS to grow. Similarly, one can inhibit the tat protein of HIV. There are also topical and systemic treatments, as well as new chemotherapy agents that are becoming available. Finally, there is the improvement of the residual immune function of the patient. For example, Australian researchers reports that some people with KS in the protease inhibitors study there actually had their KS go away.

Tat Inhibitors At UCLA, as well as at a Boston site, 23 patients with AIDS-related KS were treated with high doses of the tat inhibitor being developed by Roche Laboratories. Results were not good. We found no CD4 or p24 antigen effect, as well as no effect on KS. Further, there were serious central nervous system toxicities.

So, is this the end of tat inhibitors? I don't think so, because the Roche drug is not a true tat inhibitor. Rather the drug binds to a protein which in turn interacts with tat. I predict that when we have a true tat inhibitor, one that inhibits the protein directly, we will have both an effective anti-HIV and an effective anti-KS agent.

Studies of Cytokine Modulators One approach being studied is turning off TNF or Tumor Necrosis Factor, one of the cytokines suspected of promoting KS cell growth. UCLA is preparing to launch a 12 week Phase II study of soluble TNF receptors, a recombinant protein to be given twice a week. All 40 people on the study will get the drug. This is awide-open study for people at all stages of KS. At least 50% of study participants should have a CD4 count over 200. Soluble TNF receptors will shut off TNF. If TNF is playing a role in KS, this study will show how important that role is.

Another study at UCLA is looking at vesnarinone, a drug which has been shown to have cytokine modulating effects in the test tube. Twenty-eight patients will be enrolled for 16 weeks to receive oral doses of this drug. The study will be extended for those who remain stable or show improvement over the 16 weeks. We are accepting study participants at all stages of KS and counts of CD4, but you cannot be taking nucleoside analog antivirals, because of possible drug interaction problems.

New Chemotherapy Agents The big breakthrough in chemotherapy for KS has been the development of liposomal drugs, drugs which target the KS cells more effectively than past chemotherapy agents. The two liposomal drugs currently available are doxorubicin and daunorubicin. Both are effective, but doxorubicin (brand name DOX-SL) has more activity and less bone marrow suppression than daunorubicin. If you have a choice, choose the doxorubicin.

Both these drugs can cause severe neutropenia (depletion of red blood cells). We know that about 75% of patients on DOX-SL end up on GCSF to combat the neutropenia. In recent studies of doxorubicin's effectiveness, over 70% have a partial response and between 7 and 9% have a total response on the drug. People in the know are predicting that doxorubicin will be FDA-approved and on the market soon.

Taxol for Advanced KS Taxol is a drug that has been used in a single small study at the National Cancer Institute. NCI researchers report a 55% response rate among their participants, all of whom had advanced KS. We have used taxol on very advanced cases at UCLA and have seen some dramatic responses, such as marked reduction in edema or swelling. You should know that the drug has a lot of toxicities and is very expensive. We are currently forming an ACTG study of taxol at UCLA and another study of taxol combined with bleomycin for advanced KS is getting underway at USC.

Retinoids for Early KS Retinoids are applied topically; the most well-know is marketed as Retin-A. Now we have a whole new generation of retinoids being developed. These are very selective drugs and thus have less problems with resistance and intolerance than previously available retinoids. UCLA and Shared Medical Research are conducting trials of these topical treatments for people with early KS (i.e. people with a few isolated lesions). Each person in the study will act as their own control group. During the first eight weeks, you topically treat some lesions and don't treat others. If there is a response in the treated lesions, you can go ahead and use the medication on all.

The Future: Prophylaxis for KS Now that we have identified the causative agent for KS, we may be able to develop prophylaxis for the disease. Of course, there are a number of steps still to be taken, but the possibility exists.

We first need a more definitive identification of KSHV, so that we can develop a test for its presence. This would allow us to determine who is at risk for KS. Before KS develops, those at risk could be put on agents such as TK inhibitors that will decrease the likelihood of their developing KS. We could also treat those at risk with antivirals that target KSHV itself. We also need a better understanding of the mechanism of transformation, the point where the cell goes from normal to transformed. Once we have that knowledge, we can move on to the development of drugs that inhibit that transformation process and thus stop the spread of KS. Our growing knowledge about KS makes new and better treatments a possibility.

Summing Up KS is a devastating disease. With all the treatment options opening up, no one diagnosed with this cancer should accept "watching and waiting." Remember: observation is not treatment. I would urge those with KS to get involved in a treatment trial. APLA's Positive Living lists clinical trials in the Los Angeles area in each monthly issue. You can get information on trials US-wide by calling 1.800.TRIALS.A.

Become a part of the solution. Some things may not work for you, so go on to something else. Understand your options and aggressively pursue treatment.

(Steve Miles M.D, Assistant Professor of Medicine at UCLA, delivered these remarks at the Being Alive Medical Update, April 24, 1995.)

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