Bulletin of Experimental Treatments for AIDS, No. 28; March, 1996
Harvey S. Bartnof, MD; Member of the Scientific Advisory Committee at the San Francisco AIDS Foundation since 1987. He has been Course Director of "AIDS-HIV: Overview and Update" at the University of California at San Francisco School of Medicine since 1985.

Several advances in KS research and treatment have occurred in the past few years. These advances include identifying potential causes and the approval of new treatments.

* Types of KS

Kaposi's sarcoma can be divided into the following types:

Classical KS

Professor Moriz Kaposi Kohn, a Hungarian dermatologist, first reported the existence of KS in 1872. This relatively slow-growing type of KS on the legs or feet occurs predominantly among elderly men aged 50-70 years of Italian (Mediterranean) or Eastern European (Ashkenazic Jew) descent.

African KS

In the 1960s, it was recognized that 9% of all tumors among men from equatorial Africa were KS. This form of KS is unrelated to HIV and AIDS. It may be slow-growing like classical KS or it may be more aggressive, sometimes lethal, particularly among those under 25 years of age.

Transplant KS

Transplant patients are given immunosuppressive drugs to help prevent rejection of transplanted tissue. In 1969, the first case of KS in a kidney transplant patient was reported; many other such cases have been reported since. This type of KS also occurs among patients receiving other types of transplants and among those given immunosuppressive steroid drugs for other conditions. In some of these patients, KS regresses when immunosuppressive drugs are decreased or stopped.

AIDS-KS

Between 1992 and 1994 there were over 11,000 reported cases of AIDS-KS among adults in the U.S. Due to underreporting, the CDC estimates that there were over 15,000 cases during those 3 years. KS is the cause of death in approximately 10-12% of people with AIDS.

Non-AIDS KS in Gay/Bisexual Men

KS has also been recognized among gay/bisexual men who are negative for HIV by antibody, p24 antigen, viral culture and PCR tests. HIV negative KS is slow-growing, similar to classical KS.

* Insights Into the Causes of KS

Relevant Epidemiology

Population-based studies have provided insights into potential cause(s) and mechanism(s) of KS:

Male Predominance

Male predominance is quite striking in all types of KS. In classical KS, males outnumber females almost 15 to 1; in African KS, 13 to 1; and in kidney transplant patients, 2.5 to 1. In AIDS-KS, U.S. men currently have an approximate 10-fold higher risk of KS than women; it occurs among 9.8% of men and 1.2% of women with AIDS. The only group with an equal number of males and females with AIDS-KS is U.S. children under age 13.

Behavioral Risk Differences

From 1985 to 1992, KS was the AIDS-defining illness in approximately 20% of all gay/bisexual men with AIDS. Even more men developed the tumor at some time during the course of AIDS. This percentage has decreased as the AIDS epidemic has progressed. During the 1992-1994 period, 14% of gay/bisexual men with AIDS developed KS. This reduction may be due to increased safer sex practices and/or to underreporting of cases.

All other behavioral risk categories have much lower rates of KS: injection drug users (2.3%), transfusion recipients (2.1%), heterosexual contact (1.7%), hemophiliacs (1.1%) and mother-to-newborn (0.3%). Altogether, 8% of all U.S. adults with AIDS have KS.

Risks Among Women

In the U.S. and Europe, the greatest risk for KS among women is heterosexual contact with a bisexual man. Women with KS from the U.S. and Europe were more likely to have been born outside of the U.S., predominantly in the Caribbean or Africa.

Risks Among Children

While not statistically significant, U.S. children with AIDS-KS were 2.5 times more likely to have a mother who acquired HIV by sexual contact with a gay/bisexual man than to have a mother who acquired HIV by other means.

Geographic Location

Unlike many AIDS-related conditions that have little geographic variance, KS patients are 70% more likely to be from a metropolitan area with a population greater than 1 million. In the 1980s, a risk factor for KS among European and Australian gay/bisexual men with AIDS was sexual contact in a large U.S. city.

Genetic Marker Differences

Studies of KS patients indicate a high prevalence of the human leukocyte antigen (HLA) markers DR5, B35 and C4. The protooncogene (cancer gene) c met and the p53 cancer gene mutation may be also be cofactors in the development of KS.

Racial/Ethnic Differences

In the U.S., adult Caucasians have a 3-fold increased risk for KS compared to African-Americans. The opposite is true for U.S. children with AIDS: African-American children have a 3-fold increased risk for KS compared to Caucasian children. In the U.S., all other racial/ethnic groups are represented among AIDS-KS cases, including Latino, Asian/Pacific Islander, Alaskan Native and American Indian.

Specific Sexual Practices

Several epidemiologic studies of gay/bisexual men have demonstrated that certain practices are associated with an increased risk for developing KS. Such practices include unprotected: (1) oral-anal contact (rimming); (2) receptive anal intercourse with or without rectal gonorrhea; and (3) receptive hand-anal insertion (fisting). Several studies have linked the recreational use of inhalant amyl nitrite (poppers) with KS, however not all studies demonstrate the association, and an association does not indicate causation. The use of these agents is highly correlated with unsafe sexual practices that likely facilitate the transmission of sexually transmitted diseases (STD). Amyl nitrite dilates blood vessels and is considered a sexual stimulant.

The combination of these epidemiologic factors leads to the hypothesis that KS probably involves a sexually transmitted agent or co-factor under the influence of sex hormones and genetic markers. The agent may be transmitted from mother to newborn. The possibility of another mechanism of transmission exists early in life, probably in childhood, in developing countries.

A New Herpesvirus: a Cause of KS?

Certain viruses are known causes of cancer. In the past, several infectious agents have been hypothesized to be associated with KS, including cytomegalovirus (CMV), Epstein-Barr virus (EBV), human papillomavirus (HPV), hepatitis B virus, Mycoplasma penetrans, human herpesvirus type 6 (HHV-6) and human herpesvirus type 7 (HHV-7). With the possible exception of HPV, none have been definitively linked with KS.

In December 1994, a research team from Columbia University published findings of a new human herpesvirus as the possible cause of KS (see BETA, March 1995, page 10 and BETA Treatment Alert, December 20, 1994). Molecular biologist Yuan Chang, MD, epidemiologist Patrick Moore, MD, and their colleagues published data in the journal Science. Over the last 14 months, over 35 research papers have appeared on this new herpes virus. It has been called both Kaposi's sarcoma-associated herpesvirus (KSHV) and human herpesvirus type 8 (HHV-8). Donald Ganem, MD, and colleagues from the University of California at San Francisco have isolated and grown KSHV in vitro.

The Chang and Moore team used a unique method of amplifying DNA sequences called representational difference analysis (RDA), followed by polymerase chain reaction (PCR). The method isolates unique DNA sequences found only in diseased but not normal tissues from the same individual.

Chang, Moore and co-workers isolated the unique herpesvirus sequences from: (1) 93% of 27 AIDS-KS tissue samples, (2) 11% of 27 AIDS-related lymphoma tissue samples, and (3) 25% of lymph node samples from people with AIDS who did not have KS. They also found the sequences in normal appearing skin biopsies adjacent to KS lesions in 2 patients. They were unable to isolate the sequences from control samples including other organs from the same AIDS-KS patients, opportunistic infection biopsies from other AIDS patients and various biopsies from HIV negative people.

Chang and Moore noted that the unique sequences were dissimilar to other human herpesviruses, except for a 56% homology (similarity) with EBV. EBV is associated with lymphoma, nose-throat cancer and HIV-related oral hairy leukoplakia. In addition, the new virus sequence had a 55% homology with herpesvirus saimiri, a cause of lymphoma in New World monkeys. Chang and Moore concluded that KSHV represents a new human herpesvirus.

Since the original report of KSHV, numerous laboratory groups worldwide have reported finding KSHV DNA sequences in all types of KS and in various bodily tissues.

KSHV has been detected in KS tissue from men, women and children. In the lymph nodes of asymptomatic HIV positive persons with persistent lymphadenopathy, KSHV has been detected among gay/bisexual men, but not among injection drugs users or heterosexual men. In skin cancers (squamous cell and basal cell carcinomas), KSHV has been detected among immunocompromised transplant patients, but not among immunocompetent patients. Similarly, benign skin tumors (actinic and seborrheic keratoses) from immunocompromised transplant patients contain KSHV, but those from immunocompetent patients do not.

The CDC was able to find KSHV in semen samples from 30 of 33 (91%) HIV positive gay/bisexual men. Also, they found the virus in 7 of 30 (23%) control HIV negative healthy male semen donors. The sexual orientation of the controls was not stated. Half were CMV positive and half were CMV negative. Preliminary results of this study were discussed in the December 1995 issue of BETA (page 30).

Contrasting with the CDC, Jay A. Levy, MD, and co-workers, from the University of California at San Francisco, have been unable to isolate KSHV from seminal fluid or cells from AIDS-KS patients. Neither were they able to isolate KSHV from fluid or cells in saliva. Levy s group has determined that the blood cells containing KSHV are B-lymphocytes.

When examined by the laboratory of D. Whitby, R. Weiss, PhD, and colleagues, of the University College London School of Medicine, KSHV was detected in none of 18 stool samples and in only 1 of 21 throat swab samples from AIDS-KS patients (the 1 patient with throat swab KSHV had KS in the lung). The authors state that the lack of KSHV in the stool is not inconsistent with the epidemiologic finding of an increased risk of KS with oral-anal contact. They believe that the virus would be expected to be found in immune cells of the rectal lining. Additional studies are necessary.

Alvin Friedman-Kien, MD, and colleagues from New York University have found that KSHV DNA is localized to the nuclei of the abnormal spindle-shaped cells that are characteristic of KS. Whitby and co-workers have also localized KSHV to KS spindle cells, in addition to finding the virus in KS endothelial lining cells.

Robert Gallo, MD, of the Institute for Human Virology at the University of Maryland, is skeptical that KSHV is the cause of KS because his laboratory cannot isolate the virus from established KS cell lines in vitro. However, KS cell lines in vitro appear to be unable to sustain the virus. C. Lebbe and colleagues from the HÖpital Saint-Louis in Paris, France have found KSHV in original primary cell cultures of KS cells. However, KSHV recovery decreases with subsequent passages (growth cycles) in vitro. They found that KS cell cultures were all negative for KSHV by the third and fourth passage. Moreover, Yuan Chang agrees with the findings of Lebbe and colleagues.

Predicting KS by Finding KSHV in the Blood or Semen

Researchers from the Institute of Cancer Research and University College London Medical School have determined that the presence of KSHV in blood mononuclear cells is predictive of the future onset of KS. They followed 143 HIV positive people without KS for a median of 30 months. Eleven of 143 initially were positive for KSHV by blood testing; 6 of them (55%) developed KS within 30 months. This compared with 12 who developed KS out of 132 (9%) who initially were KSHV negative. Moreover, those with detectable KSHV in their blood progressed to KS disease much faster than those without blood KSHV who progressed to KS disease. Those with KSHV in the blood had a lower CD4 cell count (median 120 cells/mm3) compared with those without KSHV in the blood (median 300 cells/mm3). All of these findings were statistically significant. However, at the time of blood testing, both the KSHV positive and KSHV negative groups who later progressed to KS disease were similar in their CD4 counts. A similar proportion of both groups also had other AIDS diagnoses. The authors have calculated that 50% of those with KSHV in the blood will progress to clinical KS within 3.5 years.

Researchers from the London Children's Hospital detected KSHV in the blood of a 6-year-old African girl 2 years before she developed KS. After chemotherapy for the tumor, the KS regressed and KSHV was undetectable in her blood. When her KS relapsed, her blood also revealed that KSHV had returned. The authors, D. Shingadia and colleagues, concluded that not only was blood KSHV predictive of KS disease, but that it correlated with treatment efficacy and relapse.

During a 5-year follow-up period, 13 of the 30 men (43%) in the CDC study described earlier who had KSHV in their semen developed KS disease. None of the 3 KSHV negative HIV positive gay/bisexual men developed KS.

Previously, BETA (March 1995, page 72) reported on research that indicated that KS disease could be predicted by the finding of KS spindle cells in the blood. Gallo s group found KS-like spindle cells in the blood of 25 HIV positive gay/bisexual men with KS disease and in 27 HIV positive gay/bisexual men without KS disease. When compared with HIV negative controls, those with KS disease had a 78-fold higher level of KS spindle cells in their blood, while those without KS disease had an 18-fold higher level. The level among HIV positive injection drug users was similar to that of controls. The authors conclude that the presence of KS-like spindle cells in the blood may be predictive of developing KS disease.

Is KSHV Treatable with Foscarnet or Ganciclovir?

Other evidence supporting a viral cause of KS was reported in 1994 by Linda Morfeldt, MD, and colleagues from the Karolinska Institute in Sweden (see BETA June 1995, pages 58-59). They reported that KS tumors resolved in 3 of 4 AIDS patients who were treated with foscarnet (Foscavir), a drug that is FDA-approved to treat CMV disease. Foscarnet is active against many viruses, including HIV and 5 herpesviruses. Two of the 3 patients were treated for 20 days. The third patient had two 20-day treatment courses. Resolution of KS occurred after 1.5 to 13 months.

In addition, other treatment-related epidemiologic evidence supports a viral cause of KS. In February 1995, the CDC reported that AIDS patients who were treated with foscarnet for any reason were 70% less likely to develop KS than those not treated with the drug. The findings were statistically significant. There were no benefits in preventing KS for AIDS patients treated with ganciclovir (Cytovene) (see BETA, June 1995, page 59).

Lastly, a report at the September 1995 Interscience Conference on Antimicrobial Agents and Chemotherapy (see BETA, December 1995, page 30) also suggested that certain CMV treatments may help prevent the development of KS. In the Multicenter AIDS Cohort Study (MACS) from 4 U.S. cities, foscarnet treatment for CMV disease conferred a 60% decreased risk of subsequent KS. Moreover, ganciclovir treatment for CMV disease conferred a 44% decreased risk for subsequent KS. However, these results were not statistically significant.

The National Cancer Institute, under the auspices of Robert Yarchoan, MD, is planning a trial of foscarnet as a treatment for KS.

It is unproved whether foscarnet or ganciclovir has activity against the new KSHV. Before this can be tested, KSHV must be fully isolated and cultured. KSHV likely represents part of the cause of KS, probably early in the cascade of events leading to KS tumor development. Undoubtedly, future research will yield more information surrounding KSHV and its role in AIDS-KS and other conditions. One future goal will be the development of a simple blood test to screen large numbers of people in the general population and HIV cohort groups.

Other Causes of KS

KS is a Disease Due to Abnormal Growth Factors

Gallo's research group was the first to cultivate KS spindle cells in vitro. Their research and the research of other groups has shown that the growth of KS cells in vitro requires specific growth factors, including cytokines. Some of these factors must be added to the cultures, while others are derived from the cells themselves. Removal of 1 or more of these factors causes inhibition of KS cell growth. Such factors include: platelet-derived growth factor, platelet activating factor, basic fibroblast growth factor, transforming growth factor beta, interleukin 1, interleukin 6, HIV tat protein, tumor necrosis factor, granulocyte-macrophage colony-stimulating factor, oncostatin M and others. Recognition of the various factors is important, since the development of drugs that block their actions would represent viable forms of therapy to treat KS.

The proof that these cells can induce KS is shown when they are injected into an immunodeficient mouse species. At the injection sites, transient lesions occur that have the clinical and microscopic appearance of KS. The evidence indicates that the injected cells secrete factors that recruit local mouse cells to become KS-like cells. In addition, the factors promote blood vessel growth, a necessary component of the KS tumor.

The various growth factors for KS likely represent part of the cause of KS.

Hormones as Co-Factors for KS

The male predominance of almost all forms of KS has led to the long-held theory that KS may be under the regulatory influence of sex hormones or some other genetic factors associated with the sex chromosomes. There are several lines of evidence to support the sex hormone co-factor hypothesis.

Beta-HCG

One line of evidence comes from the clinical observation that pregnancy caused the resolution of KS in 2 women with AIDS. First reported by Gallo at the X International Conference on AIDS in 1994, the published report appeared in the May 4, 1995 issue of Nature. The first woman's KS lesions were completely resolved 5 months after delivery, without any treatment. The other woman's KS lesions resolved after 2 months of pregnancy.

Gallo also reported that the beta chain of the pregnancy hormone human chorionic gonadotropin (b-HCG) blocked the growth of KS cells in vitro. Also, injecting b-HCG into immunodeficient mice after KS cells were injected blocked the development of KS lesions. Similarly, pregnant immunodeficient mice injected with KS cells did not develop KS, whereas non-pregnant mice and male mice similarly injected with KS cells did develop KS lesions. Gallo's group has shown that b-HCG leads to KS cell death both in vitro and in vivo (in mice) by apoptosis (programmed cell death).

Initial reports of treating AIDS-KS patients with b-HCG have been mixed. P.J. Harris, MD, from the AIDS Clinical Research Center of Washington, DC, reported in the July 8, 1995 issue of Lancet on the use of b-HCG intramuscularly in 6 AIDS-KS patients. Injections of 150,000-700,000 international units (IU) 3 times per week led to marked tumor regression in all 6 (time frame was not stated). Toxicities included injection site pain and skin retraction around the resolved KS lesions. If the dose was less than 100,000 IU or if a dose was delayed, KS recurred. Regression persisted until financial constraints forced a tapering of the dosage.

Two other research groups from England and Switzerland have reported no benefits from injected b-HCG for AIDS-KS, although neither group used doses as high as Harris did.

The results of the 3 groups of AIDS-KS patients totaling 13 people are not inconsistent. Future trials are certainly appropriate. Since b-HCG has an 85% homology with the beta chain of luteinizing hormone (LH), it is possible that LH might achieve similar anti-KS effects. LH regulates the testes and ovaries. Gallo hypothesizes that women have lower rates of KS because: (1) LH levels are higher in women than in men, and (2) women of child-bearing age have monthly surges of LH that occur with ovulation.

Testosterone, Estrogen, DHEA

The level of male sex hormones in men with AIDS-KS has been reported to be low by some researchers and high by others. N. Christoff, MD, and colleagues, from Paris, France, reported in June 1995 that levels of the androgens (male hormones) testosterone and dehydroepiandrosterone (DHEA) were higher in men with AIDS-KS than in either HIV positive men without KS or HIV negative control men (these are considered male hormones although women also produce small amounts of each). Both the KS group and the HIV positive/KS negative group had higher levels of the female hormones estradiol and progesterone than the HIV negative control group. The report was in Journal of Clinical Pathology (see BETA, December 1995, page 49).

Nearly opposite findings were reported the September 1995 issue of AIDS by S. Klauke, MD, and colleagues from the Buerger Hospital in Frankfurt, Germany. Testosterone and estradiol levels were both significantly lower in men with AIDS-KS than either men with AIDS who did not have KS or asymptomatic HIV positive men. Levels of LH and follicle stimulating hormone (FSH) were higher than they were in either men with non-KS AIDS or asymptomatic HIV positive men. Like LH, FSH regulates the testes and ovaries. DHEA levels were not reported. This research group has previously reported that estrogen levels are similarly low in women with AIDS-KS.

The apparently conflicting findings regarding abnormal levels of sex hormones need to be resolved. It is likely that some confounding factors are causing the discrepancy. These may include: patients' medications, current or past KS therapies, individual variations in hormone levels, sampling differences and/or laboratory techniques.

Glucocorticoids

The glucocorticoid steroid hormones increase the growth of KS in vivo and in vitro. The first recognition of this was in KS among transplant patients treated with prednisone, a immunosuppressive glucocorticoid steroid. Other examples of glucocorticoids include cortisone, hydrocortisone and dexamethasone (DEX). Clinically, treatment of AIDS patients with any of these steroids increases the risk of developing KS. RU-486 is a glucocorticoid receptor antagonist and an experimental abortion-inducing pill. Adding RU-486 to KS cells in vitro with DEX blocks the stimulatory effects of the DEX.

Additional research on sex hormones and other hormones will probably lead to new treatments for KS in the next few years.

Is KS a True Cancer?

The issue of whether KS is a true cancer is controversial. A true cancer arises from 1 abnormal cancer cell that repeatedly grows and divides, becoming a clone of cells. The clone in turn will grow into a tumor mass. In some cancers, a group or groups of cells can break off, travel and start growing in other bodily locations (metastasis). However, all the cells in that cancer began from the 1 original malignant cell; that cell type can be seen in the microscope when a biopsy of the cancer is taken.

When viewed under the microscope, KS does not have just 1 cell type. There are several cell types in KS, including spindle cells (the main abnormal cell in KS), fibroblasts, inflammatory white blood cells and red blood cells that have leaked out of blood vessels. That there is more than 1 cell type in KS speaks against its being a true cancer. Microscopic examination also reveals small blood vessel slits.

Instead, KS is thought to be a multicentric tumor, that is, an abnormal proliferation of cells that occurs in several locations at the same or different times under the regulatory growth of cytokines, other growth factors, sex and other hormones and possibly KSHV.

It is also possible that the slow-growing forms of KS may represent a hyperproliferative (excessive growth) state under the regulation of several factors, whereas the more aggressive forms may result from true malignant transformation (cancer).

* Clinical Manifestations, Symptoms and Diagnosis of AIDS-KS Clinical Manifestations

KS can occur anywhere on the skin, in the mouth or on any mucous membrane lining. Common locations are the mouth, neck and head, particularly the tip of the nose or behind the ears. Common internal organs involved include the lung and intestines. When found on the skin, KS also occurs in the intestinal tract 40% of the time.

KS occurs on the skin most commonly as nodules, raised round or oval hard lumps. The size of the nodules is usually 0.5-2.0 cm (3/16-3/4 inches) in diameter. In light-skinned individuals, the color is usually violet, bluish or reddish (reflecting the presence of red blood cells). In dark-skinned individuals, the color is more brown or black. A bruise-like discoloration and minor swelling often appear at the edges of the KS nodules when they are enlarging. Less commonly, KS skin nodules can ulcerate, bleed and become secondarily infected.

Before the KS has grown to full nodule size, it may first appear flat with a pink or blood-bruise color (patch stage). Often, 1 or 2 KS lesions in the patch stage may go unnoticed by the patient.

When many nodules are present on the skin, they often appear in patterns, with symmetry on both sides of the body. The patterns can be linear or slightly curved, following the skin fold lines (Langer's lines).

Sometimes, the KS can form large plaques on the skin, with larger raised areas of skin involved. Common locations are the thighs and soles of the feet. Often, there is painful swelling involved.

KS in the mouth is common, often on the roof (palate) or gums. The color is usually violet or red. On the roof of the mouth, KS is usually flat. Sometimes mouth KS can swell, bleed or ulcerate.

Less commonly, 1 or more lymph nodes may be involved without skin involvement. This form of KS can also cause potentially painful swelling.

The clinical course of AIDS-KS is usually progressive over time. Flat lesions tend to grow into nodules and new lesions appear. Often, an opportunistic infection will cause an accelerated growth of KS. However, there can be periods of weeks to months when the KS remains stable in size, shape and number.

KS is not a common cause of death among AIDS patients. In 1987, KS was the cause of death in 10% of AIDS patients. By 1992, this number increased slightly to 12%. However, death often occurs when KS is in the lungs.

Symptoms

Usually, skin KS does not cause symptoms of pain or itching. Larger lesions can be painful. There can be associated swelling, particularly on the face or legs, and this may be painful. KS on the soles of the feet may be painful when walking.

When KS occurs in the mouth, usually there are no symptoms. Sometimes, however, there can be swelling, bleeding and ulcers, with associated pain. Uncommonly, KS in the mouth or throat may cause difficulties with chewing or swallowing.

When KS occurs in the intestines, usually there are no symptoms. Sometimes, however, internal bleeding or a blockage with pain can occur. A blockage can also cause nausea and vomiting. Intestinal KS is associated with malabsorption of nutrients.

The most serious organ involvement is KS of the lung. There may be shortness of breath, wheezing and a cough that is usually dry, but can be bloody. Lung KS is life-threatening.

Sometimes, KS is associated with fevers, night sweats and weight loss. However, these symptoms are common in AIDS, and are often due to an associated opportunistic infection.

Diagnosis

The diagnosis of KS usually is made by taking a biopsy or piece of the KS lesion. On the skin, a small punch biopsy is used. The biopsy specimen is then examined under a microscope to look for typical abnormalities.

For KS of the internal organs, a biopsy may be obtained during endoscopy or bronchoscopy. While the patient is sedated, a narrow flexible tube with a lens tip is inserted into either the swallowing tube, stomach and small intestines or the rectum and colon (endoscopy) or the windpipe and lungs (bronchoscopy). Sometimes, the KS is deep enough under the mucosal lining that the biopsy misses the KS. Taking a biopsy of the windpipe or lungs may be risky, sometimes causing a lung to collapse. This is a treatable complication, however.

According to CDC protocol, a presumptive diagnosis of AIDS-KS may be made without a biopsy if: (1) the person has documented HIV infection, and (2) there is an erythematous (red) or violaceous (purple) plaque-like lesion on the skin or mucous membrane. Through 1994, 17% of U.S. AIDS-KS cases were made presumptively, while the remaining 83% were made definitively with a biopsy.

Routine blood tests are performed, including complete blood counts, CD4 cell counts and possible viral load testing. Sometimes, skin tests are done to help measure immune functioning.

In the future, it is possible that blood levels of KSHV, spindle cells, growth factors and certain hormones may be measured to aid in the diagnosis of KS, or to follow up when therapies are given.

* Treatment for KS There is no cure for AIDS-KS, and treatments for KS are not associated with a prolongation of life. However, KS treatments can markedly improve the quality of life and ameliorate symptoms caused by the disease. Improving the cosmetic appearance of KS lesions often improves people s outlook as well. KS treatment is helpful when there are painful lesions, bulky lesions, associated swelling, lung or intestinal KS symptoms, rapidly progressive disease or disfigurement.

After a diagnosis of KS is made, several factors enter into the decision as to the type(s) of therapy:

* What is the total KS tumor burden (total quantity or volume of KS in the body)?

* What is the state of the immune system? Is the CD4 cell count low or normal?

* Are there associated symptoms of fever, night sweats or weight loss?

* Were there any prior opportunistic infections?

* What is the overall functional ability of the patient?

A better prognosis for KS is expected when: (1) there is a low tumor burden, (2) the CD4 cell count is normal or only mildly decreased, (3) there are no associated symptoms of fever, night sweats or weight loss, (4) there have been no prior opportunistic infections, and (5) the patient has essentially normal functional capabilities.

For those with minimal KS disease that is stable or only slowly progressive, the choice may be observation only. When the KS appears to be increasing in number or size, or if there are associated symptoms, a decision may be made to initiate appropriate therapy. Treatments for KS fall into 2 categories, local and systemic.

Local Therapies

Due to the disfigurement and stigma of skin and mouth KS, local therapies are often indicated. One should be mindful, however, that KS is a systemic disease, and that new lesions are likely to appear in the future.

Radiation Therapy

Localized radiation therapy (radiotherapy) is very effective for those with a single lesion or a localized group of lesions. It is effective for relieving localized swelling, particularly on the face, and less so on the legs. Painful or cosmetically displeasing lesions are often successfully treated with radiotherapy. The eyelids and conjunctiva (white parts of the eye) respond well to radiotherapy. Mouth and throat KS can be treated this way as well, although painful inflammation of the mucous membranes (mucositis) is a common side effect. For this reason, many clinicians try to avoid radiotherapy to the mouth. Toxic side effects limit the use of radiotherapy for the soles of the feet. Symptoms associated with lung or intestinal KS can be improved temporarily with radiotherapy.

Localized Chemotherapy Injections

Small KS lesions on the skin or in the mouth may be successfully treated with 1 or more injections of chemotherapy. Injecting directly into the KS lesion is somewhat painful, and sometimes repeated injections are necessary for an optimal cosmetic result. Usually, diluted vinblastine (Velban) is used. Vinblastine therapy may leave some hyperpigmentation (darkening of the skin), even after the lesion has resolved. Response rates are 92%, for a mean duration of 4.5 months (including complete and partial response rates). Some oral surgeons and dentists may use sodium tetradecyl (Sotradecol) for lesions in the mouth. Multiple local injections of interferon alpha (IFN-a) have also led to significant response rates of individual lesions.

Cryotherapy

Freezing a lesion on the skin with liquid nitrogen (cryotherapy) has also proved successful in treating unsightly skin lesions, especially on the face. Cryotherapy is usually reserved for thinner skin areas on the face and the thin skin of the genitals. Often, the lesion needs more than 1 treatment. Response rates are 88%, including complete and partial responses. Cryotherapy is most successful if the KS lesion is smaller than 4/5 inch in diameter and flat, not nodular.

Systemic Therapies

When KS is widespread, rapidly progressive or in more than 1 organ, systemic therapy is indicated. Since most of the systemic therapies for KS have toxic side effects, often to cells of the immune system itself, sometimes the side effects may outweigh the potential benefits of therapy. There are several cancer chemotherapies that lead to significant response rates in KS. The chemotherapies may be single drugs or combinations of drugs.

Vincristine and Vinblastine

Both vincristine (Oncovin) and vinblastine are active against AIDS-KS. These 2 drugs are often given as a single drug at a time alternating weekly with the other drug, to minimize toxicities. Vincristine can cause peripheral neuropathy (pain and tingling in the feet, legs and hands). This may be increased when taking anti-HIV therapies that also cause peripheral neuropathy, including ddI (Videx) and ddC (Hivid). Vinblastine can cause toxicity to the bone marrow, leading to low white cell counts (neutropenia) and increased risk of infection. Low white cell counts may be offset by using the white cell boosters granulocyte colony-stimulating factor (G-CSF [Neupogen]) or granulocyte-macrophage colony-stimulating factor (GM-CSF [Leukine]).

Etoposide

Etoposide (VP-16) is an active agent against KS, but is not usually a first choice drug. It is available in an oral formulation, an attractive characteristic. However, like some cancer therapies, it can cause reversible hair loss. This side effect makes it somewhat unattractive when KS is being treated for cosmetic purposes.

Doxorubicin

As a single agent, doxorubicin (Adriamycin) has significant activity against AIDS-KS. It is helpful for those who have not responded to other therapies or for those with more advanced disease. This agent is toxic to white blood cells. Triple combination therapy with doxorubicin, bleomycin and vincristine (ABV) is more effective than doxorubicin alone.

In late 1995, the FDA approved a new formulation of doxorubicin called Doxil (liposomal doxorubicin). The drug is encapsulated in liposomes (fat bubbles). This allows for greater uptake of the drug by KS cells and fewer toxicities. In one study, the concentration of drug in KS cells was 5-10 times higher with the new formulation than with the non-liposomal type. Doxil is approved for those whose KS has progressed while on prior combination therapy or those who were intolerant to such treatment. Phase II studies have yielded an 80-100% response rate to the new formulation and its first cousin, liposomal daunorubicin. A study of Doxil was presented at the December 1995 American Society of Hematology meeting in Seattle by Donald Northfelt, MD, and colleagues, from the University of California at San Francisco. In 228 AIDS-KS patients with extensive, progressive disease (skin and mouth and/or internal organs), Doxil was significantly more effective than ABV in producing partial or stable responses. Also, side effects were more favorable in the Doxil group. Side effects for Doxil and ABV, respectively, were: fever (24%, 37%), nausea (31%, 56%), neuropathy (5%, 9%), leukopenia (low white cells: 44%, 47%), and severe toxicities (54%, 66%). Bone marrow toxicity appears to be similar with the liposomal and non-liposomal formulations of doxorubicin. One Doxil patient and 6 ABV patients had progressive disease.

Daunorubicin

FDA approval has been granted for the first liposomal derivative of daunorubicin (DaunoXome) for advanced AIDS-KS; exact labelling is now being worked out. It is closely related to doxorubicin. KS response rates were in the 80-100% range in Phase II trials of the drug, significantly higher than response rates with older regimens. Toxicities with liposome-encapsulated daunorubicin and doxorubicin reveal lower rates of vomiting, mouth inflammation and hair loss than non-liposomal formulations.

Doxorubicin plus Bleomycin and Vincristine

Triple combination chemotherapy with doxorubicin, bleomycin and vincristine (ABV) is well tolerated and successful in treating AIDS-KS that is widespread, including cases involving the lung and/or swelling of the extremities. Sometimes, 1 treatment with the 3 drugs can lead to marked improvement of leg swelling and shortness of breath. Due to pre-existing low white cell counts, sometimes bleomycin and vincristine are used as a double therapy without doxorubicin. Alternatively, GM-CSF or G-CSF may be added to the triple therapy. Common AIDS drugs that cause low white cell counts include AZT (Retrovir), ganciclovir (Cytovene) and sulfa-containing drugs (e.g., Septra, Bactrim).

Alpha Interferon Alone or with Anti-HIV Therapy

Alpha interferon (IFN-a [Intron A, Roferon A]) with or without AZT has shown significant benefit in treating AIDS-KS. It is used alone for those with progressive disease with minimal or no symptoms and with a CD4 cell count greater than 200 cells/mm3. The drug does not work as well when the CD4 cell count is low or if there have been prior opportunistic infections. IFN-a has anti-tumor and anti-HIV effects. When used alone, a dose greater than 20 million units/meter2 daily has led to the highest response rate. However, side effects are significant, including flu-like symptoms (fever, weakness, sweats, fatigue), loss of appetite and weight loss. Long-term treatment with the drug can be difficult because some of these symptoms persist. Response to IFN-a may take as long as 1-2 months. Optimal response may take 6 months. If patients respond to the drug and can tolerate it, treatment continues indefinitely. Otherwise, KS returns when IFN-a is stopped. Patients can give themselves injections of IFN-a, obviating the need for a clinic or office visit for therapy.

Combining AZT with IFN-a is a common drug regimen used to treat AIDS-KS. When used with AZT, a lower dose of IFN-a is used, 4-18 million units/meter2 daily. Low white cell counts are common with this regimen, often requiring the use of GM-CSF or G-CSF. Even though a lower dose of IFN-a is used with AZT, the response rate is better using the 2 drugs than IFN-a alone.

One recent study evaluated the use of an even lower dose of IFN-a with AZT for early limited but progressive KS. In 1995, S. Mauss, MD, and H. Jablonowski, MD, from the Heinrich-Heine University in Duesseldorf, Germany, reported their findings in the Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology. They treated 17 AIDS-KS patients who had a median of 8 lesions. All had skin KS; 3 also had oral KS, and another 7 also had lymph node or intestinal KS. The median entry CD4 cell count was 315 cells/mm3. The researchers used an IFN-a dose of 3 million units injected 3 times weekly along with AZT 250 mg twice daily.

A complete response occurred in 3 of 17 patients (18%), while a partial response occurred in 8 of 17 (47%). Stable disease occurred in 2 of 17 (12%), while progressive disease occurred in 4 of 17 (24%). KS tumor reduction was documented after 6-8 weeks among responders. Those with complete responses had CD4 counts greater than 513 cells/mm3, while those with progressive disease had CD4 counts less than 222 cells/mm3. Remissions among responders were maintained for a median 2.5 years while still taking IFN-a and AZT. Such responses are similar to or slightly better than responses in earlier studies using higher doses of IFN-a. Side effects were much milder than those observed with higher doses of IFN-a. Mild flu-like symptoms occurred. No patient required white cell boosters since severe neutropenia did not occur. The authors conclude that this low-dose regimen of IFN-a plus AZT for AIDS-KS patients with a low tumor burden and CD4 cell counts greater than 250 cells/mm3 has a substantial and sustained antiproliferative (anti-KS) effect. They recommend large scale studies.

It remains to be seen whether using IFN-a with other anti-HIV drugs will be better than a combination with AZT alone. It will be particularly interesting to see whether combining IFN-a with AZT and 3TC (Epivir) and/or a protease inhibitor (e.g., saquinavir [Invirase]) will yield even better responses than the double combination of IFN-a and AZT.

Photodynamic Therapy

Photodynamic therapy for AIDS-KS, which involves exposure to ultraviolet light after the ingestion of hematoporphyrin (Photofrin), has led to disappointing cosmetic results due to scarring and increased pigmentation. Lower doses may have more favorable results.

* Experimental Therapies Retinoic Acid Derivatives

Currently, Phase I/II studies are underway using the oral form of 9-cis-retinoic acid (ALRT 1057) and Phase II/III studies are underway using a topical form. Tretinoin (Retin-A) is in Phase I/II trials.

All-trans retinoic acid monotherapy followed by dual therapy with IFN-a has completed Phase I/II trials. The results were published in August 1995 in the Journal of Clinical Oncology. At the doses used, little anti-KS activity was demonstrated.

LGD 1069

LGD 1069 (Targretin) is in Phase I/II trials in both an oral and topical form.

Topotecan

Phase II trials are underway for topotecan for KS and for lymphoma.

Paclitaxel

Paclitaxel (Taxol) is derived from the bark of yew trees. This experimental therapy has led to a major response rate of 59% in AIDS patients with advanced or refractory KS, according to a paper presented at the December 1995 American Society of Hematology meeting in Seattle. None have had progressive disease. Half of 30 patients had more than 50 lesions, and half had significant swelling. The lungs or intestines were involved in 27%. A 3-hour infusion was given every 2 weeks for a median of 5 doses. Swelling was reduced in 95% of patients.

Foscarnet

Foscarnet was discussed earlier in this article. The National Cancer Institute is planning a trial to treat KS with foscarnet.

Immune Globulin

Intravenous immune globulins (IVIG) used to treat polymyositis (muscle inflammation) has been reported to cause regression of KS. Human trials or retrospective analyses of HIV/AIDS cohort groups would seem appropriate.

Apolipoprotein E

Apolipoprotein E (Apo E), a subtype of which is associated with Alzheimer s disease, has been shown to block the development of KS in immunodeficient mice. A Phase I trial in humans is indicated.

Hormone Therapy

Trials using experimental therapies such as b-HCG, beta-LH, and possibly glucocorticoid receptor inhibitors will likely progress in the next few years. Manipulation of testosterone and estrogen sex hormone profiles will likely lead to new experimental therapies as well.

Angiogenesis and Growth Factor Inhibitors

Tumors require new blood vessel growth in order to receive oxygen and nutrients from the blood. An intriguing area of cancer research involves using experimental therapies that block angiogenesis, or the formation of new blood vessels. This may be particularly promising for KS, with its high density of microscopic blood vessels.

Many of the growth factors discussed previously are potential targets for anti-KS therapies. Molecules that bind to the RNA strands of KS growth factors represent viable candidates for therapies. One antisense molecule that has shown promise in vitro is a nucleotide that binds basic fibroblast growth factor, a potent promoter of blood vessel growth. Other growth inhibitor candidates include sulfated polysaccharide-peptidoglycan (SP-PG), fumagillin analog TNP-470, platelet factor 4, interleukin 4 (IL-4, an inhibitor of IL-6) and HIV tat protein inhibitor. Trials of the latter 3 are underway. Vitamin D3 and its analogs inhibit KS cell growth in vitro, possibly by inhibiting IL-6 and IL-8.

Telomerase Inhibitors

Telomeres are structures at the end of chromosomes in every cell. With each normal cell division, the telomeres undergo progressive shortening. After a predetermined amount of telomere shortening, cell death occurs. This may be a normal part of the aging process. Many cancer cells are under an abnormal influence of telomerase, which inhibits the normal shortening of telomeres. Such cancer cells are immortal, and they continue dividing, leading to cancerous growth. Isolating inhibitors of telomerase may lead to potential cancer chemotherapies, including therapies for KS.

Hyperthermia

In one report of heat therapy in 31 patients with widespread KS and severe immune impairment, a partial or complete response was seen in 69%, 30 days after the 1-hour treatment. After 1 year, 14% maintained KS tumor regression. One patient remained in complete remission 26 months after the therapy; he reportedly became HIV negative by both culture and PCR test after the treatment. Moreover, this man had a rise in his CD4 cell count from 250 cells/mm3 to approximately 800 cells/mm3. The treatment heats the body to 42 C (107.6 F), while the blood is circulated out of the body and heated to 49 C (120 F). Two patients died as a result of the treatment: 1 had a stroke and the other had a lethal abnormal heart rhythm. Two additional cases had severe bleeding from the procedure (intravascular coagulopathy).

References

Chang Y and others. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi s sarcoma. Science 266: 1865-1869. December 16, 1994.

Charnow J. NCI's Gallo downplays evidence that a herpesvirus causes KS. Infectious Disease News 8(9):3,9. September 1995.

Chuck S and others. Frequent presence of a novel herpesvirus genome in lesions of human immunodeficiency virus-negative Kaposi's sarcoma. Journal of Infectious Diseases 173:248-251. January 1996.

Denning P and others. Current trends in the epidemiology of Kaposi's sarcoma. Centers for Disease Control and Prevention. 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, September 17-20, 1995. Abstract and poster I23.

Harris PJ. Treatment of Kaposi's sarcoma and other manifestations of AIDS with human chorionic gonadotropin. The Lancet 346:118. July 8, 1995.

Kaposi M. Archives of Dermatology and Syphilology 4: 742-749, 1872.

Levy JA. A new human herpesvirus: KSHV or HHV8? The Lancet 146(8978):786. September 23, 1995. Lin J-C and others. Is Kaposi's sarcoma-associated herpesvirus detectable in semen of HIV-infected homosexual men? The Lancet 346:1601-1602. December 16, 1995.

Moore, P and others. Detection of herpesvirus-like sequences in Kaposi's sarcoma in patients with and without HIV infection. New England Journal of Medicine 332(18): 1181-1185. May 4, 1995.

Morfeldt L and others. Long-term remission of Kaposi's sarcoma following foscarnet treatment in HIV-infected individuals. Scandinavian Journal of Infectious Diseases 26(6):749-752. 1994.

Northfelt DW and others. Randomized comparative trial of Doxil vs Adriamycin, bleomycin, and vincristine (ABV) in the treatment of severe AIDS-related Kaposi's sarcoma. 37th Annual Meeting of the American Society of Hematology. Seattle, WA, December 1-5, 1995. Abstract 1515.

Rady PL and others. Herpes-like DNA sequences in non-Kaposi's sarcoma skin lesions of transplant patients. The Lancet 345:1339-1340. May 27, 1995.

Schalling M and others. A role for a new herpes virus (KSHV) in different forms of Kaposi's sarcoma. Nature Medicine 1(7): 707-708. July 1995.

Whitby D and others. Detection of Kaposi sarcoma associated herpesvirus in peripheral blood of HIV-infected individuals and progression to Kaposi's sarcoma. The Lancet 346:799-802. September 23, 1995.

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