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As people with HIV live longer, cancer is a risk.

A dual diagnosis of AIDS and cancer-namely Kaposi's sarcoma (KS) and non-Hodgkin's lymphoma (NHL)-is not something I or any HIV-positive person ever wants. Yet it happens, and we still don't know who will get it or why.

Cancer is something that has been around forever, but AIDS is relatively new. Virologists have largely modeled our current "hit early, hit hard" aggressive approach to HIV on cancer, hoping to produce the goal of long-term remission that's been achieved with many cancers. In neither disease have we abandoned the ultimate goal of eradication. But both diseases stump us with fundamental mysteries about the true cause and nature of illness. An analysis of both diseases reveals that they share many similarities, and we've learned a great deal about each by studying the other.

For example, cytokine research, which focuses on deepening our understanding of the complex chemical interplay of the immune response to infection, is a hot crossover field for HIV and cancer scientists.

Other similarities include common sexually transmitted viruses linked to HIV-related cancers, such as human papillomavirus (cervical and anal cancers), Epstein-Barr virus (non-Hodgkins lymphoma), and a relatively new herpes-like sequence, HHV-8, which is a second cousin to EBV and directly linked to Kaposi's sarcoma. In recent years, there's also been a crossover of activism, as cancer advocates, including breast cancer activists, have followed the lead of AIDS activists, and in some instances the two have come to work side by side to push research in certain areas.

Yet AIDS and cancer also have important differences that may never be resolved. These include patient populations affected, the general attitude of physicians, and how clinical trials and the FDA drug-approval process are carried out. For starters, HIV is now the biggest global epidemic in modern times, threatening the future of entire nations. But it also carries a heavy negative social stigma that is linked in the public eye to promiscuity, drug use, and homosexuality, among other things.

Meanwhile, some cancer researchers, not really a part of the HIV community, have been slower in pushing for clinical trials of therapies for HIV-related cancers.

The three most common AIDS cancers, generally referred to as "AIDS malignancies," are KS, NHL, and cervical and anal cancer, and all of them developed in people many years before the onset on HIV/AIDS. Kaposi's sarcoma, the dreaded purplish spots that signaled the arrival of HIV among young gay men as far back as 1981, was actually discovered over 200 years ago by Moritz Kaposi. Classic Kaposi's sarcoma predominantly affects older men of Mediterranean decent, while endemic KS was later found among African men, women, and children. But at the beginning of the AIDS epidemic, when it was still called GRID-gay-related immune deficiency-no one in the gay community, not even most doctors treating these young gay men, had a true understanding of what KS was. Moritz Kaposi was not a household name and the disease he discovered was barely, if at all, covered in American medical text books.

As the history of AIDS already shows us, KS quickly changed all that. In a few short years, the incidence of KS increased 100,000-fold compared with pre-AIDS years. By then, the appearance of small purple spots on one's arms, hands, neck, and face, became the unique visual sign that you had "it"-AIDS-and were probably gay, too. Like those with the plague in medieval times, gay men with KS were treated like lepers and outcasts by people afraid to be around them for fear of contacting the disease.

No other AIDS-related opportunistic disease attacks and singles out one segment of the population as KS does with HIV-positive gay men. Many epidemiological studies in AIDS-related KS conducted over the past 15 years have documented this truism: Men with KS outnumber women approximately 95 percent to 5 percent; HIV-positive homosexual men with KS outnumber heterosexual men almost as significantly; and KS is extremely rare in hemophiliacs with HIV. In fact, in one major study of hemophiliacs with HIV, only one in 93 developed KS, and he happened to be a gay man.

That makes having KS different from any other cancer. I can walk down a street and spot someone with KS, but I'm unable to identify people with lung, colon, or prostate cancer. The trauma and disfigurement of the KS lesion, a social stigma and constant visual reminder of one's dual diagnosis of cancer and AIDS, can take a serious psychological toll on patients. According to Steve Miles, a prominent AIDS oncologist from UCLA, "A patient's psychological distress may bear no relationship to the actual extent of cutaneous [skin] involvement by KS." As he points out, "Treating a patient with asymptomatic indolent lesions might be appropriate for some simply for its psychological benefit."

Add to that more serious problems caused by treating HIV-related KS such as baldness, a common side effect of chemotherapy, or weight loss, caused by chemo-induced nausea and loss of appetite. HIV drugs are bad enough, and as cancer advocates have long pointed, chemo is no picnic.

For many years, there were no effective drugs for KS; treatment was considered palliative rather than curative. The primary cause of death in many people who died of AIDS was pulmonary KS, the development of internal lesions in the lungs. In recent years, a number of new drugs have been developed for KS that work better. But the greatest prevention advance against the disease has come from protease inhibitors.

In October, the CDC released statistics showing a dramatic 45 percent decline in the incidence of KS in the United States between 1996 and 1997, a decline that began several years earlier. Looking back, there is an unsolved medical mystery behind these numbers. Nobody can truly explain (and I've been asking for five years) why KS went from being so prevalent and one of the first opportunistic diseases to develop in people with HIV to being an illness that now commonly appears later in HIV disease, when people have less than 100 CD4 T-cells. The widespread use of PCP prophylaxis and treatment is not a sufficient answer. A leading, though unproved, theory suggests that as they shut down viral activity and boost immune responses, HIV protease drugs also thwart the action of inflammatory molecules called cytokines as well as growth factors needed to grow cancer cells (called an angiogenic process). A number of cancer drugs in development are angiogenesis inhibitors.

Like KS, lymphomas are also not new; they predate AIDS. Lymphomas, which develop in an individual's lymph system, are cancerous tumors. We've known for some time that organ and bone-marrow transplant patients with cancer and others from the general population developed non-Hodgkin's lymphoma (NHL). A pathologist can differentiate Hodgkin's and non-Hodgkin's lymphoma based on the cancer cell's histology (how a cell looks under a microscope). Both lymphomas differ in their clinical presentation and in specific therapies used to treat them. Because there is lymph tissue throughout the body, lymphomas that originated in the lymph nodes often spread to distant organs. In HIV-positive individuals, it is very common that NHL tumors will be extra nodal (occurring outside the lymph node), developing in the liver, colon, brain, etc.

As early as 1982, people with HIV, mostly gay men, were developing what experts initially called Burkitts-like lymphomas (actually NHL) at an alarming rate. But it wasn't until 1985 that the Centers for Disease Control caught on and added NHL to the list of AIDS-defining illnesses. It also took AIDS activists a while to realize that since HIV causes severe immunosuppression, men and women alike are at high-risk for developing this HIV-related cancer. By the mid '90s, studies showed that NHL had increased 230-fold in people with HIV and AIDS.

Today, non-Hodgkin's lymphoma is the second most common HIV-related malignancy, affecting an estimated 13 percent of people with AIDS. About 6 percent of people with AIDS die of the cancer. As of last year, these rates had increased steadily over the past seven years. And as doctors like to point out, the longer people live with HIV, the greater their risk of developing HIV-related malignancies. In people with HIV, NHL is said to be an aggressive cancer that's difficult to treat; compared with non-AIDS NHL, the average five-year survival rate for patients with AIDS and NHL has never been more than 7 percent, based on a comprehensive survey in the August 1997 issue of The PRN Notebook, a physician's research journal. But it's important to remember that these statistics predate the widespread use of protease inhibitors, which haven't made the same impact on NHL and other cancers as they have on Kaposi's sarcoma.

So far, there's been little change in the incidence of HIV-related NHL in the era of HAART, based on a recent study by Susan Buchbinder and colleagues at the AIDS Office in San Francisco. But others have found it is increasing. A MACS study by L.P. Jacobson and colleagues showed that "the incidence of NHL has continued to increase significantly, at a rate of 21 percent per year since 1985." Nonetheless, cases of primary CNS (brain) lymphoma are on the decline, based on CDC data from 1994 to 1996.

The connection between Epstein-Barr virus and non-Hodgkins lymphoma is also elusive. Studies conducted in the past 10 years note that the rate of EBV in HIV-NHL tumors is between 40 to 60 percent, while the rate of EBV found in HIV-primary, central-nervous-system (brain) lymphomas is close to 100 percent. These numbers are much higher than the approximate 25 percent rate of EBV found in people without HIV who have non-Hodgkin's lymphoma.

What about cervical and anal cancer? There are dozens of papillomaviruses; several are linked to anal and cervical cancers, others to genital warts. Cancer researchers are looking at the complex interaction of human papillomavirus and cancer-causing genes. For the future, the big question is whether cervical and anal cancers will increase as people with HIV live longer. Or will it decrease in people on potent HIV therapies whose immune responses have been strengthened to the point of controlling HPV?

Even though the CDC categorized cervical cancer as an AIDS-defining illness, the National Cancer Institute (NCI) database only documents a fourfold increase compared with the general population. This increase can be seen five years prior to the onset of AIDS and isn't reflected in women in their post-AIDS years. Recent documentation has shown this modest increase to be the effect of sexual practices (that is, the number of multiple partners) that place women at risk for HPV, and subsequently HIV. Likewise, the increased rates of anal cancer-also thought to be caused by HPV-may not be totally due to HIV's immunosuppressive effects but to sexually active lifestyles. (Before AIDS, Dowling and colleagues documented that gay men had a 10 percent to 15 percent higher incidence of anal cancer than heterosexual men.) Sounding the alarm, the NCI has documented the increased risk of and propensity toward anal cancer (15-fold to 30-fold) as HIV progresses to AIDS.

So what's the connection? Well, for starters, all of these cancers have viruses associated with them. But knowing that still doesn't fully explain exactly how they develop, nor has it led to curative therapies. It's been four years since Chang and Moore discovered the link between human herpes virus-8 and KS, a finding quickly confirmed by virologists Robin Weiss and Jay Levy , among others. After continually finding HHV-8 in biopsied lesions taken from patients with AIDS and non-AIDS-related KS, there is little if any doubt in the scientific community that HHV-8 is a root cause of KS. In fact, NCI's über-AIDS malignancy epidemiologist, Robert Biggar, believes the HHV-8 viral link to KS is "scientifically remarkable," contending, "You don't get the cancer [KS] if you don't get the virus!" Similarly, human papillomavirus turns up time after time in cervical cancer, but that hasn't nailed it down.

The question that's still heavily debated is whether HHV-8 alone causes KS to develop? Most would say no. Cancer specialist Barbara Ensoli is a pioneer in the KS field who thinks that KS is probably caused by a cycle of events starting with immunosuppression-itself caused by HIV infection. That in turn causes the release of inflammatory cytokines and angiogenic growth factors (like IL-6, the HIV-1 tat protein, interferon gamma, and basic fibroblast growth factor), which then trigger or amplify the herpes virus to create the new lesions. So one plausible explanation for the dramatic decrease in KS is that if you stop immunosuppression with HAART therapy, you also stop the chemical cascade that leads to the creation of KS lesions.

So far, HHV-8 has also been linked to several other cancers, including body cavity-based lymphomas (BCBLs), basal cell carcinoma, Castleman's disease, and, most recently, multiple myeloma. Likewise, Monini and colleagues recently found HHV-8 DNA sequences in 44 percent of prostate-tissue specimens taken from HIV-negative Italian men. Today a number of tests exist to screen for HHV-8, but their sensitivity varies and some researchers feel their ability to detect HHV-8 is limited.

So what has AIDS taught us about cancer? The answer is a deeper understanding of the causes of cancer and the link to viruses. Our 15-year experience using drugs for the treatment and prevention of HIV-related infections like PCP, CMV, MAC, and fungal infections has helped oncologists treat cancer patients who develop opportunistic infections due to bone-marrow or organ transplants. AIDS activists have also fueled a broader patient advocacy movement, prompting those with cancer, particular women with breast cancer, to take control of their disease and to question and dialogue with their doctors, not just follow advice blindly.

But here, too, there are important differences that stem in part from the social roots of both diseases. It's interesting to note that while those involved in AIDS advocacy continue to call themselves AIDS activists, most people working on cancer issues, including federal researchers and drug-company officials, shy away from the militant connotation of those words. They prefer to call themselves "cancer advocates."

Nonetheless, like AIDS activists, cancer advocates now run efficient and vitally important advocacy organizations, and some sit on important committees and federal boards overseeing the direction of cancer research. They too are confronting complacency and profit motives in cancer research and have had to take their gloves off to fight hard. Breast cancer advocates scored a major victory recently by forcing Genentech (a drug company with several HIV drugs) to open a compassionate-use program (via lottery) for Herceptin (HER-2-neu), a very promising cancer drug. The drug has just been approved by the FDA.

Looking ahead, it's the hope of many that leading players in both diseases work more closely together, something that's beginning to happen among researchers. That means HIV activists might hop on board the breast cancer train and, for example, begin pushing for drugs like angiostatin and other angiogenesis inhibitors that appear promising against HIV-related cancers. It also means cancer advocates might join HIV activists in pushing for increased government research into the compelling and complex interaction between sexually transmitted viruses, cancers, and the immune system.

Will HIV research one day lead to a cancer cure or vaccine? Stay tuned.