Apr. 3, 1998 Kaposi's sarcoma, a debilitating cancer most often seen in HIV-positive homosexual men, is caused by a virus called HHV-8, and, among homosexual men, is most often transmitted sexually, according to a UC San Francisco study published in the April 2 issue of the New England Journal of Medicine.
Moreover, according to the study, transmission of HHV-8 increases with the number of years of regular sexual intercourse among homosexual men, the number of past homosexual partners and a past history of several sexually transmitted diseases. The study found that HIV-positive men infected with HHV-8 have, approximately, a 50 percent chance of developing Kaposi's sarcoma within 10 years.
The investigators found that HHV-8 antibodies preceded the subsequent development of Kaposi's sarcoma, and that the markedly increased risk of developing Kaposi's sarcoma in the HIV-positive men studied was dependent on infection with HHV-8 alone, rather than on some other sexually transmitted organism. This finding provides the strongest proof to date that HHV-8 is a cause, not a result, of Kaposi's sarcoma.
The UCSF finding solves a mystery that has puzzled researchers since 1994, when they discovered unusual DNA sequences in the cells of skin lesions associated with Kaposi's sarcoma. Until now, scientists have not known whether the virus represented by these sequences, which they called human herpesvirus 8, or HHV-8, caused the disease or was an "innocent bystander" that merely traveled with another, as yet undiscovered, culprit agent.
The UCSF study is the first large-scale investigation to demonstrate a direct association between HHV-8 and Kaposi's sarcoma, by showing that HHV-8 infection precedes the development of Kaposi's sarcoma and by meticulously eliminating other variables that could explain the cause. It is also the first study to examine the frequency of the virus in a randomly chosen sample of the population and to examine modes of transmission of the virus directly.
"This study establishes clearly that the virus is sexually transmitted, and strongly suggests that it plays an important role in causing the disease," says Donald Ganem, MD, UCSF professor of microbiology and medicine, a Howard Hughes Medical Institute Investigator and a co-author of the study.
"Our finding does not mean that HHV-8 is only transmitted via homosexual sex," says Dean Kedes, MD, PhD, UCSF assistant research microbiologist and senior author of the study. "But it does suggest that in the population that is overwhelmingly the most likely to develop Kaposi's sarcoma, the major mode of transmission is sexual."
The researchers conducted their investigation using data from the San Francisco Men's Health Study, a National Institutes of Health-sponsored study begun in 1984 and conducted jointly by UCSF and UC Berkeley. The data includes behavioral histories, blood samples and a 10-year follow-up evaluation of men living in the city's Castro district, an area with a high incidence of HIV (human immunodeficiency virus) infection.
The investigators focused on 400 men who were infected with HIV from the start of the San Francisco Men's Health Study, as well as 400 men from the study who were not infected with HIV. Using a test they had previously developed, they examined stored blood specimens from all 800 men for evidence of antibodies to a specific protein made by cells infected with HHV-8. A positive antibody test indicates the presence of the virus in the body.
The researchers detected these antibodies to HHV-8 in 37.5 percent, or 223, of 594 men who reported any homosexual activity in the previous five years. In contrast, these antibodies were not found in any of the 195 exclusively heterosexual men studied.
"By conducting the study in one well-defined population of men observed over a narrow time frame, and by controlling for our subject's sexual behavior and degree of HIV-related disease, we believe we have eliminated the possibility that the apparent association between HHV-8 and Kaposi's sarcoma, seen in prior studies, was caused by anything but a direct causal relationship," says Jeffrey Martin, MD, MPH, the lead author of the study and an assistant professor of epidemiology and biostatistics and medicine at the UCSF AIDS Research Institute.
"This independent causal relationship is one of the most important findings," says Kedes. "Even if we negate the differences in the numbers of sexual partners and just separate those HHV-8-infected versus not infected, if you are infected and HIV positive, you're in trouble."
"Our findings are yet another example of the rich source of data that are provided by long-term population-based epidemiologic studies of this kind," says Dennis Osmond, PhD, UCSF associate professor of epidemiology and biostatistics, the principal investigator of the Men's Health Study and a co-author of this study.
"Knowing the virus that causes Kaposi's sarcoma may lead to development of therapies," says Kedes, "including the use of available anti-viral drugs to inhibit viral spread within the body." Hopefully, he says, "this would, in turn, suppress development of Kaposi's sarcoma itself."
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