Kaposi's sarcoma (KS) is a cancer of cells lining blood vessels and is commonly seen as a complication of HIV infection. Prior to the HIV era, KS was rarely seen, and when it was seen, it seemed to favor males over 50 years of age who were of Mediterranean or African origin. Otherwise healthy women and children were rarely affected by KS. Since the beginning of the AIDS epidemic, KS has been seen primarily in gay men with HIV infection. KS is also seen in people who have received organ transplants, due to the use of drugs that suppress their immune response to the transplanted organ.

Recently, Chang and Moore found sequences of viral DNA in KS lesions (1). This viral DNA was found to belong to new virus belonging to the herpesvirus family. Several investigators have found human herpesvirus-8 (HHV-8) DNA in almost all KS lesions examined (2-5). Other more common viral DNA has also been found in KS lesions; however, no other virus appears as consistently as HHV-8.

It is clear that HHV-8 DNA is consistently found in KS lesions and recent studies report finding HHV-8 DNA in saliva, certain white blood cells (B-lymphocytes), semen, prostate tissue, fecal material, and occasionally in normal skin of people with KS (6-8). However, not all of these reports have been confirmed by other investigators, so that controversy remains regarding the prevalence of HHV-8 at various sites.

There are two reports from investigators who have been able to grow infectious HHV-8 virus from KS lesions (Foreman) and from white blood cells (Blackbourn) of a healthy blood donor (9, 10). These findings suggest HHV-8 can be transmitted through contact with infected secretions. However, the exact mode of transmission and the efficacy of transmission of HHV-8 remain unknown.

HHV-8 is likely to be transmitted via sexual contact. While some epidemiological studies suggest that oral-anal contact may be a risk factor for development of KS (11), such contact would not be expected to be a strong risk factor for transmission of a herpesvirus. Therefore, these findings must be interpreted cautiously. Other risk factors for KS include past history of having an sexually-transmitted disease (STD) other than HIV, a high number of casual sex partners, and a high frequency of sex acts. A report from McCarthy details the case of an HIV-positive mother and vertically (at birth) HIV-infected child who both developed KS (12).

This is further support for transmission via infected secretions or blood.

There are numerous reports of HHV-8 DNA recovery from circulating white blood cells and one report of viable HHV-8 recovery from blood. There are no reports of HHV-8 DNA recovery or of seroconversion (acquisition of HHV-8 antibody) after receiving blood products. And, it has been shown that those people who become HIV-positive from blood product receipt (e.g., hemophiliacs) are very unlikely to show evidence of HHV-8 infection. However, it remains unknown if blood and/or blood products can transmit HHV-8. Blood tests for HHV-8 antibodies have been developed and are available in some research laboratories. The sensitivity and specificity of these tests are under study and newer methods to detect HHV-8 infection are also under development.

The prevalence of HHV-8 seropositivity (presence of the antibody that indicates infection) in different groups has been examined. It appears that HHV-8 seropositivity is greatest (80%) in HIV-positive gay men with KS. HHV-8 seropositivity is 18% in HIV-positive/KS-negative gay males. In contrast, among HIV-positive hemophiliacs and HIV-negative healthy blood donors, none had antibody to HHV-8 (13). Among people presenting to the STD clinic with a positive serologic test for syphilis, 13% had antibody to HHV-8 (14).

The strongest evidence for causal role of HHV-8 in the pathogenesis of KS is the temporal association between seroconversion to HHV-8 and the development of KS. In a study of 40 men with HIV and KS, 52% had seroconverted to HHV-8 a median of 33 months prior to development of KS.

While the association between HHV-8 infection, immunosuppression, and subsequent development of KS appears strong, much more work needs to be done on HHV-8 epidemiology to gain a clear definition of risk transmission. Thereafter, strategies can be recommended. Laboratory studies suggest that HHV-8 is susceptible to ganciclovir, foscarnet, and cidofovir, and resistant to acyclovir (14). It is unclear if antiviral treatment of HHV-8 infection prior to KS onset can prevent KS or eliminate HHV-8 carriage. The latter seems unlikely, as all other herpesviruses establish life-long latency in the human host. In addition, available effective antivirals can cause significant toxicity and their use as KS prophylaxis may not be appropriate.

The treatment of established KS varies from no treatment to systemic multi-drug chemotherapy. Liquid nitrogen has been used on small isolated lesions and local radiation therapy has been used to treat diffuse lesions of the lower extremities. Topical retinoids (vitamin A compounds) are showing promise and are likely to be approved for use soon. In non-HIV immunosuppressed people, withdrawal of some or all of the immunosuppressive drugs sometimes results in clearance of KS. More often, systemic chemotherapy is required and many times response to therapy is incomplete (15).

Even when complete clearance is achieved, later recurrence is not uncommon in all forms of KS. It is unknown if long-term clearance of KS could be achieved by antiviral treatment and suppression of HHV-8 infection. Co-treatment of HHV-8 infection and KS is likely to be studied in the future. There is little information on the relationship between the quantity of HHV-8 DNA in blood (and perhaps tumor) and response to treatment.

The relationship, if any, between HHV-8, DNA quantity, and treatment response needs further study. Intra-lesional human chorionic gonadotropin (hCG) has been shown to induce KS regression in ten of 12 human KS lesions; HHV-8 DNA levels were not reported. Interferon alpha-2a has also shown promise in treating KS. Much progress has been made in understanding the etiology and pathophysiology of KS.

As our research progresses and our understanding of HHV-8-KS increases, better treatment will evolve. The University of Washington has an active research program investigating the basic science, clinical and epidemiological aspects of HHV-8 infection. An antibody test for HHV-8 has been developed for research purposes. The Virology Research Clinic can be contacted at (206)720-4340.

University of Washington Virology Research Clinic 1001 Broadway, Suite 320 Seattle, Washington 98122 (206)720-4340 (206)720-4371 fax

References cited:

Said, J. "Kaposi's sarcoma-associated herpesvirus (KSHV): a new viral pathogen associated with Kaposi's sarcoma, primary effusion lymphoma, and multicentric Cattlemans disease", West J Med 1997 Jul;167(1):37-8.

Moore PS, Kingsley LA, Holmberg SD, Spira T, Gupta P, Hoover DR, Parry JP, Conley LJ, Jaffe HW, Chang Y. "Kaposi's sarcoma associated herpesvirus infection prior to onset of Kaposi's sarcoma", AIDS 1996 Feb;10(2):175-80.

Ziegler JL, Katongole-Mbidde E. "Kaposi's sarcoma in childhood: an analysis of 100 cases from Uganda and relationship to HIV infection", Int J Cancer 1996 Jan 17;65(2):200-3.

Schalling M, Ekman M, Kaaya EE, Linde A, Biberfeld P. "A role for a new herpes virus (KSHV) in different forms of Kaposi's sarcoma", Nat Med 1995 Jul;1(7):707-8.

Schatz O, Bogner JR, Goebel FD. "Kaposi's sarcoma: is the hunt for the culprit over now?", J Mol Med 1997 Jan;75(1):28-34.

Koelle DM, Huang ML, Chandran B, Vieira J, Piepkorn M, Corey L. "Frequent detection of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) DNA in saliva of human immunodeficiency virus-infected men: clinical and immunologic correlates", J Infect Dis 1997 Jul;176(1):94-102.

Howard MR, Whitby D, Bahadur G, Suggett F, Boshoff C, Tenant-Flowers M, Schulz TF, Kirk S, Matthews S, Weller IV, Tedder RS, Weiss RA. "Detection of human herpesvirus 8 DNA in semen from HIV-infected individuals but not healthy semen donors", AIDS 1997 Feb;11(2):F15-9.

Purvis SF, Katongole-Mbidde E, Johnson JL, Leonard DG, Byabazaire N, Luckey C, Schick HE, Wallis R, Elmets CA, Giam CZ. "High incidence of Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus in tumor lesions and peripheral blood mononuclear cells from people with Kaposi's sarcoma in Uganda", J Infect Dis 1997 Apr;175(4):947-50.

Foreman KE, Friborg J Jr, Kong WP, Woffendin C, Polverini PJ, Nickoloff BJ, Nabel GJ. "Propagation of a human herpesvirus from AIDS-associated Kaposi's sarcoma", N Engl J Med 1997 Jan 16;336(3):163-71.

Blackbourn DJ, Ambroziak J, Lennette E, Adams M, Ramachandran B, Levy JA. "Infectious human herpesvirus 8 in a healthy North American blood donor", Lancet 1997 Mar 1;349(9052):609-11.

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